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WO2025054498A1 - Methods of treating hidradenitis suppurativa - Google Patents

Methods of treating hidradenitis suppurativa Download PDF

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Publication number
WO2025054498A1
WO2025054498A1 PCT/US2024/045651 US2024045651W WO2025054498A1 WO 2025054498 A1 WO2025054498 A1 WO 2025054498A1 US 2024045651 W US2024045651 W US 2024045651W WO 2025054498 A1 WO2025054498 A1 WO 2025054498A1
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WIPO (PCT)
Prior art keywords
patient
izokibep
study
medicament
treatment
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PCT/US2024/045651
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French (fr)
Inventor
Amol KAMBOJ
Shao-Lee LIN
Paul PELOSO
Martha CRUZ
Fredrik Frejd
Dieter Wetzel
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Affibody AB
Acelyrin Inc
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Affibody AB
Acelyrin Inc
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Publication of WO2025054498A1 publication Critical patent/WO2025054498A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]

Definitions

  • Tumor necrosis factor alpha is a pro-inflammatory cytokine that mediates a diverse range of inflammatory, infectious and immune-related processes and pathologies.
  • Intratriginous occurrence is the intertriginous occurrence, although, other areas of skin may also be affected.
  • the affected areas are in decreasing order of frequency: inguinal, axillary, perineal and perianal as well as the submammary and/or intermammary fold in women, buttocks, mons pubis, scalp, area behind the ears and eyelids.
  • Patients with HS often develop painful inflamed nodules, abscesses, and pus-discharging tracts and fistulas, which typically occur in skin folds of axillary (armpits), inguinal (groin), gluteal and perianal areas of the body.
  • Hidradenitis suppurativa is also known to cause severe pain, purulent secretions that smell bad, and movement restrictions that have a profound negative influence on patients’ lives (Sabat et al. 2020).
  • the present disclosure recognizes that certain conditions, such as Hidradenitis suppurativa (HS) can be treated by compositions comprising izokibep or a salt thereof, in patients who have or would otherwise receive a TNF-a inhibitor.
  • the disclosure provides novel methods for the treatment of HS by administering once a week to a patient a therapeutically effective amount of pharmaceutical composition comprising izokibep or a salt thereof.
  • the disclosure also provides a composition comprising izokibep or a salt thereof for use in the treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor.
  • TNF-a tumor necrosis factor alpha
  • the disclosure provides use of a composition comprising izokibep or a salt thereof in the manufacture of a medicament for the treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor.
  • TNF-a tumor necrosis factor alpha
  • the present disclosure provides methods and compositions for treatment of a condition(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever,
  • a condition selected from
  • the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
  • the disclosure provides a method of treatment of a condition, such as HS, in a patient that has received a TNF-a inhibitor by administration to a patient a composition comprising izokibep or a salt thereof.
  • the composition comprises between about 100 and about 200 mg of izokibep or a salt thereof. More preferably, the composition comprises between about 150 and about 170 mg of izokibep or a salt thereof. In more preferred aspects, the composition comprises about 160 mg of izokibep or a salt thereof or does comprise 160 mg of izokibep or a salt thereof.
  • treatment with the TNF-a inhibitor did not resolve the patient’s HS.
  • the composition further comprises one or more of sodium phosphate, NaCl, and EDTA.
  • the composition is administered to the patient subcutaneously.
  • the composition is administered in an arm, upper thigh, and/or abdomen of the patient.
  • the composition is administered to the patient once weekly.
  • the composition is administered to patient twice weekly.
  • composition is administered once a week to a patient for between 1 and 52 weeks.
  • the composition is administered once a week to a patient for at least 16 weeks.
  • the condition is HS.
  • the HS is a severe or a moderate HS.
  • the HS presents as lesions in at least 2 anatomic areas of the patient, wherein the patient is Hurley Stage II or Hurley Stage III, and/or wherein the patient has an abscess and inflammatory nodule (AN) count of > 5 prior to the administration.
  • the patient has received a TNF-a inhibitor to treat HS.
  • the patient prior to receiving the izokibep composition, the patient exhibited an inadequate response to > 3 month treatment with an oral antibiotic for treatment of the condition, exhibited recurrence of the condition after discontinuing an antibiotic treatment, and/or the patient demonstrated intolerance to and/or exhibits a contraindication to oral antibiotics for treatment of the condition.
  • the HS affects areas of the patient’s skin, and in conjunction to receiving the izokibep composition, the patient applies a topical antiseptic to the affected areas.
  • the condition is HS and administration of the izokibep composition provides to the patient at least a 75% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
  • the 75% reduction occurs before or at a sixteenth week of the administration of the medicament.
  • the condition is HS and administration of the izokibep composition provides to the patient at least a 90% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
  • the 90% reduction occurs before or at a sixteenth week of the administration of the medicament.
  • the condition is HS and wherein administration of the izokibep composition to the patient provides to the patient an AN count of 0, 1, or 2. [0019] In some preferred aspects, the condition is HS and wherein administration of the izokibep composition to the patient provides to the patient at least a 3 -point reduction from baseline in an NRS Patient Global Assessment of Skin Pain.
  • the condition is uveitis, including one or more of the group consisting of an intermediate-uveitis, a posterior-uveitis, and a pan-uveitis.
  • the uveitis is an intermediate-uveitis.
  • the uveitis is a posterior-uveitis.
  • the uveitis is a pan-uveitis.
  • the uveitis is a non-infectious uveitis.
  • the treatment reduces IL-17 expression in the patient. Accordingly, the treatment provides quiescence at between about 1 week and 15 weeks.
  • the patient prior to administration, has received a corticosteroid treatment.
  • the patient tapers use of the corticosteroid during the administration.
  • the patient may discontinue use of the corticosteroid by a fifteenth week of administration.
  • the present disclosure provides methods and compositions for treatment of a condition(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever,
  • a condition selected from
  • the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
  • a medicament comprising izokibep or a salt thereof used for treatment of a condition, such as HS, in a patient that has received a TNF-a inhibitor.
  • the medicament comprises between about 100 and about 200 mg of izokibep or a salt thereof. More preferably, the medicament comprises between about 150 and about 170 mg of izokibep or a salt thereof.
  • the medicament comprises about 160 mg of izokibep or a salt thereof or does comprise 160 mg of izokibep or a salt thereof.
  • treatment with the TNF-a inhibitor did not resolve the patient’s HS.
  • the medicament further comprises one or more of sodium phosphate, NaCl, and EDTA.
  • the medicament is formulated for subcutaneous administration.
  • the composition is formulated for administration in an arm, upper thigh, and/or abdomen of the patient.
  • the medicament is formulated for administration to the patient once weekly.
  • the medicament is formulated for administration to the patient twice weekly.
  • medicament is formulated for administration once a week to a patient for between 1 and 52 weeks.
  • the medicament is formulated for administration once a week to a patient for at least 16 weeks.
  • the patient prior to receiving the izokibep medicament, the patient exhibited an inadequate response to > 3 month treatment with an oral antibiotic for treatment of the condition, exhibited recurrence of the condition after discontinuing an antibiotic treatment, and/or the patient demonstrated intolerance to and/or exhibits a contraindication to oral antibiotics for treatment of the condition.
  • the HS affects areas of the patient’s skin, and in conjunction to receiving the izokibep medicament, the patient applies a topical antiseptic to the affected areas.
  • the condition is HS and the medicament provides to the patient at least a 75% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
  • the 75% reduction occurs before or at a sixteenth week of the administration of the medicament.
  • the condition is HS and administration of the izokibep composition provides to the patient at least a 90% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
  • the 90% reduction occurs before or at a sixteenth week of the administration of the medicament.
  • the condition is HS and wherein administration of the izokibep medicament to the patient provides to the patient an AN count of 0, 1, or 2.
  • the condition is HS and wherein administration of the izokibep medicament to the patient provides to the patient at least a 3 -point reduction from baseline in an NRS Patient Global Assessment of Skin Pain.
  • the disclosure provides a composition comprising 160 mg of izokibep or a salt thereof for administration once weekly (QW) for the treatment of HS in patients who have received treatment with a TNF-a inhibitor.
  • the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once weekly (QW) or twice weekly for the treatment of HS.
  • the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once every two weeks (Q2W) for the treatment of HS.
  • the methods of the disclosure alleviate the symptoms of HS via administration of the izokibep compositions and dosing regimes disclosed herein, which may improve the time to treatment failure compared to placebo in subjects with HS, including those who have received prior therapy with a TNF-a inhibitor.
  • FIG. 1 demonstrates the adalimumab serum concentrations in patients suffering from HS and Psoriasis.
  • FIG. 2 provides a depiction of izokibep bound to IL-17A homodimer.
  • FIG. 3 provides an overview of a study for treating HS with izokibep.
  • FIG. 4 provides liver chemistry considerations for subjects in the study.
  • FIG. 7 supports that discontinuation in the study was not related to adverse events.
  • FIG. 8 provides an overview of results from the study.
  • FIG. 9 shows the Hi SCR response at week 16.
  • FIG. 10 describes the drug exposure as consistent with observed dose response.
  • FIG. 11 provides a last observation carried forward sensitivity analysis.
  • FIG. 13 shows Hi SCR responses over time.
  • FIG. 14 shows results of a pre-planned interim analysis at week 12.
  • FIG. 15 shows where izokibep performed closely between Part A & Part B pre-planned week 12 interim.
  • FIG. 16 provides results of an independently conducted part B interim analysis demonstrating greater & deeper izokibep responses compared to Bimekizumab.
  • FIG. 17 provides part B pre-planned interim over time.
  • FIG. 18 provides data for the pre-planned part B interim with NRI at week 12.
  • FIG. 20 provides a summary of the week 16 results of the phase 2b study part B.
  • FIG. 21 shows an overview of the Phase 2b clinical trial, outlined in Fig. 5, for izokibep in patients with HS through week 32.
  • FIG. 22 shows patient dispositions through week 32 of the Phase 2b clinical trial.
  • FIG. 23 shows the patient demographics and baseline measurements for the Phase 2b clinical trial.
  • FIG. 26 shows sustained HiSCR75, HiSCR90, and HiSCRIOO data for the Phase 2b clinical trial.
  • FIG. 27 shows a comparison of HiSCRIOO data for the Phase 2b clinical trial compared with other therapeutic agents.
  • FIG. 28 shows data indicating draining tunnel resolution for the Phase 2b clinical trial.
  • FIG. 29 shows data indicating reductions in skin pain for the Phase 2b clinical trial.
  • FIG. 30 shows DLQI data for the Phase 2b clinical trial.
  • FIG. 31 provides and overview of a Phase 3 clinical trial using a QW 160 mg dose.
  • FIG. 32 provides the baseline characteristics (left) and the patient disposition of trial participants (right) as assessed at week 12 of the Phase 3 clinical trial.
  • FIG. 33 shows the measured HiSCR75 responses through week 12 of the Phase 3 trial.
  • FIG. 34 shows the measured HiSCR75 responses through week 16 of the Phase 3 trial.
  • FIG. 35 shows the HiSCR90 (left) and HiSCRIOO responses at week 12.
  • FIG. 36 shows HiSCR90 (left) and HiSCRIOO responses at week 16.
  • FIG. 37 summarizes the HiSCR50, HiSCR75, HiSCR90, and HiSCRIOO responses through week 12 for the Phase 3 trial.
  • FIG. 38 summarizes the HiSCR50, HiSCR75, HiSCR90, and HiSCRIOO responses through week 16.
  • FIG. 39 summarizes the higher order responses (HiSCR90, and HiSCRIOO) for both the phase 3 trial through 12 weeks and across the Phase 2b trial and the Phase 3 trial.
  • FIG. 40 shows data measuring skin pain reductions and DLQI through week 12 of the Phase 3 trial.
  • FIG. 41 shows data measuring skin pain reductions and DLQI through week 16 of the Phase 3 trial.
  • FIG. 42 provides interim safety data through 12 weeks of the Phase 3 clinical trial.
  • the present disclosure recognizes that certain conditions, such as Hidradenitis suppurativa (HS) can be treated by compositions comprising izokibep or a salt thereof, in patients who have or would otherwise receive a TNF-a inhibitor.
  • the disclosure provides novel methods for the treatment of HS by administering once a week to a patient a therapeutically effective amount of pharmaceutical composition comprising izokibep or a salt thereof.
  • Such compositions may provide therapeutic benefit, e.g., symptom relief and/or complete cessation or remission of a condition, even where prior therapy with a TNF-a inhibitor has failed to provide the desired therapeutic benefit.
  • the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
  • Hidradenitis suppurativa is a chronic inflammatory skin disease characterized by occlusion of hair follicles as a primary pathogenic factor associated with a chronic cycle of inflammation, healing, and scarring (Sabat et al. 2020).
  • a recent meta-regression analysis found an overall HS prevalence of 0.40% (95% confidence interval [CI]: 0.26% to 0.63%) among the populations studied around the world (Jfri et al. 2021).
  • the overall point prevalence of HS in the United States (US) was 0.10%, or 98 per 100 000 persons.
  • Prevalence was highest among women (137 per 100 000), those aged 30 to 39 years (172 per 100000), and African American (296 per 100 000) and biracial (218 per 100 000) patient groups (Garg et al. 2017).
  • Patients with HS develop painful inflamed nodules, abscesses, and pus-discharging tracts and fistulas, which typically occur in skin folds of axillary (armpits), inguinal (groin), gluteal and perianal areas of the body.
  • Hidradenitis suppurativa causes severe pain, purulent secretions that smell bad, and movement restrictions that have a profound negative influence on patients’ lives (Sabat et al. 2020).
  • a genetic predisposition, smoking, obesity, and hormonal factors are established etiological factors for HS (Sabat et al. 2020). Cutaneous changes begin around hair follicles and involve activation of cells of the innate and adaptive immune systems, with pivotal roles for proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)- IB, and IL- 17 (Sabat et al. 2020).
  • TNF-a tumor necrosis factor-a
  • IL- IB interleukin
  • IL- 17 IL- 17
  • Clinical management of HS is challenging and consists of both medical and surgical approaches. Topical therapies, systemic antibiotics, hormonal therapies, and immunosuppressant medications have been used.
  • adalimumab is currently the only approved biologic immunomodulator by the US Food and Drug Administration for treating moderate to severe HS (HUMIRA® USPI 2021).
  • HUMIRA® USPI 2021 The TNF-a inhibitor, adalimumab is currently the only approved biologic immunomodulator by the US Food and Drug Administration for treating moderate to severe HS.
  • HUMIRA® USPI 2021 Only around 50% of subjects achieved a clinical response at Week 12 in the 2 randomized, double-blind, placebo-controlled studies of adalimumab in a total of 633 adult subjects with moderate to severe HS.
  • a broad range of immune mediators are highly expressed in established HS lesions compared with healthy control skin.
  • Patients with HS have imbalances in the T-helper 17 cell (Thl7) axis that are similar to those in patients with psoriasis (Wolk et al., 2020). They have high serum levels of the proinflammatory cytokine IL-17A, which leads to neutrophil recruitment and provides positive feedback to maintain the population of proinflammatory Th 17 cells (Matusiak et al. 2017).
  • These imbalances improved in patients treated with TNF-a inhibitors hypothesized that by reducing circulating IL-17A, anti-IL-17A inhibitors like izokibep may also provide benefit for patients with HS.
  • Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A. Izokibep has the potential to be an efficacious treatment for a variety of IL- 17A-related diseases.
  • the smaller size of izokibep compared to monoclonal antibodies offers advantages in terms of required dosing volumes and potential for alternative pharmacological formulations.
  • Izokibep is based on a small protein binding to and blocking the biological effect of the cytokine IL-17A.
  • the izokibep protein molecule contains an albumin-binding domain which confers specific binding to a single site on endogenous serum albumin and thereby a prolonged half-life (t 1 /?) in the circulation and in tissues after parenteral administration IL- 17 inhibitors have already demonstrated efficacy and a favorable safety profile in different inflammatory diseases, including psoriasis and PsA. These include secukinumab (Cosentyx®) and ixekizumab (Taltz®) in the US, Canada, and the European Union.
  • the izokibep protein comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% similarity with the amino acid sequence of: AEAKYAKEADDAAVEIASLPNLTWDQWYAFIQKLRDDPSQSSELLSEAKKLNDSQAPK ASGSLAEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALPGTGGGGSA EAKYAKEADDAAVEIASLPNLTWDQWYAFIQKLRDDPSQSSELLSEAKKLNDSQAPK (SEQ ID NO. 1), or a fragment thereof.
  • PK Pharmacokinetic
  • IV intravenous
  • SC SC-administered izokibep
  • Pharmacokinetic assessments in rat and monkey indicate that the time course of izokibep concentrations after a bolus IV injection and SC injection is well described by a 2- or 3 -compartment model.
  • Pharmacokinetic assessments indicate that the elimination rate of izokibep is similar to that of albumin in the respective species.
  • Study ABY-035-202 is a dose-finding trial of 40 mg or 80 mg izokibep or placebo SC Q2W.
  • the primary endpoint is the ACR 50% (ACR50) response at Week 16; further key secondary endpoints comprise other ACR responses, PASI scores, enthesitis endpoints, proportion of subjects achieving MDA, adverse events (AEs; safety), and izokibep blood levels (PK), and anti-drug antibody (ADA) assessments.
  • Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A.
  • IL-17A inhibitors including secukinumab at 10 mg/kg and 30 mg/kg and ixekizumab as well as izokibep at doses up to 160 mg SC, do not appear to have dose-limiting AEs.
  • izokibep is designed to demonstrate whether treatment is associated with a reduction in the extent of inflammation in patients who have received a TNF-a inhibitor to treat a condition, such as those with moderate to severe HS manifested as a specific reduction in the number of inflammatory nodules and abscesses. As these inflammatory lesions are associated with considerable pain and impairment in quality of life, a reduction in the number of such lesions could directly benefit patients.
  • Hidradenitis suppurativa is a chronic inflammatory skin disease causing scarring, abscesses, malodor, and pain. HS typically occurs in areas with high concentrations of sweat glands and is typically accompanied by pain, malodor, drainage, and disfigurement that contribute to disability and a devastating impact on quality of life. Patients with HS miss a greater number of days of work and have increased disability compared to the average population. In 2019, there were an estimated 317,000 HS patients in the U.S., of which 50-60% were moderate-to-severe HS patients. In certain cases of HS, occlusion of hair follicles is a primary pathogenic factor. This is often characterized by cycles of scarring, abscesses, malodor, and pain. It may also result in permanent disfigurement and social stigma. Such a disease may also negatively impact quality of life and earning potential of patients suffering from such a disease.
  • HiSCR Hidradenitis Suppurativa Clinical Response
  • AN inflammatory nodule
  • HiSCR50 indicates > 50% reduction
  • HiSCR75 indicates > 75% reduction
  • HiSCR90 indicates > 90% reduction
  • HiSCRIOO indicates 100% reduction.
  • the historical HiSCR75 response rate is 25-46% for adalimumab and 10-17% placebo
  • HiSCR90 at weeks 12-16 has a 13- 32% response rate for adalimumab, and 0-8% for placebo.
  • HiSCRIOO at weeks 12-16 has not been reported.
  • FIG. 1 demonstrates the serum adalimumab concentration is lower in HS patients as compared to the Psoriasis patients.
  • the data in FIG. 1 demonstrates that adalimumab serum concentration was lower in HS patients, despite increased dosing frequency of adalimumab in HS patients as compared to psoriasis patients.
  • a similar observation was made for bimekizumab in Phase II studies with HS patients.
  • Izokibep is a small protein therapeutic designed to inhibit interleukin- 17A (IL-17A) with higher potency and the potential for greater tissue penetration due to its markedly smaller size when compared to traditional monoclonal antibodies.
  • IL-17A interleukin- 17A
  • Izokibep has enhanced potency as it blocks the homodimeric IL-17A target protein by binding to both sub-units simultaneously with a very high affinity.
  • KD for izokibep binding to IL-17A is as low as 0.3 pM.
  • FIG. 2 provides a representation of izokibep bound to the IL-17A homodimer.
  • the two IL- 17A binding domains bind to the dimeric IL-17A homodimers at the same time, and the two IL17A binding domains are connected by albumin binding domain.
  • the presence of albumin binding domain increases the half-life of izokibep.
  • the half-life of izokibep may be a few days. In certain embodiments, the half-life of izokibep is from about 5 to about 20 days. In certain embodiments, the half-life of izokibep is from about 10 to about 15 days. In certain embodiments, the half-life of izokibep is about 12 days.
  • Izokibep also has a well-established safety profile.
  • izokibep is safe for patients up to 3 years without any observed increased risk of infection or any significant increase in anti -drug antibodies (ADAs).
  • ADAs anti -drug antibodies
  • the presence of or a significant increase in ADAs can impact exposure of the drug and/or the clinical response of the drug in the patients.
  • the size of izokibep is one-tenth (l/10 th ) of those of typical monoclonal IL- 17A antibodies.
  • izokibep has quick and therapeutic effects in patients suffering from HS.
  • the present disclosure provides methods and compositions for treatment of a condition(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever,
  • a condition selected from
  • the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
  • compositions useful in treating conditions in patients who have received prior treatment with a TNF-a inhibitor comprising izokibep or a salt thereof are provided.
  • the current disclosure also provides methods and compositions for treating inflammation of the eye, and in particular, uveitis, in patients who have received a TNF- a inhibitor.
  • the TNF-a inhibitor failed to provide an adequate response to the patient’s uveitis and/or the patient is intolerant to a TNF-a inhibitor.
  • the disclosure provides methods for treating uveitis by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep, and preferably about or exactly 160 mg izokibep or a salt thereof per dose.
  • izokibep has quick and therapeutic effects in patients who received a TNF- a therapy and are suffering from uveitis.
  • Uveitis is a type of eye inflammation, which traditionally described a type of inflammation in the uvea, which includes the iris, ciliary body, and the choroid. Overtime, Uveitis has become used to describe this type of inflammation in any area of the eye. Uveitis results from a heterogeneous collection of disorders with diverse etiologies and pathogenic mechanisms (Prete et al, 2016). Uveitis can be classified, according to the primary anatomical location of the inflammation, into anterior and non-anterior uveitis.
  • Non-anterior uveitis can be further classified into intermediate-, posterior- or pan-uveitis (affecting more than 1 eye segment). Symptoms include severe intraocular inflammation, vision impairment with blurred or cloudy vision, floaters-spots in the eye and eye pain.
  • current disclosure also provides methods and compositions for treating Ankylosing spondylitis (AS), and in particular in patients who have received a TNF-a inhibitor.
  • AS Ankylosing spondylitis
  • the TNF-a inhibitor failed to provide an adequate response to the patient’s AS and/or the patient is intolerant to a TNF-a inhibitor.
  • the disclosure provides methods for treating AS by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep, and preferably about or exactly 160 mg izokibep or a salt thereof per dose.
  • izokibep has quick and therapeutic effects in patients who received a TNF- a therapy and are suffering from uveitis.
  • the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • aqueous solutions such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical composition comprising 160 mg izokibep is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks for 15 weeks or 16 weeks.
  • a pharmaceutical composition comprising 160 mg izokibep is administered to a patient, who has received prior TNF-a inhibitor therapy, once every week for 31 weeks.
  • a pharmaceutical composition comprising 160 mg izokibep is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks for 31 weeks.
  • a pharmaceutical composition comprising 160 mg izokibep is administered to a patient, who has received prior TNF-a inhibitor therapy, once every week for 30 weeks.
  • a pharmaceutical composition comprising 160 mg izokibep is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks for 30 weeks.
  • the administration of the pharmaceutical compositions comprising izokibep leads to a clinical response as assessed by Hidradenitis suppurativa clinical response (HiSCRl) response after 16 weeks or 52 weeks in subjects with active HS.
  • HiSCRl Hidradenitis suppurativa clinical response
  • the patient suffering from HS achieves a Hi SCR1 response after 16 weeks.
  • the HS patient being administered a pharmaceutical composition comprising izokibep has had an inadequate response to a previous therapy for the treatment of HS.
  • the HS patient being administered a pharmaceutical composition comprising izokibep has had an inadequate response to a previous therapy for the treatment of HS comprising an administration of Janus Kinase (JK) inhibitors.
  • JK Janus Kinase
  • the course of clinical trials thirty (30) participants received 160 mg of izokibep dosed subcutaneously once every week.
  • the patients for the clinical trials may have been selected on the basis of that they were required to have HS lesions in > 2 anatomic areas, with at least one Hurley Stage 11/111; minimum abscess/nodule (AN) count of 3; and inadequate response, intolerance or contraindication to oral antibiotics.
  • the participant demographics were highly consistent with historical studies in the disease and included Hurley Stage II and III patients.
  • HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO were assessed.
  • Izokibep demonstrated efficacy in for alleviating conditions of patients suffering from HS.
  • week 12 observed HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO rates are > 50, > 40%, > 30% and > 25%, respectively.
  • week 12 observed HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO rates were about 65%, 57%, 38% and 33%, respectively.
  • week 12 observed HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO rates were about 71%, 57%, 38% and 33%, respectively.
  • the safety profile of izokibep was consistent with the anti-IL-17A class, with localized mild-to-moderate injection site reactions (ISRs) being the most common adverse event.
  • ISRs localized mild-to-moderate injection site reactions
  • SAEs three (3) serious adverse events (SAEs) were observed in two (2) subjects: inflammatory bowel disease, an exclusionary criterion, in one (1) subject with pre-existing symptoms; and peri-colonic abscess/sepsis in another subject with preexisting symptoms and known diverticulosis.
  • SAEs serious adverse events
  • pure isomeric compound or “isomerically pure” denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified structure.
  • the weights are based upon total weight of all isomers of the compound.
  • pure stereoisomeric compound or “stereoisomerically pure” denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified stereochemistry.
  • the weights are based upon total weight of all stereoisomers of the compound.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S" form of the compound is substantially free from the "R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • Compounds described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • N may be any isotopic form, including 14 N and 15 N;
  • O may be in any isotopic form, including 16 O and 18 O; and the like.
  • analogue means one analogue or more than one analogue.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.
  • Solvate refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid, and the like.
  • the compounds of the disclosure may be prepared e g., in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solutionphase and isolable solvates.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an “isotopic variant” of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H orD), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H orD), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
  • the disclosure may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon- 14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as n C, 18 F, 13 O, and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the disclosure.
  • Stereoisomers It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers”, and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, and an atom, such as a carbon atom, is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment").
  • the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a cancer.
  • the effective amount of a compound, composition, or formulation of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder, or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent, i.e., to produce a reduction in the amount and/or severity of the symptoms associated with that disorder.
  • Therapeutically effective amounts vary with the type and extent of brain damage, and can also vary depending on the overall condition of the subject.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the izokibep compositions of the disclosure may be formulated for administration by a particular mechanism.
  • the compositions may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration.
  • the compositions may be formulated for administration by injection or on an implantable medical device (e.g., stent or drugeluting stent or balloon equivalents).
  • the compositions are formulated for subcutaneous administration.
  • compositions may be formulated a single weekly, bi-weekly, or twice-weekly dosage.
  • the compositions may be formulated to provide the weekly dose of izokibep split up in multiple daily doses, e.g., two, three, four, five, six or more daily doses.
  • the compositions may be provided to the subject according to any dosing schedule, but is preferably once weekly as described herein.
  • the methods of treating a subject of the present disclosure include providing an izokibep composition, as described above, to the subject. Providing may include administering the composition to the subject.
  • composition may be administered by any suitable route or means, such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • suitable route or means such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • the composition may be provided as a single unit dosage.
  • the composition may be provided as a divided dosage.
  • the composition may be provided under any suitable dosing regimen.
  • the composition may be provided as a single dose or in multiple doses.
  • Doses may be provided once a week or twice a week over a duration of 1 week, 2 weeks, 3 weeks, 4 weeks, 4 weeks to 8 weeks, 8 weeks to 12 weeks, 12 weeks to 16 weeks, 16 weeks to 20 weeks, 20 weeks to 24 weeks, 24 weeks to 28 weeks, 28 weeks to 32 weeks, 32 weeks to 36 weeks, 36 weeks to 40 weeks, 40 weeks to 44 weeks, 44 weeks to 48 weeks, 48 weeks to 52 weeks, or more than 52 weeks.
  • Multiple doses may be provided within a period of time.
  • multiple doses may be provided over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more.
  • the compositions may be provided repeatedly for a specified duration.
  • the compositions may be provided for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months or more.
  • a pharmaceutical composition containing the izokibep may be in a form suitable for oral use, such as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No. 6,214,841 and U.S. Pub. No. 2003/0232877, the contents of which are incorporated herein by reference.
  • Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • An alternative oral formulation where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the disclosure is encapsulated in an enteric coating.
  • Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present.
  • the pharmaceutical compositions of the disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • EXAMPLE 1 treatment of HS axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis in patients that received a TNF-alpha inhibitor
  • Izokibep has been investigated in nonclinical and clinical studies including healthy subjects, and subjects with hidradenitis suppurativa (HS).
  • the clinical development plan also includes axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
  • This study investigates izokibep in subjects with active HS, including tumor necrosis factor alpha inhibitor (TNFi) naive subjects, and those who had an inadequate response or intolerance to TNFi, or for whom TNFi is contraindicated.
  • the study is to be 1 of 2 adequate and well-controlled studies to support a claim of efficacy of izokibep in subjects with HS.
  • TNFi tumor necrosis factor alpha inhibitor
  • Subjects will be screened within 28 days of study drug administration. Subjects meeting eligibility criteria will be randomized 1 : 1 to 1 of 2 treatment groups on Day 1 , and will receive via subcutaneous injection:
  • the first dose of study drug i.e., izokibep or placebo
  • Day 1 Week 0
  • Randomization will be stratified by prior TNFi use for HS (Yes/No) and Hurley Stage (II or III).
  • the AN count is the sum of abscesses and inflammatory nodules.
  • Subjects enrolled with stable concomitant antibiotic use (dosing regimen has been stable for >4 weeks prior to first dose of study drug) will be capped at approximately 30%.
  • Subjects will complete study assessments according to the study visits outlined in the SoA. The primary endpoint will be assessed at Week 16. The last dose of study drug will be administered on Week 51.
  • An End of Treatment Visit will be conducted at Week 52.
  • a Safety Follow-up Visit will be conducted at Week 59.
  • the End of Treatment visit should be completed 1 week after last dose of study drug ( ⁇ 5 days), and Safety Follow-up Visit should be completed 8 weeks after last dose of study drug ( ⁇ 5 days), where possible.
  • Summaries of continuous variables will include mean, median, standard deviation, minimum, and maximum; change from baseline will additionally include standard error.
  • Summaries of dichotomous, categorical, and ordinal variables will include counts and percentages.
  • Baseline characteristics and demographics will be summarized by randomized treatment group using the last value obtained before randomization. Efficacy and safety data will be summarized by randomized treatment group during the first 16 weeks of treatment; these data will also be summarized by randomized treatment group over 52 weeks for subjects randomized to receive izokibep during the first 16 weeks, and separately over the last 36 weeks for subjects randomized to receive placebo during the first 16 weeks. Efficacy variables (primary, secondary) will be summarized at each planned collection timepoint. Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs; percent of subjects reporting each TEAE and each SAE) will be summarized.
  • TEAEs treatment-emergent adverse events
  • SAEs serious adverse events
  • the primary efficacy analyses will use the treatment policy estimands, using all available data from all randomized subjects regardless of treatment compliance. Subjects will be analyzed in the group to which they are randomized. Subjects who do not have an evaluation for a dichotomous endpoint at a given timepoint will be imputed as non-responders. Subjects who do not have a continuous measure at a given timepoint will have available data at other timepoints included in the longitudinal model, resulting in an analysis that is robust to data that are missing or completely at random. Sensitivity and supplementary analyses will be used to assess the impact of missing data assumptions.
  • Incidence of TEAEs over the first 16 weeks will be summarized by randomized treatment group. No p-values will be reported. Incidence will also be summarized over all 52 weeks for subjects randomized to receive izokibep, and summarized over the last 36 weeks for subjects randomized to receive placebo for the first 16 weeks. Serious adverse events will be summarized analogously. Subjects will be summarized for safety according to treatment actually received.
  • HiSCR75 response rates are 15% for placebo and 35% for izokibep. With 125 subjects receiving placebo and 125 subjects receiving izokibep, this study has 94% power for the true difference in HiSCR75 response rates of 20 percentage points.
  • compositions in treating HS in patients who received TNFi are designed to demonstrate whether treatment is associated with a reduction in the extent of inflammation in patients who have received a TNF-a inhibitor to treat a condition, such as those with moderate to severe HS manifested as a specific reduction in the number of inflammatory nodules and abscesses. As these inflammatory lesions are associated with considerable pain and impairment in quality of life, a reduction in the number of such lesions could directly benefit patients.
  • a 16-week, placebo-controlled period does not entail any additional risk of irreversible harm to subjects.
  • Specified analgesics are permitted for HS-associated pain, and for subjects with increases in abscess and inflammatory node counts (2: 150% of Day 1 abscess and inflammatory nodule [AN] count), investigators may provide permitted antibiotic rescue therapy. Additionally, subjects with a draining fistula count > 20 at screening or Day 1 are excluded from enrolling in the study to exclude the most severe forms of the disease that may place subjects at a higher risk of disease-related complications.
  • the inclusion and exclusion criteria will ensure that patients who might be predisposed to a higher risk of drug-related TEAEs are either excluded or identified and treated with caution. Class effects seen with other IL- 17 inhibitors have been taken into account when designing the eligibility criteria. Subjects with active infections or with a history of autoimmune, chronic inflammatory, or connective tissue disease will be excluded from participating in the study.
  • the primary aim of the study is to evaluate the efficacy of izokibep administered SC 160 mg QW for the treatment of active HS.
  • the primary endpoint of HiSCR75 response will be evaluated after all subjects have the opportunity to complete the 16-week, placebo-controlled study period.
  • subjects randomized to placebo will receive blinded active treatment (izokibep 160 mg QW) until Week 51. Long-term efficacy beyond Week 16 will be explored up to Week 52 and safety will be explored up to the End of Study visit at Week 59.
  • ICE handling treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
  • Part A Single-arm, open-label, proof-of-concept investigation to explore preliminary efficacy and safety of izokibep in adult subjects with moderate to severe hi dradenitis suppurativa (HS).
  • HS hi dradenitis suppurativa
  • Part B Randomized, double-blind, placebo-controlled, parallel group, dose-finding investigation to evaluate the efficacy, safety, and immunogenicity of izokibep in subjects with moderate to severe HS.
  • Subject or legally authorized representative has provided signed informed consent including consenting to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • ICF informed consent form
  • Subject must be > 18 (or the legal age of consent in the jurisdiction in which the study is taking place) and ⁇ 75 years of age, at the time of signing the informed consent.
  • Hidradenitis suppurativa lesions present in > 2 distinct anatomic areas (e.g., left and right axilla; or left axilla and left inguino-crural fold), one of which is Hurley Stage II or Hurley Stage III at screening and Day 1 prior to enrollment/randomization.
  • Subject must have had an inadequate response to oral antibiotics (defined as > 3-month treatment with an oral antibiotic for treatment of HS) OR exhibited recurrence after discontinuation to, OR demonstrated intolerance to, OR have a contraindication to oral antibiotics for treatment of their HS as assessed by the investigator through subject interview and review of medical history.
  • Subject must be willing to complete a daily skin pain diary 7 consecutive days prior to Day 1; if skin pain diaries are not completed for at least 3 of the 7 consecutive days prior to the Day 1 visit, the subject may not be enrolled/randomized. No known history of active tuberculosis (TB). Subject has a negative TB test at screening, as defined by 1 :
  • Negative QuantiFERON test OR Negative purified protein derivative (PPD) test ( ⁇ 5 mm of induration at 48 to 72 hours after the test is placed). Subjects with a positive PPD test and a history of Bacillus Calmette-Guerin vaccination will be allowed with a negative QuantiFERON test.
  • PPD Purified protein derivative
  • T-SPOT TB test may be used to establish eligibility if agreed upon with the medical monitor.
  • Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male subjects Male subjects are eligible to participate if they agree to the following during the study drug period and for at least 8 weeks after the last dose of study drug:
  • Female subjects A female subject is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
  • the investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study drug.
  • a WOCBP must have a negative highly sensitive serum pregnancy test at screening and a negative urine pregnancy test on Day 1 prior to the first dose of study drug.
  • Chronic pain not associated with HS e g., fibromyalgia
  • autoimmune, chronic inflammatory, or connective tissue disease e.g., rheumatoid arthritis, psoriasis, psoriatic arthritis, axial spondyloarthritis, system lupus erythematosus, inflammatory bowel disease (IBD)
  • IBD inflammatory bowel disease
  • TNF-a inhibitors Prior exposure to biologies that had a potential or known association with progressive eukoencephalopathy (i.e., natalizumab [Tysabri], rituximab [Rituxan], orefalizumab [Raptiva]). Exposure to TNF-a inhibitors, TL-1, IL-12, IL-23, or IL-12/23 receptor inhibitors within 5 half-lives prior to first dose of study drug 18. Exposure to any of the following:
  • JAK Janus-kinase inhibitors
  • non-opioid analgesics not on a stable dose for >5 days prior to first dose of study drug. Exception is acetaminophen is allowed ⁇ 2 g per day.
  • opioid analgesics for any reason (excluding tramadol) during the study.
  • Lifestyle C onsiderations The investigator should encourage subject to limit alcohol consumption to ⁇ 2 per day, ⁇ 7 alcoholic drinks per week.
  • An alcoholic drink is defined as a 6 oz (175 mL) glass of wine, a 1 oz (30 mL) glass of hard liquor (e.g., whiskey), or an 8 oz (250 mL) glass of beer.
  • Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently enrolled/randomized to the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs. [0254] Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened up to 2 times (i.e., total of 3 screens including initial screen).
  • Criteria for Temporarily Delaying Dosing Subject should be dosed within the window as detailed in the SoA. All missed or delayed doses should be documented. If the investigator determines a subject should not be dosed within the defined window for a safety reason (e g., an AE, SAE), then a missed dose should be recorded.
  • a safety reason e g., an AE, SAE
  • COVID-19-related Precautions Risk mitigation measures, including COVID-19-related precautions and procedures (including SARS-CoV-2 testing/screening) will be implemented based on the prevailing situation during the study conduct, at the investigator’s discretion, and in accordance with local and institutional guidelines as applicable. Subjects should be routinely monitored for any AEs at every visit, including signs or symptoms of infection. Should subjects demonstrate any symptoms or AEs (including known COVID-19 symptoms or tested positive for COVID-19), the symptoms or AEs will be reported to the site as per study procedures and assessed by the investigator. As with any AEs, AE data will be collected on the appropriate electronic case report form (eCRF).
  • eCRF electronic case report form
  • Study drugs are all pre-specified, investigational and non-IMPs, medical devices and other interventions (e.g., surgical and behavioral) intended to be administered to the study subjects during the study conduct.
  • Study drug (izokibep 160 mg QW or placebo) are dosed by SC injection as described below. Study drug vials for placebo and izokibep are visually indistinguishable. Study drug doses are fixed and are not adjusted for individual subjects during the study. Throughout treatment period, 2 SC injections are given for each study drug administration. The anatomical sites for administration of study drug are the upper arm, upper thigh, or abdomen.
  • Group 1 placebo QW from Day 1/Week 0 to Week 15, then izokibep 160 mg QW from Week 16 to Week 51
  • Group 2 izokibep 160 mg QW from Day 1/Week 0 to Week 51
  • the investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all study drug received, and any discrepancies are reported and resolved before use of the study drug. Only subjects randomized in the study may receive study drug. All study drug must be stored prior to dispensing in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff.
  • the investigator, institution, or the head of the medical institution (where applicable) is responsible for study drug accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition records).
  • a subject is considered enrolled when the investigator decides that the subject has met all eligibility criteria and registered the subject as enrolled/randomized within the Interactive Voice/Web Response System (IXRS).
  • IXRS Interactive Voice/Web Response System
  • the investigator is to document this decision and date in the subject’s medical record.
  • the screening period starts when the subject signs and dates the ICF and ends when the subject is enrolled/randomized, or screen failed.
  • the screening period is up to 28 days.
  • Certain initial screening period procedures may be repeated during the original initial screening period. (Note: Repeating procedures during the original initial screening period is a part of screening and is not considered “rescreening.”) These procedures include laboratory assessments due to value(s) out of range due to potential sampling error or that could be within range with repeat sampling.
  • Laboratory value(s) out of range due to sampling error or that might be within range after medically appropriate supplementation may be repeated up to 2 times within the screening window before the subject is considered a screen failure.
  • All subjects entering the screening period for the study receive a unique subject identification number assigned by the IXRS system. This number identifies the subject throughout the clinical study and is used on all study documentation related to that subject. The subject identification number remains constant throughout the entire clinical study; it is not changed after initial assignment, including if a subject is rescreened.
  • First 3 digits correspond to the last 3 digits of the study protocol number (i.e., 103 in the example below)
  • a subject who is determined to be ineligible is registered as a screen fail in the IXRS system.
  • Investigators may rescreen a subject if the investigator is reasonably certain that reasons for screen failure will be resolved prior to or during a repeat screening attempt.
  • Reasons to rescreen may include but are not limited to the following:
  • a subject provides informed consent prior to the initiation of any rescreening procedures only if 30 or more days have elapsed since the date of the subject’s initial informed consent.
  • the subject enters into rescreening in the IXRS system, and all screening procedures are repeated except as noted in the inclusion/exclusion criteria.
  • a subject is screened up to 3 times (i.e., no more than 2 rescreens). Near to the end of study enrollment, sites are or may be notified when no additional subjects will be screened or rescreened.
  • a chest x-ray does not need to be repeated if a previous chest x-ray was performed ⁇ 3 months prior to day 1.
  • Subjects are randomized to the study drug or placebo (in a 1 : 1 ratio) on Day 1 by the IXRS system.
  • the subject, site personnel, and sponsor/Contract Research Organization (CRO) study personnel and designees are blinded to the randomization treatment group assignment (i.e., izokibep or placebo).
  • the randomization dates are documented in the subject’s medical record.
  • Randomization is stratified by prior TNFi use for HS (Yes/No) and Hurley Stage (II or III). Izokibep and matching placebo is visually indistinguishable to prevent unblinding during preparation or administration of study material.
  • a subject’s treatment assignment should be unblinded only when knowledge of the treatment is essential for the further management of the subject in this study. Unblinding at the study site for any other reason is considered a protocol deviation. The investigator is strongly encouraged to contact the medical monitor before unblinding any subject’s treatment assignment but must do so within 1 working day after the unblinding event. If an SAE requires an expedited regulatory report to be sent to 1 or more regulatory agencies, sponsor/designee’s safety staff may unblind the intervention assignment for the subject. A copy of the report, identifying the subject’s intervention assignment, may be sent to that regulatory agency in accordance with local regulations.
  • Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the patient is receiving at the time of enrollment or receives during the study is recorded along with: z. reason for use ii. dates of administration including start and end dates
  • Hi. dosage information including route, dose and frequency.
  • Concomitant medications should be used in alignment with the approved label in the respective country, and per doses as outlined below.
  • the medical monitor should be contacted if there are any questions regarding concomitant or prior therapy.
  • the dose For a subject entering the study on oral non-opioid analgesic, the dose must be stable for >5 days.
  • the subject may continue the analgesic, provided the dose is stable for 5 days prior to the first dose of study drug and is anticipated to remain stable throughout study participation. If a subject's pain (HS-related or non- HS-related) worsens after Day 1, they may initiate analgesic therapy at any time as follows:
  • HS-related pain permitted analgesics are limited to: i. Ibuprofen (at a dose of up to 800 mg by mouth every 6 hours) not to exceed 2.0 grams/per 24 hours; AND/OR acetaminophen/paracetamol as per local labeling. ii. If HS-related pain is uncontrolled with ibuprofen or acetaminophen/paracetamol at the above dosing regimens after the Day 1 visit, subjects can be prescribed tramadol (at a dose of up to 100 mg po every 4 hours), not to exceed 400 mg per 24 hours. iii. From screening through Week 16, subjects complete a daily diary of their analgesic use.
  • Antibiotic Therapy In approximately 30% of subjects, concomitant antibiotic use is permitted if dosing regimen has > 4 weeks prior to first dose of study drug, and dosing regimen is maintained through the placebo-controlled period (Week 16 assessment). Antibiotics taken on an ‘as-needed’ basis are not considered a stable dose.
  • Permitted oral concomitant antibiotics include: i. Oral: doxycycline (at a dose of up to 100 mg twice daily [BID]); minocycline (at a dose of up to 100 mg, BID). z/. If another oral concomitant antibiotic for HS is medically necessary at the time of enrollment/randomization, the medical monitor must be contacted for approval. If systemic antibiotics are used concomitantly, the dose should remain stable and constant.
  • Concomitant antibiotic use for the treatment of an AE other than HS may be permitted per standard of care (e.g., for treatment of pneumonia, tonsillitis) and should be captured and documented appropriately.
  • a total of 2 protocol-allowed interventions are permissible up until Week 16 visit.
  • An intervention can occur on maximally 2 different lesions at the same or different visits or on the same lesion at 2 different study visits. The same lesion cannot be treated 2 times at the same visit. If a subject requires more than 2 interventions within the first 16 weeks, then they must be discontinued from study drug. After Week 16, maximally 2 interventions every 4 weeks are permitted. If a subject requires more than 2 interventions within a 4-week period or has 2 of the same interventions on the same lesion within that period, then he or she must be discontinued from the study drug.
  • All other biologic therapies with a potential therapeutic impact on HS including but not limited to TNF-alpha inhibitors, IL-1, IL- 12, IL- 17, IL-23, or IL- 12/23 inhibitors
  • Any other immunomodulatory therapy e.g., cyclosporine, azathioprine, tacrolimus, IV gamma-globulin or Prosorba column therapy
  • immunomodulatory therapy e.g., cyclosporine, azathioprine, tacrolimus, IV gamma-globulin or Prosorba column therapy
  • JAK inhibitors e.g., tofacitinib, upadacitinib
  • Non-oral concomitant analgesics e.g., IV, SC
  • antibiotic rescue medication may be initiated.
  • Subjects who qualify may initiate treatment with minocycline or doxycycline up to 100 mg BID.
  • the dosing regimen must remain stable throughout study participation.
  • the medical monitor should review to determine whether another rescue medication would be more appropriate.
  • Rescue antibiotic therapy should be captured in the source and on the appropriate electronic CRF. The date and time of rescue medication administration as well as the name and dosage regimen of the rescue medication must be recorded.
  • Subject develops Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3 or higher cardiovascular AE(s) that would put the subject at risk for continued participation in the trial as determined by the investigator or medical monitor.
  • CTCAE Common Terminology Criteria for Adverse Events
  • xiii Any CTCAE version 5.0 grade 4 AE (life-threatening consequences; urgent intervention indicated considered by the investigator to be related to the study treatment).
  • xiv Subject develops an illness that, in the opinion of the investigator, would interfere with his or her continued participation, if the risk of continuing with study drug outweighs the potential benefit.
  • Subject uses prohibited concomitant medications, as defined herein, that may present a risk to the safety of the subject in the opinion of the investigator following discussion and agreement with the medical monitor.
  • Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time during the study.
  • Subj ect is significantly non-compliant with study procedures which would put the subj ect at risk for continued participation in the trial as determined by the investigator or medical monitor.
  • xviii Subjects with disease progression or not responding to treatment are to be withdrawn from study drug treatment based on investigator’s discretion.
  • Subjects with newly diagnosed IBD during the study must: (i) discontinue study drug and be followed-up until resolution of active IBD symptoms; and (ii) be referred, as appropriate, to a health care professional treating IBD, such as a gastroenterologist.
  • Study drug must be interrupted in case of any SAE or AE with a CTCAE version 5.0 grade 3 or above, unless obviously unrelated to study medication (e.g., motor vehicle accident). The option to restart study drug after interruption, if felt warranted by the investigator, should be discussed with, and cannot be implemented before agreement from, the medical monitor. [0316] If the subject has a clinical laboratory value meeting any of the following criteria, study drug must be interrupted. The laboratory test must be repeated in 1 to 2 weeks at a scheduled or unscheduled visit. The option to restart study drug after interruption, if felt warranted by the investigator, should be discussed with, and cannot be implemented, before agreement from the medical monitor: i. neutrophil count ⁇ 1.0 x 10 9 /L ii. platelets ⁇ 50 000/mm 3
  • the investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination.
  • Reasons for the early closure of a study site by the sponsor or investigator may include but are not limited to:
  • the sponsor will comply with the requirements for publication of study results. In accordance with standard editorial and ethical practice, the sponsor will generally support publication of multi -center studies only in their entirety and not as individual site data. In this case, a coordinating investigator will be designated.
  • Protocol-specific requirements for inclusion or exclusion of subjects are detailed hereinabove as part of the subject protocol.
  • Additional tests may be performed at any time during the study as determined necessary by the investigator or required by local regulations. All study-required laboratory tests will be performed by a central laboratory, with the exception of i. urine pregnancy test ii. PPD test.
  • AEs and SAEs Definitions and Procedures for Recording, Evaluating, follow-up, and Reporting Definition of AE
  • An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug.
  • an AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug.
  • Any abnormal laboratory test results hematology, clinical chemistry, or urinalysis
  • other safety assessments e.g., ECG, radiological scans, vital signs measurements
  • ECG electrospray, radiological scans, vital signs measurements
  • Medical or surgical procedure e.g., endoscopy, appendectomy: The condition that leads to the procedure is the AE.
  • An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed:
  • life threatening in the definition of serious refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.
  • hospitalization signifies that the subject has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or outpatient setting.
  • Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not considered an AE.
  • disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption.
  • trauma e. Is a congenital anomaly /birth defect
  • Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions not resulting in hospitalization, or development of intervention dependency or intervention abuse.
  • the investigator will then record all relevant AE/SAE information in the required eCRF and SAE Report Form (if applicable).
  • the investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.
  • Moderate (Grade 2): Minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental activities of daily living (ADL). Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
  • Severe Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care ADL.
  • Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
  • Severity is a measure of intensity (e.g., Grades 1 through 5 or mild, moderate, severe), whereas seriousness is based on subject/event outcome as defined by the criteria provided herein.
  • the investigator is obligated to assess the relationship between study drug and each occurrence of each AE/SAE.
  • the investigator will use clinical judgment in the assessment of causality according to the following categories:
  • a reasonable possibility of a relationship conveys that there are facts, evidence, and/or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
  • the investigator will also consult the Investigator’s Brochure and/or product information, for marketed products, in his/her assessment.
  • the investigator may change his/her opinion of causality in light of follow-up information and send an SAE follow-up report with the updated causality assessment.
  • the causality assessment is one of the criteria used when determining regulatory reporting requirements.
  • the investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as medically indicated or as requested by the sponsor or designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.
  • the investigator will submit any updated SAE data to the sponsor/ designee within 24 hours of receipt of the information.
  • Email transmission of the SAE Report Form is the preferred method to transmit this information to the sponsor/designee.
  • Investigator signature is required to be collected on the SAE Report Form prior to submission. With rare exception, the form may be sent without signature in order to meet the reporting deadline; however, investigator signature is required to be obtained as soon as possible after submission.
  • Phase 2 liver chemistry stopping criteria are designed to assure subject safety and to evaluate liver chemistry stopping criteria are designed to assure subject safety and to evaluate liver event etiology.
  • the guidelines provided below are based on the EASL Clinical Practice Guidelines: Drug Induced Liver Injury (2019) and Food and Drug Administration 2009 Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation.
  • ALT alanine transaminase
  • AST aspartate transaminase
  • eCRF electronic case report form
  • PK pharmacokinetic
  • SAE serious adverse event
  • ULN upper limit of normal.
  • Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.
  • ALT or AST t3 x ULN and total bilirubin t2 x ULN (> 35% direct bilirubin) or ALT or AST t3 x ULN and INR > 1.5 may indicate severe liver injury (possible “Hy’s Law”) and must be reported to sponsor in an expedited manner and as an SAE.
  • the INR stated threshold value will not apply to subjects receiving anticoagulants.
  • liver injury such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice
  • hypersensitivity such as fever, rash, or eosinophilia
  • Hidradenitis Suppurativa [0544] The following are results of Part B of a Phase 2b trial evaluating izokibep for the treatment of moderate-to-severe Hidradenitis Suppurativa (HS).
  • HiSCR75 Hidradenitis Suppurativa Clinical Response
  • FIG. 5 provides a schematic of the Phase 2b study for use of Izokibep in treating HS and FIG. 6 provides an overview of the subjects in the study. Results and conclusions of the study are provided in FIGS. 7-20.
  • FIG. 7 The data shown in FIG. 7 reveals that any discontinuation of subjects in the study was not related to adverse events.
  • FIG. 8 provides an overview of results from the study.
  • FIG. 9 shows the HiSCR response at week 16.
  • FIG. 10 describes the drug exposure as consistent with observed dose response.
  • FIG. 11 provides a last observation carried forward sensitivity analysis.
  • FIG. 12 shows study discontinuations over time.
  • FIG. 13 shows HiSCR responses over time.
  • FIG. 14 shows results of a pre-planned interim analysis a week 12.
  • FIG. 15 shows izokibep performed closely between Part A & B Pre-planned interim.
  • FIG. 16 provides results of an independently conducted part B interim analysis demonstrating greater & deeper izokibep responses compared to Bimekizumab.
  • FIG. 17 provides part B pre-planned interim over time.
  • FIG. 18 provides data for the pre-planned part B interim with NRI at week 12.
  • FIG. 19 provides data of a modified NRI approach to the part B interim data set revealing a
  • FIGS. 14-20 show the consistency of Part A open label results relative to the Part B placebo-controlled interim analysis, which was pre-specified to be an as observed analysis at week 12.
  • Fig. 21 An overview of the Phase 2b trial through week 32 (and the subsequent follow ups at weeks 39 and 45) is provided in Fig. 21.
  • Fig. 22 provides the disposition of the trial participants through week 32, while Fig. 23 provides the participants’ baseline characteristics.
  • the 160 mg QW or Q2W izokibep dosages reaches HiSCRIOO responses at a rate that far surpasses currently-marketed IL-17A agents or comparable with currently-marketed IL-17A/F agents, but with a far improved safety profile.
  • Fig. 28 Draining tunnel resolution with 160 mg QW continued to improve through week 32 of the trial. Further, as provided in Fig. 29, patients receiving the 160 mg QW dosage reported marked reductions in skin pain through week 32. Similarly, Fig. 30 provides data indicating that in patients receiving the 160 gm QW dose, marked improvements in DLQI were observed with a corresponding, clinically meaningful improvement in QOL.
  • Fig. 31 An overview of the Phase 3 trial through week 59 is provided in Fig. 31.
  • Fig. 32 provides the baseline characteristics (left) and the patient disposition of trial participants (right) as assessed at week 12 of the Phase 3 clinical trial.
  • the trial initially included 129 patients randomly selected for each of the placebo and Izokibep arms of the study. As shown, patient dropouts were mostly equivalent between both arms of the study. However, while the placebo arm lost a participant due to disease progression, no such dropout occurred in the active treatment arm.
  • Fig. 33 As shown in Fig. 33, through week 12, the measured HiSCR75 responses with 160 mg QW in HS patients were positive, statistically relevant, and surpassed the placebo.
  • Fig. 34 provides the HiSCR75 through week 16. As shown, both relative to the placebo arm, and from a quantitative perspective, the HiSCR75 values continued to increase in the active treatment arm through week 16, with 40% of participants meeting HiSCR75 on the 160 QW dose.
  • Fig. 35 shows the HiSCR90 (left) and HiSCRIOO responses at week 12.
  • Fig. 36 shows HiSCR90 (left) and HiSCRIOO responses at week 16. As shown, over 20% of patients met HiSCRIOO at week 12, with 25% of participants meeting HiSCRIOO by week 16.
  • Fig. 37 summarizes the HiSCR50, HiSCR75, HiSCR90, andHiSCRIOO responses through week 12 for the Phase 3 trial.
  • Fig. 38 summarizes the HiSCR50, HiSCR75, HiSCR90, and HiSCRIOO responses through week 16.
  • Fig. 40 through week 12 of the Phase 3 trial, the 160 mg QW dosage produced marked reductions in skin pain.
  • Fig. 40 also provides DLQI data (right) indicating that through week 12, patients in the active treatment arm showed marked improvements in DLQI, which were observed with a corresponding, clinically meaningful improvement in QOL.
  • Fig. 41 through week 16, the 160 mg QW dosage produced increased reductions in skin pain (left) and maintained the improved DLQI (right).
  • Fig. 42 provides the safety results through week 12 of the Phase 3 trial. As shown, the only 1 serious TEAE was reported in the active treatment arm, with four times that number reported in the placebo arm. Overall, the results are consistent with those from the earlier trials, which helps confirm the safety profile of the tested treatment dose.
  • the Phase 3 trial also provides a differentiated profile.
  • the rapidity, magnitude and depth of responses support the hypothesis that the characteristics of izokibep - including small size and highly potent and selective inhibition of IL-17A - provide differentiated clinical benefits. This is evident as resolution of abscesses and inflammatory nodules (HiSCRIOO) achieved twice as fast in twice as many patients compared to current, approved IL-17A agents. Moreover, there was no reported increased risk of fungal infection, which is a serious side effect of the IL-17A&F agents. Equivalents
  • ADL means activities of daily living
  • AN means abscess and inflammatory nodule
  • AUG means area under the concentration-time curve
  • AUCO-oo means area under the plasma concentration time curve extrapolated to infinity AUCO-T means area under the plasma concentration time curve over a dosing interval BID means twice daily
  • COVID- 19 means coronavirus disease of 2019
  • C-SSRS means Columbia-Suicide Severity Rating Scale
  • CTCAE means Common Terminology Criteria for Adverse Events
  • CV% means percent coefficient of variation
  • DLQI Dermatology Life Quality Index
  • DMC means data monitoring committee
  • DNA means deoxyribonucleic acid
  • ECG electrocardiogram
  • eCRF electronic case report form
  • FSH means follicle-stimulating hormone
  • GCP Good Clinical Practice
  • HiSCR50 means hidradenitis suppurativa clinical response 50 is defined as at least a 50% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count
  • HiSCR75 is defined as at least a 75% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count
  • HiSCR90 is defined as at least a 90% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count
  • HiSCRIOO is defined as a 100% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscesses or draining fistula count.
  • HIV means human immunodeficiency virus.
  • HRT means hormonal replacement therapy
  • HS means hidradenitis suppurativa
  • IBD means inflammatory bowel disease
  • ICH means International Council for Harmonisation
  • ICF means informed consent form
  • IL means interleukin
  • IL-17A means interleukin 17A
  • IRB Institutional Review Board
  • ISR injection site reaction
  • IV means intravenous(ly)
  • IXRS Interactive Voice/Web Response System
  • JAK means Janus-kinase
  • NRI means non-response imputation
  • NRS means numeric rating scale
  • PASI Psoriasis Area and Severity Index
  • PASI90 Psoriasis Area and Severity Index response of 90%
  • PK means pharmacokinetic(s)
  • PPD means purified protein derivative
  • PsA means psoriatic arthritis
  • SARS-CoV-2 means severe acute respiratory syndrome coronavirus
  • SC means subcutaneous(ly)
  • SoA Schedule of Activities
  • SUS AR means suspected unexpected serious adverse reaction tU means half-life
  • TEAE treatment-emergent adverse events
  • Th 17 means T-helper 17 cell tmax means time to maximum observed concentration
  • TNF-a means tumor necrosis factor-a
  • WOCBP women of childbearing potential
  • HUMIRA® USPI. 2021 “HUMIRA® USPI. 2021, Highlights of Prescribing Information.” www.fda.gov/medwatch.

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Abstract

The disclosure relates to novel regimens for treating hidradenitis suppurativa by administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of izokibep.

Description

METHODS OF TREATING HIDRADENITIS SUPPURATIVA
FIELD OF THE DISCLOSURE
[0001] The application relates generally to novel dosing regimen for treating conditions, such as hidradenitis suppurativa (HS), in patients who have or otherwise would be treated with a Tumor necrosis factor alpha (TNFa) inhibitor by administration of a therapeutically effective amount of pharmaceutical composition comprising an engineered protein that comprises an IL-17A binding motif.
BACKGROUND
[0002] Tumor necrosis factor alpha (TNFa) is a pro-inflammatory cytokine that mediates a diverse range of inflammatory, infectious and immune-related processes and pathologies.
[0003] The activity or hyperactivity of TNF-alpha can induce many undesired cellular responses. Consequently, TNF-alpha has been implicated in a variety of human diseases and conditions, including inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, and vasculitis.
[0004] Unfortunately, for many patients, existing TNF-inhibitors do not resolve their conditions. Among these conditions is hidradenitis suppurativa (HS), which is a chronic, inflammatory, recurrent, debilitating skin characterized by occlusion of hair follicles as a primary pathogenic factor associated with a chronic cycle of inflammation, healing, and scarring. HS generally presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body. Zouboulis, C., etal., Dermatology, 231 (2), pp. 184-190 (2015). HS presents a variable clinical course. One of the main features of the disease is the intertriginous occurrence, although, other areas of skin may also be affected. The affected areas are in decreasing order of frequency: inguinal, axillary, perineal and perianal as well as the submammary and/or intermammary fold in women, buttocks, mons pubis, scalp, area behind the ears and eyelids. Patients with HS often develop painful inflamed nodules, abscesses, and pus-discharging tracts and fistulas, which typically occur in skin folds of axillary (armpits), inguinal (groin), gluteal and perianal areas of the body. Hidradenitis suppurativa is also known to cause severe pain, purulent secretions that smell bad, and movement restrictions that have a profound negative influence on patients’ lives (Sabat et al. 2020).
[0005] A genetic predisposition, smoking, obesity, and hormonal factors are established etiological factors for HS (Sabat et al. 2020). Cutaneous changes begin around hair follicles and involve activation of cells of the innate and adaptive immune systems, with pivotal roles for proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-IB, and IL- 17 (Sabat et al. 2020).
[0006] Clinical management of HS is challenging and consists of both medical and surgical approaches. Topical therapies, systemic antibiotics, hormonal therapies, and immunosuppressant medications have been used. However, there are patients where HS remains resistant to conventional treatment particularly those with moderate to severe disease (Alikhan et al. 2019). The TNF-a inhibitor, adalimumab is currently the only approved biologic immunomodulator by the US Food and Drug Administration for treating moderate to severe HS (HUMIRA® USPI 2021) Only around 50% of subjects achieved a clinical response at Week 12 in the 2 randomized, doubleblind, placebo-controlled studies of adalimumab in a total of 633 adult subjects with moderate to severe HS. During the second part of both studies (up to 36-week treatment duration), approximately 40% of subjects who initially responded to adalimumab weekly therapy continued to benefit from this drug (Kimball et al. 2016).
[0007] In summary, there continues to be a significant unmet medical need for additional therapies to treat patients with HS and other diseases in which current TNF-alpha inhibitors fail to provide satisfactory outcomes. As shown in the context of HS, additional therapies are needed to manage pain, abscess formation, and disease progression. In addition, given the significant reduction in quality of life and functional impairment experienced by patients diagnosed with HS and other TNF-alpha-implicated conditions, there is an unmet need for medical therapies that can have a substantial impact on improving a patient’s quality of life.
SUMMARY
[0008] The present disclosure recognizes that certain conditions, such as Hidradenitis suppurativa (HS) can be treated by compositions comprising izokibep or a salt thereof, in patients who have or would otherwise receive a TNF-a inhibitor. In that manner, the disclosure provides novel methods for the treatment of HS by administering once a week to a patient a therapeutically effective amount of pharmaceutical composition comprising izokibep or a salt thereof. In a related aspect, the disclosure also provides a composition comprising izokibep or a salt thereof for use in the treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor. In another related aspect, the disclosure provides use of a composition comprising izokibep or a salt thereof in the manufacture of a medicament for the treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor.
[0009] In certain aspects, the present disclosure provides methods and compositions for treatment of a condition(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or pan-uveitis, thyroiditis, and/or vasculitis.
[0010] In more preferred aspects, the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
[0011] In certain aspects, the disclosure provides a method of treatment of a condition, such as HS, in a patient that has received a TNF-a inhibitor by administration to a patient a composition comprising izokibep or a salt thereof. Preferably, the composition comprises between about 100 and about 200 mg of izokibep or a salt thereof. More preferably, the composition comprises between about 150 and about 170 mg of izokibep or a salt thereof. In more preferred aspects, the composition comprises about 160 mg of izokibep or a salt thereof or does comprise 160 mg of izokibep or a salt thereof. In preferred aspects, treatment with the TNF-a inhibitor did not resolve the patient’s HS. [0012] In certain methods, the composition further comprises one or more of sodium phosphate, NaCl, and EDTA.
[0013] In certain methods, the composition is administered to the patient subcutaneously. In such methods, in preferred aspects, the composition is administered in an arm, upper thigh, and/or abdomen of the patient. Preferably, the composition is administered to the patient once weekly. In alternative or supplementary methods, the composition is administered to patient twice weekly. In certain aspects, composition is administered once a week to a patient for between 1 and 52 weeks. In certain aspects, the composition is administered once a week to a patient for at least 16 weeks. [0014] In preferred aspects, the condition is HS. In certain embodiments, the HS is a severe or a moderate HS. In certain aspects, the HS presents as lesions in at least 2 anatomic areas of the patient, wherein the patient is Hurley Stage II or Hurley Stage III, and/or wherein the patient has an abscess and inflammatory nodule (AN) count of > 5 prior to the administration. In preferred aspects, the patient has received a TNF-a inhibitor to treat HS.
[0015] In certain aspects, prior to receiving the izokibep composition, the patient exhibited an inadequate response to > 3 month treatment with an oral antibiotic for treatment of the condition, exhibited recurrence of the condition after discontinuing an antibiotic treatment, and/or the patient demonstrated intolerance to and/or exhibits a contraindication to oral antibiotics for treatment of the condition.
[0016] In certain aspects, the HS affects areas of the patient’s skin, and in conjunction to receiving the izokibep composition, the patient applies a topical antiseptic to the affected areas.
[0017] In preferred aspects, the condition is HS and administration of the izokibep composition provides to the patient at least a 75% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count. In exemplary methods, the 75% reduction occurs before or at a sixteenth week of the administration of the medicament. In preferred aspects, the condition is HS and administration of the izokibep composition provides to the patient at least a 90% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count. In exemplary methods, the 90% reduction occurs before or at a sixteenth week of the administration of the medicament.
[0018] In some preferred aspects, the condition is HS and wherein administration of the izokibep composition to the patient provides to the patient an AN count of 0, 1, or 2. [0019] In some preferred aspects, the condition is HS and wherein administration of the izokibep composition to the patient provides to the patient at least a 3 -point reduction from baseline in an NRS Patient Global Assessment of Skin Pain.
[0020] In certain methods, the condition is uveitis, including one or more of the group consisting of an intermediate-uveitis, a posterior-uveitis, and a pan-uveitis. In some methods, the uveitis is an intermediate-uveitis. In some methods the uveitis is a posterior-uveitis. In some methods the uveitis is a pan-uveitis. In preferred methods, the uveitis is a non-infectious uveitis.
[0021] In methods of the disclosure, the treatment reduces IL-17 expression in the patient. Accordingly, the treatment provides quiescence at between about 1 week and 15 weeks.
[0022] In certain methods of the disclosure, prior to administration, the patient has received a corticosteroid treatment. In such methods, preferably the patient tapers use of the corticosteroid during the administration. In methods of the disclosure, the patient may discontinue use of the corticosteroid by a fifteenth week of administration.
[0023] In certain methods of the disclosure, the patient receives one or more doses of prednisone or prednisolone. In exemplary methods, the patient receives one dose of prednisone or prednisolone daily for a first fourteen days of the administration. In some methods of the disclosure, prior and/or during the administration, the patient receives an immunosuppressant.
[0024] In certain aspects, the present disclosure provides methods and compositions for treatment of a condition(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or pan-uveitis, thyroiditis, and/or vasculitis.
[0025] In more preferred aspects, the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis. [0026] In certain aspects, the disclosure provides a medicament comprising izokibep or a salt thereof used for treatment of a condition, such as HS, in a patient that has received a TNF-a inhibitor. Preferably, the medicament comprises between about 100 and about 200 mg of izokibep or a salt thereof. More preferably, the medicament comprises between about 150 and about 170 mg of izokibep or a salt thereof. In more preferred aspects, the medicament comprises about 160 mg of izokibep or a salt thereof or does comprise 160 mg of izokibep or a salt thereof. In preferred aspects, treatment with the TNF-a inhibitor did not resolve the patient’s HS.
[0027] In certain methods, the medicament further comprises one or more of sodium phosphate, NaCl, and EDTA.
[0028] In certain methods, the medicament is formulated for subcutaneous administration. In such methods, in preferred aspects, the composition is formulated for administration in an arm, upper thigh, and/or abdomen of the patient. Preferably, the medicament is formulated for administration to the patient once weekly. In alternative or supplementary aspects, the medicament is formulated for administration to the patient twice weekly. In certain aspects, medicament is formulated for administration once a week to a patient for between 1 and 52 weeks. In certain aspects, the medicament is formulated for administration once a week to a patient for at least 16 weeks.
[0029] In preferred aspects, the condition is HS. In certain embodiments, the HS is a severe or a moderate HS. In certain aspects, the HS presents as lesions in at least 2 anatomic areas of the patient, wherein the patient is Hurley Stage II or Hurley Stage III, and/or wherein the patient has an abscess and inflammatory nodule (AN) count of > 5 prior to the administration. In preferred aspects, the patient has received a TNF-a inhibitor to treat HS.
[0030] In certain aspects, prior to receiving the izokibep medicament, the patient exhibited an inadequate response to > 3 month treatment with an oral antibiotic for treatment of the condition, exhibited recurrence of the condition after discontinuing an antibiotic treatment, and/or the patient demonstrated intolerance to and/or exhibits a contraindication to oral antibiotics for treatment of the condition.
[0031] In certain aspects, the HS affects areas of the patient’s skin, and in conjunction to receiving the izokibep medicament, the patient applies a topical antiseptic to the affected areas.
[0032] In preferred aspects, the condition is HS and the medicament provides to the patient at least a 75% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count. In exemplary methods, the 75% reduction occurs before or at a sixteenth week of the administration of the medicament. In preferred aspects, the condition is HS and administration of the izokibep composition provides to the patient at least a 90% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count. In exemplary methods, the 90% reduction occurs before or at a sixteenth week of the administration of the medicament.
[0033] In some preferred aspects, the condition is HS and wherein administration of the izokibep medicament to the patient provides to the patient an AN count of 0, 1, or 2.
[0034] In some preferred aspects, the condition is HS and wherein administration of the izokibep medicament to the patient provides to the patient at least a 3 -point reduction from baseline in an NRS Patient Global Assessment of Skin Pain.
[0035] In certain embodiments, the disclosure provides a composition comprising 160 mg of izokibep or a salt thereof for administration once weekly (QW) for the treatment of HS in patients who have received treatment with a TNF-a inhibitor. In certain embodiments, the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once weekly (QW) or twice weekly for the treatment of HS. In certain embodiments, the methods of the disclosure include providing a composition comprising 160 mg of izokibep or a salt thereof once every two weeks (Q2W) for the treatment of HS.
[0036] In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as an injection for treatment of HS. In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as an intravenous infusion for treatment of HS. In certain embodiments, the methods of the disclosure provide that the composition comprising izokibep is administered as a subcutaneous for treatment ofHS.
[0037] In certain aspects, the methods of the disclosure provide that the composition comprising izokibep is administered for a duration for which the therapeutic effect is observed. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of HS for a duration of at least 16 weeks. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of HS for a duration of at least 52 weeks. In certain embodiments, the disclosure provides that the composition comprising izokibep may be administered for treatment of HS for a duration of at least 14 weeks. [0038] The disclosure provides novel and efficacious compositions comprising at least 160 mg izokibep or a salt thereof are safe and efficacious for the treatment of HS. The methods of the disclosure provide a clear benefit and utility in treating HS, including via complete quiescence, especially compared with existing therapies. Moreover, unexpectedly, the izokibep compositions and methods disclosed herein are able to treat HS in patients that received a TNF-a inhibitor therapy to treat HS. The disclosure also recognizes that it is unexpected that a composition comprising 160 mg izokibep or a salt thereof would not have significant adverse events and will be generally well tolerated. Surprisingly, administration of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, are well-tolerated, and have better efficacy in the treatment of HS, even in in patients that received a TNF-a inhibitor therapy to treat HS.
[0039] The disclosure also recognizes that, in particular, subcutaneous administrations of compositions comprising 160 mg izokibep or a salt thereof, administered either QW or Q2W, are well-tolerated. This provides a benefit for patients experiencing HS, as subcutaneous may be selfadministered by patients or less-technical medical staff, obviating the need to visit a doctor to receive the QW or Q2W dose, depending on the regiment.
[0040] In certain embodiments, the methods of the disclosure alleviate the symptoms of HS via administration of the izokibep compositions and dosing regimes disclosed herein, which may improve the time to treatment failure compared to placebo in subjects with HS, including those who have received prior therapy with a TNF-a inhibitor.
BRIEF DESCRIPTION OF DRAWINGS
[0041] FIG. 1 demonstrates the adalimumab serum concentrations in patients suffering from HS and Psoriasis.
[0042] FIG. 2 provides a depiction of izokibep bound to IL-17A homodimer.
[0043] FIG. 3 provides an overview of a study for treating HS with izokibep.
[0044] FIG. 4 provides liver chemistry considerations for subjects in the study.
[0045] FIG. 5 provides a schematic of a Phase 2b study for use of izokibep in treating HS.
[0046] FIG. 6 provides an overview of the subjects in the study.
[0047] FIG. 7 supports that discontinuation in the study was not related to adverse events.
[0048] FIG. 8 provides an overview of results from the study.
[0049] FIG. 9 shows the Hi SCR response at week 16. [0050] FIG. 10 describes the drug exposure as consistent with observed dose response.
[0051] FIG. 11 provides a last observation carried forward sensitivity analysis.
[0052] FIG. 12 shows study discontinuations over time.
[0053] FIG. 13 shows Hi SCR responses over time.
[0054] FIG. 14 shows results of a pre-planned interim analysis at week 12.
[0055] FIG. 15 shows where izokibep performed closely between Part A & Part B pre-planned week 12 interim.
[0056] FIG. 16 provides results of an independently conducted part B interim analysis demonstrating greater & deeper izokibep responses compared to Bimekizumab.
[0057] FIG. 17 provides part B pre-planned interim over time.
[0058] FIG. 18 provides data for the pre-planned part B interim with NRI at week 12.
[0059] FIG. 19 provides data of a modified NRI approach to the part B interim data set revealing a high statistical significance.
[0060] FIG. 20 provides a summary of the week 16 results of the phase 2b study part B.
[0061] FIG. 21 shows an overview of the Phase 2b clinical trial, outlined in Fig. 5, for izokibep in patients with HS through week 32.
[0062] FIG. 22 shows patient dispositions through week 32 of the Phase 2b clinical trial.
[0063] FIG. 23 shows the patient demographics and baseline measurements for the Phase 2b clinical trial.
[0064] FIG. 24 shows HiSCR75 Response data from the Phase 2b clinical trial.
[0065] FIG. 25 shows HiSCR75, HiSCR90, and HiSCRIOO data for the Phase 2b clinical trial.
[0066] FIG. 26 shows sustained HiSCR75, HiSCR90, and HiSCRIOO data for the Phase 2b clinical trial.
[0067] FIG. 27 shows a comparison of HiSCRIOO data for the Phase 2b clinical trial compared with other therapeutic agents.
[0068] FIG. 28 shows data indicating draining tunnel resolution for the Phase 2b clinical trial.
[0069] FIG. 29 shows data indicating reductions in skin pain for the Phase 2b clinical trial.
[0070] FIG. 30 shows DLQI data for the Phase 2b clinical trial.
[0071] FIG. 31 provides and overview of a Phase 3 clinical trial using a QW 160 mg dose.
[0072] FIG. 32 provides the baseline characteristics (left) and the patient disposition of trial participants (right) as assessed at week 12 of the Phase 3 clinical trial. [0073] FIG. 33 shows the measured HiSCR75 responses through week 12 of the Phase 3 trial.
[0074] FIG. 34 shows the measured HiSCR75 responses through week 16 of the Phase 3 trial.
[0075] FIG. 35 shows the HiSCR90 (left) and HiSCRIOO responses at week 12.
[0076] FIG. 36 shows HiSCR90 (left) and HiSCRIOO responses at week 16.
[0077] FIG. 37 summarizes the HiSCR50, HiSCR75, HiSCR90, and HiSCRIOO responses through week 12 for the Phase 3 trial.
[0078] FIG. 38 summarizes the HiSCR50, HiSCR75, HiSCR90, and HiSCRIOO responses through week 16.
[0079] FIG. 39 summarizes the higher order responses (HiSCR90, and HiSCRIOO) for both the phase 3 trial through 12 weeks and across the Phase 2b trial and the Phase 3 trial.
[0080] FIG. 40 shows data measuring skin pain reductions and DLQI through week 12 of the Phase 3 trial.
[0081] FIG. 41 shows data measuring skin pain reductions and DLQI through week 16 of the Phase 3 trial.
[0082] FIG. 42 provides interim safety data through 12 weeks of the Phase 3 clinical trial.
DETAILED DESCRIPTION
[0083] The present disclosure recognizes that certain conditions, such as Hidradenitis suppurativa (HS) can be treated by compositions comprising izokibep or a salt thereof, in patients who have or would otherwise receive a TNF-a inhibitor. In that manner, the disclosure provides novel methods for the treatment of HS by administering once a week to a patient a therapeutically effective amount of pharmaceutical composition comprising izokibep or a salt thereof. Such compositions may provide therapeutic benefit, e.g., symptom relief and/or complete cessation or remission of a condition, even where prior therapy with a TNF-a inhibitor has failed to provide the desired therapeutic benefit.
[0084] In certain aspects, the present disclosure provides methods and compositions for treatment of a condi tion(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or pan-uveitis, thyroiditis, and/or vasculitis.
[0085] In more preferred aspects, the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
[0086] In certain aspects, the disclosure provides a method of treatment of a condition, such as HS, in a patient that has received a TNF-a inhibitor by administration to a patient a composition comprising izokibep or a salt thereof.
[0087] Hidradenitis suppurativa is a chronic inflammatory skin disease characterized by occlusion of hair follicles as a primary pathogenic factor associated with a chronic cycle of inflammation, healing, and scarring (Sabat et al. 2020). A recent meta-regression analysis found an overall HS prevalence of 0.40% (95% confidence interval [CI]: 0.26% to 0.63%) among the populations studied around the world (Jfri et al. 2021). In a population-based analysis, the overall point prevalence of HS in the United States (US) was 0.10%, or 98 per 100 000 persons. Prevalence was highest among women (137 per 100 000), those aged 30 to 39 years (172 per 100000), and African American (296 per 100 000) and biracial (218 per 100 000) patient groups (Garg et al. 2017). Patients with HS develop painful inflamed nodules, abscesses, and pus-discharging tracts and fistulas, which typically occur in skin folds of axillary (armpits), inguinal (groin), gluteal and perianal areas of the body. Hidradenitis suppurativa causes severe pain, purulent secretions that smell bad, and movement restrictions that have a profound negative influence on patients’ lives (Sabat et al. 2020).
[0088] A genetic predisposition, smoking, obesity, and hormonal factors are established etiological factors for HS (Sabat et al. 2020). Cutaneous changes begin around hair follicles and involve activation of cells of the innate and adaptive immune systems, with pivotal roles for proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)- IB, and IL- 17 (Sabat et al. 2020). [0089] Clinical management of HS is challenging and consists of both medical and surgical approaches. Topical therapies, systemic antibiotics, hormonal therapies, and immunosuppressant medications have been used. However, there are patients where HS remains resistant to conventional treatment particularly those with moderate to severe disease (Alikhan et al. 2019). The TNF-a inhibitor, adalimumab is currently the only approved biologic immunomodulator by the US Food and Drug Administration for treating moderate to severe HS (HUMIRA® USPI 2021). Only around 50% of subjects achieved a clinical response at Week 12 in the 2 randomized, double-blind, placebo-controlled studies of adalimumab in a total of 633 adult subjects with moderate to severe HS. During the second part of both studies (up to 36-week treatment duration), approximately 40% of subjects who initially responded to adalimumab weekly therapy continued to benefit from this drug (Kimball et al. 2016).
[0090] In summary, there continues to be a significant unmet medical need for additional therapies to treat patients with HS. Additional therapies are needed to manage pain, abscess formation, and disease progression. In addition, given the significant reduction in quality of life and functional impairment experienced by patients diagnosed with HS, there is an unmet need for medical therapies that can have a substantial impact on improving a patient’s quality of life. Interleukin 17 (IL- 17)
[0091] A broad range of immune mediators are highly expressed in established HS lesions compared with healthy control skin. Patients with HS have imbalances in the T-helper 17 cell (Thl7) axis that are similar to those in patients with psoriasis (Wolk et al., 2020). They have high serum levels of the proinflammatory cytokine IL-17A, which leads to neutrophil recruitment and provides positive feedback to maintain the population of proinflammatory Th 17 cells (Matusiak et al. 2017). These imbalances improved in patients treated with TNF-a inhibitors hypothesized that by reducing circulating IL-17A, anti-IL-17A inhibitors like izokibep may also provide benefit for patients with HS. Clinical evidence for this benefit comes from 2 open-label trials with secukinumab 300 mg and brodalumab 270 mg, where 70% of 20 patients and 100% of 10 patients responded at 24 weeks based on the hi dradenitis suppurativa clinical response (HiSCR) (Casseres et al. 2020; Frew et al. 2020). In addition, bimekizumab 320 mg dosed every 2 weeks appeared to deliver greater efficacy than adalimumab dosed based on the prescribing information, at 12 weeks based on the HiSCR75 and HiSCR90 responses (Glatt et al. 2021). Phase 3 trials in patients with HS for secukinumab and bimekizumab are underway. Safety and tolerability of izokibep compositions and dosing regimes of the disclosure
[0092] Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A. Izokibep has the potential to be an efficacious treatment for a variety of IL- 17A-related diseases. The smaller size of izokibep compared to monoclonal antibodies offers advantages in terms of required dosing volumes and potential for alternative pharmacological formulations.
[0093] Izokibep is based on a small protein binding to and blocking the biological effect of the cytokine IL-17A. The izokibep protein molecule contains an albumin-binding domain which confers specific binding to a single site on endogenous serum albumin and thereby a prolonged half-life (t1/?) in the circulation and in tissues after parenteral administration IL- 17 inhibitors have already demonstrated efficacy and a favorable safety profile in different inflammatory diseases, including psoriasis and PsA. These include secukinumab (Cosentyx®) and ixekizumab (Taltz®) in the US, Canada, and the European Union.
[0094] Doses up to 160 mg every other week (Q2W) have been tested and were well tolerated. [0095] In certain embodiments of the disclosure, the izokibep protein comprises an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% similarity with the amino acid sequence of: AEAKYAKEADDAAVEIASLPNLTWDQWYAFIQKLRDDPSQSSELLSEAKKLNDSQAPK ASGSLAEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALPGTGGGGSA EAKYAKEADDAAVEIASLPNLTWDQWYAFIQKLRDDPSQSSELLSEAKKLNDSQAPK (SEQ ID NO. 1), or a fragment thereof.
Non-clinical Studies
[0096] Assessments of target binding specificity have demonstrated high specificity and affinity of izokibep to IL-17A and to albumin. The in vitro and in vivo pharmacodynamics evaluations show that izokibep has a 3- to 5-fold higher potency than the anti-IL-17A monoclonal antibody secukinumab on a molar basis and appears to be approximately equipotent to ixekizumab.
[0097] Pharmacokinetic (PK) data for intravenous (IV)- and SC-administered izokibep have been obtained in rat and monkey. Pharmacokinetic assessments in rat and monkey indicate that the time course of izokibep concentrations after a bolus IV injection and SC injection is well described by a 2- or 3 -compartment model. Pharmacokinetic assessments indicate that the elimination rate of izokibep is similar to that of albumin in the respective species.
[0098] Repeated (10-day to 3-month) SC or IV administration of izokibep to cynomolgus monkeys was well tolerated with no observed adverse effect levels (NOAELs) of 40 mg/kg/dose (IV, 28-day study) and 20 mg/dose (SC, 28-day) and 20 mg/kg/week (SC, 3-month study), being the highest dose levels tested in the respective studies.
[0099] In the 26-week repeated-dose toxicity study in cynomolgus monkeys, weekly SC injection of 10, 20, or 40 mg/kg/week izokibep to monkeys for 26 weeks was generally well tolerated. However, due to the presence of local abscesses and systemic sequelae in 1 female administered 40 mg/kg/week, which was considered adverse, the NOAEL for SC administration is considered to be 20 mg/kg/week.
[0100] In the enhanced pre- and post-natal developmental toxicity study in cynomolgus monkeys, SC izokibep administration of up to 40 mg/kg/week to pregnant monkeys for approximately 21 weeks was well tolerated. The NOAEL was 40 mg/kg/week.
[0101] The results from the immunotoxicity screening assays do not suggest that izokibep has an intrinsic capacity for immune system activation.
[0102] Metabolism and genotoxicity have not been investigated, since izokibep is a protein molecule and contains only naturally occurring amino acids.
[0103] The present disclosure provides a preferred 160 mg izokibep dose, administered once a week, twice a week, or once every two weeks based on the safety profile deduced by the present Inventors. A first-in-human multipart clinical study (Study ABY-O35-OO1, EudraCT number 2015- 004531-13, NCT02690142) has been conducted with the parenteral formulation of izokibep. Izokibep was administered IV and SC to healthy subjects and plaque psoriasis patients, in doses ranging from 2 mg to 40 mg in a single- or multiple-dose regimen.
[0104] Moreover, a Phase 2 dose-finding study in subjects with moderate to severe plaque psoriasis was recently completed with up to 3 years of exposure (Study ABY-035-002, EudraCT number 2017-001615-36, NCT03591887). One hundred eight subjects were randomized into 5 dose groups: 2 mg, 20 mg, 80 mg, and 160 mg izokibep or placebo. The treatment period consisted of an induction period (12 weeks), an optimization period (12 weeks), and an individualization period including 4 weeks follow-up (28 weeks), and 2 further years of extension. The induction period was double blind and placebo controlled.
[0105] The primary endpoint of the study was the proportion of patients that achieved a Psoriasis Area and Severity Index (PASI) response of 90% (PASI90) after 12 weeks of treatment. The PASI90 at 12 weeks was 71.4% and 59.1% in subjects treated with 80 mg and 160 mg Q2W of izokibep, respectively. In the lower dose groups, 2 mg and 20 mg izokibep, only 5.0% and 19.0% of subjects, respectively, reached the primary endpoint. None of the subjects receiving placebo reached PASI90 response at Week 12. At Week 24, PASI90 responses were comparable between the initial 80 mg and 160 mg treatment groups. The safety and efficacy data obtained from the 52-week core period of the study with izokibep suggest a favorable benefit-risk profile in plaque psoriasis.
[0106] A Phase 2 clinical trial in subjects with active PsA has recently been completed (Study ABY-035-202). Study ABY-035-202 is a dose-finding trial of 40 mg or 80 mg izokibep or placebo SC Q2W. The primary endpoint is the ACR 50% (ACR50) response at Week 16; further key secondary endpoints comprise other ACR responses, PASI scores, enthesitis endpoints, proportion of subjects achieving MDA, adverse events (AEs; safety), and izokibep blood levels (PK), and anti-drug antibody (ADA) assessments.
[0107] The primary endpoint of ACR50 at 16 weeks was met with 52% response rate in subjects receiving 80 mg Q2W of izokibep versus 13% for placebo (p-value = 0.0006). Subjects receiving 40 mg Q2W had an ACR50 response rate of 48%. The PASI response of 75%, in subjects with a minimum psoriasis body surface area (BSA) > 3% at baseline, at 16 weeks was 85% and 83% in subjects treated with 80 mg and 40 mg Q2W, respectively versus 14% for those receiving placebo. In subjects with enthesitis at baseline utilizing the Leeds Enthesitis Index (LEI), resolution of enthesitis was achieved by 88% of subjects receiving 80 mg Q2W, 63% of subjects receiving 40 mg Q2W of izokibep and 10% receiving placebo.
[0108] As disclosed herein, there are no dose-limiting adverse events (AEs) for izokibep moving from the 2 mg, 20 mg, 80 mg and 160 mg SC dosing, which support the testing of the 160 mg QW and 160 mg Q2W dosing.
[0109] In the first-in-human study in healthy subjects and subjects with psoriasis (Study ABY- 035-001), doses of up to 40 mg IV and SC of izokibep (n = 62) were well tolerated, with no deaths or treatment-related serious AEs (SAEs). [0110] Intravenous administration (single doses up to 40 mg in 46 subjects in total) resulted in the following treatment-emergent AEs (TEAEs) by preferred term: oropharyngeal pain (10.9%), nasopharyngitis (6.5%), diarrhea (4.3%), and headache (4.3%). A further 9 TEAEs were reported, which affected 1 subject each (2.2% each). Subcutaneous administration (single and multiple doses up to 40 mg in 21 subjects in total) resulted in the following TEAEs by preferred term: injection site reaction (61.9%) and injection site pain (28.6%). A further 11 TEAEs were reported, which affected 1 subject each (5.2% each). The majority of the ISRs were of mild intensity and required no treatment or limited therapy.
[0U1] In the Phase 2, 52-week core period in subjects with plaque psoriasis (ABY-035-002), multiple doses of up to 160 mg Q2W SC of izokibep (n = 108) were well tolerated with no deaths or treatment-related SAEs. A total of 65 subjects (60.2%) experienced at least 1 izokibep- related TEAE. The most common izokibep-related TEAEs (n/%) were ISR (42/38.9%), nasopharyngitis (13/12.0%), diarrhea (7/6.5%) and fatigue (6/5.6%) consistent with the first-inhuman study.
[0112] In the Phase 2, randomized, double-blind, placebo-controlled clinical trial in subjects with active PsA (ABY-035-202), doses of 40 mg and 80 mg Q2W were well tolerated. Safety evaluation showed no serious or severe AEs up to Week 16. Treatment-emergent AE rate overall was 52.3% for placebo, 65.9% for 40 mg Q2W and 55.3% for 80 mg Q2W. The most common AEs (> 5% in either arm with active treatment) were ISR or erythema, headache, hyperkalemia, and upper respiratory tract infection. Three patients had AEs of special interest: 2 subjects experienced ISR and 1 subject experienced vulvovaginal candidiasis.
[0113] Following SC administration of single izokibep doses in the first in human study (Study ABY-O35-OO1), median time to maximum observed concentration (tmax) was 60 hours post dose. After reaching maximum observed plasma concentration (Cmax), plasma levels of izokibep declined in an apparent mono- or bi-phasic manner with the geometric mean t’A being 278 hours which was similar to that after IV administration (288 hours). Individual t’A estimates ranged from 199 to 464 hours and 220 to 340 hours for SC and IV treatments, respectively. In general, as assessed by the geometric percent coefficient of variation (CV%) low between-subject variability was noted for area under the concentration-time curve (AUC) extrapolated to infinity (AUCO-oo) and Cmax for both dose routes, with values ranging from 20% to 22% and 14% to 15%, respectively. [0114] Following 40 mg repeated SC doses, Cmax occurred at a median tmax of 48.0 hours post dose on Days 1 and 29 (individual range: 24.0 to 71.0 hours post dose). On Day 85, median tmax was slightly later at 71.6 hours post dose (individual range: 66.6 to 73.1 hours post dose). After reaching Cmax on Day 85, plasma concentrations of izokibep declined in an apparent mono- or biphasic manner with a geometric mean tU of 279 hours with individual patients ranging from 229 to 423 hours. Pre-dose trough izokibep plasma concentrations showed that steady-state was achieved by Day 71, following 5 doses of izokibep administered Q2W. There was evidence of accumulation following repeated dosing by Day 85 with geometric mean accumulation ratio, based on AUC over a dosing interval (AUCO-r), of 1.95, and individual patients ranging from 1.35 to 5.09. Between-patient variability, based on geometric CV%, was moderate on the monitored study days for AUCO-r with values ranging from 29.4% to 36.0%, and low-to-moderate for Cmax with values ranging from 20.4% to 28.8%.
[0115] Izokibep is a biologic drug that binds IL-17A with high affinity and with a potency corresponding to clinically tested monoclonal antibodies in terms of blocking the biological activity of IL-17A. IL-17A inhibitors, including secukinumab at 10 mg/kg and 30 mg/kg and ixekizumab as well as izokibep at doses up to 160 mg SC, do not appear to have dose-limiting AEs.
[0116] Class effects and potential risks seen with other IL-17 inhibitors have not been identified with izokibep. Given small numbers of subjects treated to date, class effects and potential risks of IL-17 inhibitors will be explicitly monitored (i.e., events of special interest) and have been taken into consideration in the development of inclusion and exclusion criteria. These events include Candida infection inflammatory bowel disease (IBD), and suicidal ideation and behavior risk monitoring.
[0117] Non-serious, mild-to-moderate ISRs are the most common AE reported in association with SC administration of izokibep. These are typically self-resolving, however additional measures to mitigate/manage ISRs include the following:
• Allow study drug to warm to room temp prior to administration, about 15 to 20 minutes;
• Administer study drug slowly;
• Use ice/ice packs following study drug administration;
• Rotate sites of administration; avoid injecting the same site twice during any visit;
• Use of oral antihistamines; • Use of acetaminophen or ibuprofen for pain or discomfort; and/or
• Topical corticosteroids may be used for localized erythema, edema or pruritis.
[0118] No genotoxicity or carcinogenicity is foreseen as izokibep is a protein consisting of natural amino acids. However, since no data are available at this stage of clinical development on possible effects on the reproductive system, the following precautionary measure will be taken:
Females of childbearing potential as well as reproductive female partners of male subjects must use an adequate method of contraception while participating in the clinical study until at least 8 weeks after the last dose of study drug. Pregnancy testing will be performed at regular intervals prior to, during treatment, and after the end of treatment (i.e., 8 weeks after last investigational medicinal product (IMP) dosing.
Benefit of disclosed compositions in treating HS in patients who received TNFi
[0119] The potential benefit of izokibep is that it is designed to demonstrate whether treatment is associated with a reduction in the extent of inflammation in patients who have received a TNF-a inhibitor to treat a condition, such as those with moderate to severe HS manifested as a specific reduction in the number of inflammatory nodules and abscesses. As these inflammatory lesions are associated with considerable pain and impairment in quality of life, a reduction in the number of such lesions could directly benefit patients.
[0120] Safety, efficacy, and PK data obtained in clinical trials with izokibep in healthy volunteers and in patients with psoriasis and PsA suggest a favorable benefit-risk profile in conditions such as HS. Based on published data showing efficacy and safety for other IL-17 inhibitors, including in patients with HS, the benefit-risk relationship also in patients with HS appears favorable and justifies clinical development of izokibep in HS as well. Due to its small molecular size as compared to monoclonal antibodies and its binding to albumin, izokibep may have the potential to better reach inflamed tissues and may provide higher exposure relative to monoclonal antibodies.
Izokibep used to treat HS
[0121] Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease causing scarring, abscesses, malodor, and pain. HS typically occurs in areas with high concentrations of sweat glands and is typically accompanied by pain, malodor, drainage, and disfigurement that contribute to disability and a devastating impact on quality of life. Patients with HS miss a greater number of days of work and have increased disability compared to the average population. In 2019, there were an estimated 317,000 HS patients in the U.S., of which 50-60% were moderate-to-severe HS patients. In certain cases of HS, occlusion of hair follicles is a primary pathogenic factor. This is often characterized by cycles of scarring, abscesses, malodor, and pain. It may also result in permanent disfigurement and social stigma. Such a disease may also negatively impact quality of life and earning potential of patients suffering from such a disease.
[0122] A commonly used parameter to track the efficacy of treatment for HS is Hidradenitis Suppurativa Clinical Response (HiSCR) is a reduction from baseline in the total abscess and inflammatory nodule (AN) count, with no increase from baseline in abscess or draining fistula count. For convenience, HiSCR50 indicates > 50% reduction, HiSCR75 indicates > 75% reduction, HiSCR90 indicates > 90% reduction, and HiSCRIOO indicates 100% reduction.
[0123] Adalimumab is a therapy for the treatment of HS. Nonetheless, this therapy has limited impact for patients suffering from HS. Approximately 50% of patients treated with weekly adalimumab reach HiSCR50 at 12 weeks after start of the administration of adalimumab. Moreover, only approximately 40% of the initial responders to treatment of adalimumab continue to benefit up to 36 weeks. In addition, treatment of patients with high body mass index (BMI) is more challenging with adalimumab. In particular, at weeks 12-16, the historical HiSCR75 response rate is 25-46% for adalimumab and 10-17% placebo, whereas HiSCR90, at weeks 12-16 has a 13- 32% response rate for adalimumab, and 0-8% for placebo. HiSCRIOO at weeks 12-16 has not been reported.
[0124] Thus, there is an unmet need for the treatment of HS. Once the dose of adalimumab is doubled, the patients receiving adalimumab have a better response to the drug. This demonstrates the importance of higher exposure to the drugs for treatment of HS. Thus, continued improvements in reduction of abscess formation, pain, and disease progression remain unmet clinical needs for patients suffering from HS.
[0125] In particular, the drug exposure in HS is lower as compared to other inflammatory conditions. For example, FIG. 1 demonstrates the serum adalimumab concentration is lower in HS patients as compared to the Psoriasis patients. In particular, the data in FIG. 1 demonstrates that adalimumab serum concentration was lower in HS patients, despite increased dosing frequency of adalimumab in HS patients as compared to psoriasis patients. A similar observation was made for bimekizumab in Phase II studies with HS patients. In this study, circulating drug levels of bimekizumab were lower than expected in HS patients, especially as compared to pharmacokinetic properties in other populations, supporting the use of higher doses of bimekizumab compared with other immune and inflammatory diseases. Glatt et al., JAMA Dermatol. 2021; 157(11): 1279-1288. These observations underscore the need for increased potency and enhanced tissue penetration.
[0126] Izokibep is a small protein therapeutic designed to inhibit interleukin- 17A (IL-17A) with higher potency and the potential for greater tissue penetration due to its markedly smaller size when compared to traditional monoclonal antibodies.
[0127] Izokibep has enhanced potency as it blocks the homodimeric IL-17A target protein by binding to both sub-units simultaneously with a very high affinity. In certain embodiments, KD for izokibep binding to IL-17A is as low as 0.3 pM. Klint et al. Izokibep - Preclinical Development and First-in-Human Study of a Novel IL-17A Neutralizing Affibody Molecule in Patients with Plaque Psoriasis. mAbs. 2023 (manuscript accepted, in publication). FIG. 2 provides a representation of izokibep bound to the IL-17A homodimer. In particular, the two IL- 17A binding domains bind to the dimeric IL-17A homodimers at the same time, and the two IL17A binding domains are connected by albumin binding domain.
[0128] Advantageously, the presence of albumin binding domain increases the half-life of izokibep. The half-life of izokibep may be a few days. In certain embodiments, the half-life of izokibep is from about 5 to about 20 days. In certain embodiments, the half-life of izokibep is from about 10 to about 15 days. In certain embodiments, the half-life of izokibep is about 12 days. Importantly, as a result of enhanced half-life of izokibep, it can engage with the pharmacological targets for longer duration. Izokibep also has a well-established safety profile. In certain embodiments of the disclosure, izokibep is safe for patients up to 3 years without any observed increased risk of infection or any significant increase in anti -drug antibodies (ADAs). The presence of or a significant increase in ADAs can impact exposure of the drug and/or the clinical response of the drug in the patients.
[0129] In contemporary treatments for HS, exposures of the drugs are lower compared to other inflammatory conditions. Advantageously, the high potency of izokibep to IL-17A, as well as the small molecular size of izokibep, leads to improved tissue penetration and target engagement and therefore provide the potential for differentiated clinically meaningful benefit for patients. In certain embodiments, the size of izokibep is one-tenth (l/10th) of those of typical monoclonal IL- 17A antibodies.
[0130] In certain embodiments, izokibep has quick and therapeutic effects in patients suffering from HS.
Exemplary Methods and Compositions
[0131] In certain aspects, the present disclosure provides methods and compositions for treatment of a condition(s) in patients who have received a TNF-a inhibitor, including patients with one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or pan-uveitis, thyroiditis, and/or vasculitis, via administration of a composition comprising izokibep.
[0132] In more preferred aspects, the disclosure provides methods and compositions used for treatment of a condition selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
[0133] Another aspect of the disclosure provides for pharmaceutical compositions useful in treating conditions in patients who have received prior treatment with a TNF-a inhibitor comprising izokibep or a salt thereof.
[0134] In certain aspects, the current disclosure also provides methods and compositions for treating inflammation of the eye, and in particular, uveitis, in patients who have received a TNF- a inhibitor. In preferred aspects, the TNF-a inhibitor failed to provide an adequate response to the patient’s uveitis and/or the patient is intolerant to a TNF-a inhibitor. In certain aspects, the disclosure provides methods for treating uveitis by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep, and preferably about or exactly 160 mg izokibep or a salt thereof per dose. Unexpectedly, the present Inventors discovered that such a relatively high dose of izokibep, when provided once weekly, once every two weeks, or twice a week is well tolerated and provides efficacious treatment of uveitis who have otherwise received a TNF-a inhibitor therapy. In certain embodiments, izokibep has quick and therapeutic effects in patients who received a TNF- a therapy and are suffering from uveitis.
[0135] Uveitis is a type of eye inflammation, which traditionally described a type of inflammation in the uvea, which includes the iris, ciliary body, and the choroid. Overtime, Uveitis has become used to describe this type of inflammation in any area of the eye. Uveitis results from a heterogeneous collection of disorders with diverse etiologies and pathogenic mechanisms (Prete et al, 2016). Uveitis can be classified, according to the primary anatomical location of the inflammation, into anterior and non-anterior uveitis.
[0136] Non-anterior uveitis can be further classified into intermediate-, posterior- or pan-uveitis (affecting more than 1 eye segment). Symptoms include severe intraocular inflammation, vision impairment with blurred or cloudy vision, floaters-spots in the eye and eye pain.
[0137] In certain aspects, current disclosure also provides methods and compositions for treating Ankylosing spondylitis (AS), and in particular in patients who have received a TNF-a inhibitor. In preferred aspects, the TNF-a inhibitor failed to provide an adequate response to the patient’s AS and/or the patient is intolerant to a TNF-a inhibitor. In certain aspects, the disclosure provides methods for treating AS by administration to a patient a composition comprising between about 150 mg and 170 mg of izokibep, and preferably about or exactly 160 mg izokibep or a salt thereof per dose. Unexpectedly, the present Inventors discovered that such a relatively high dose of izokibep, when provided once weekly, once every two weeks, or twice a week is well tolerated and provides efficacious treatment of AS who have otherwise received a TNF-a inhibitor therapy. In certain embodiments, izokibep has quick and therapeutic effects in patients who received a TNF- a therapy and are suffering from uveitis.
[0138] Ankylosing spondylitis (AS) is a chronic, progressive, inflammatory disease with considerable impact on patient functioning, well-being, and disability. Axial spondyloarthritis (AxSpA) is a type of spondyloarthritis that affects mainly the spine and pelvic joints. In radiographic axial spondyloarthritis (r-AxSpA), the chief symptom is back pain and evidence of fusion on imaging tests. R-AxSpA is chronic, inflammatory disease that impacts the axial skeleton or sacroiliac joints and spine. Non-radiographic axial spondyloarthritis (nr-axSpA) is a type of arthritis in the spine. It causes inflammation, which leads to symptoms like redness, swelling, heat, stiffness, and pain. The condition affects the joints and the entheses, tissues that connect bones to ligaments or tendons.
[0139] In another aspect of the disclosure, the pharmaceutical composition comprises additional excipients. The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide pharmaceutically elegant and palatable preparations.
[0140] Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
[0141] For injection, the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0142] Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure. With proper choice of carrier and suitable manufacturing practice, the compositions of the present disclosure, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.
[0143] The composition may be provided according to a dosing regimen. A dosing regimen may include one or more of a dosage, a dosing frequency, and a duration.
[0144] In one aspect of the disclosure, such compositions are administered to patients who have received a TNF-ot inhibitor for treating one or more condition selected from inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa (HS), hemolytic anemia, juvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or pan-uveitis, thyroiditis, and/or vasculitis, via administration of a composition comprising izokibep. In more preferred aspects, the one or more conditions are selected from HS, axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis.
[0145] Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week. In preferred aspects, doses are provided once weekly, twice weekly, or once every two weeks.
[0146] In another preferred aspect of the disclosure, a pharmaceutical composition comprising izokibep is administered to a patient who has received a TNF-a inhibitor, but has not experienced the desired alleviation of a condition as described herein. In another aspect, there is provided a composition comprising a izokibep, as described herein, and at least one pharmaceutically acceptable excipient or carrier. In one embodiment, said composition further comprises at least one additional active agent, such as at least two additional active agents, such as at least three additional active agents. Non-limiting examples of additional active agents that may prove useful in such a composition are the therapeutically active polypeptides, immune response modifying agents and toxic compounds described herein.
[0147] In another aspect of the disclosure, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered by a subcutaneous injection. a. In another aspect of the disclosure, the pharmaceutical composition comprises about 20 mg to about 400 mg izokibep. b. In another aspect of the disclosure, the pharmaceutical composition comprises about 160 mg izokibep.
[0148] In another aspect of the disclosure, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection once weekly, twice weekly, or once every four weeks. In another aspect of the disclosure, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection is administered for at least 16 weeks. In another aspect of the disclosure, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection is administered for at least 31 weeks. In another aspect of the disclosure, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection is administered for at least 52 weeks.
[0149] In another embodiment, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient who has received prior TNF-a inhibitor therapy. In preferred aspects, the composition is administered once every week. In another embodiment of the, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, every week for 15 weeks or 16 weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every week for 31 weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks for 15 weeks or 16 weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every week for 31 weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks for 31 weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every week for 30 weeks. In another embodiment of the disclosure, a pharmaceutical composition comprising 160 mg izokibep, is administered to a patient, who has received prior TNF-a inhibitor therapy, once every two weeks for 30 weeks.
[0150] In another aspect of the disclosure, the administration of the pharmaceutical compositions comprising izokibep leads to a clinical response as assessed by Hidradenitis suppurativa clinical response (HiSCRl) response after 16 weeks or 52 weeks in subjects with active HS. In a preferred embodiment, the patient suffering from HS achieves a Hi SCR1 response after 16 weeks. In another aspect of the disclosure, the HS patient being administered a pharmaceutical composition comprising izokibep has had an inadequate response to a previous therapy for the treatment of HS. In another aspect of the disclosure, the HS patient being administered a pharmaceutical composition comprising izokibep has had an inadequate response to a previous therapy for the treatment of HS comprising an administration of Janus Kinase (JK) inhibitors.
[0151] In certain embodiments, in the course of clinical trials, thirty (30) participants received 160 mg of izokibep dosed subcutaneously once every week. The patients for the clinical trials may have been selected on the basis of that they were required to have HS lesions in > 2 anatomic areas, with at least one Hurley Stage 11/111; minimum abscess/nodule (AN) count of 3; and inadequate response, intolerance or contraindication to oral antibiotics. The participant demographics were highly consistent with historical studies in the disease and included Hurley Stage II and III patients. In course of clinical trials, HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO were assessed.
[0152] Izokibep demonstrated efficacy in for alleviating conditions of patients suffering from HS. In certain embodiments, week 12 observed HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO rates are > 50, > 40%, > 30% and > 25%, respectively. In certain embodiments, week 12 observed HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO rates were about 65%, 57%, 38% and 33%, respectively. In certain embodiments, week 12 observed HiSCR50, HiSCR75, HiSCR90 and HiSCRIOO rates were about 71%, 57%, 38% and 33%, respectively.
[0153] The data from these clinical trials demonstrated that at 12 weeks after the start of administration of izokibep, 71% of participants in the clinical trials achieved HiSCR50, 57% achieved HiSCR75, 38% achieved HiSCR90, and 33% achieved HiSCRIOO. These therapeutic responses were not previously reported for any other therapeutic agents in this timeframe after the administration of the drug. At HiSCR75 and above, placebo responses are historically minimal.
[0154] In certain embodiments of the disclosure, the safety profile of izokibep was consistent with the anti-IL-17A class, with localized mild-to-moderate injection site reactions (ISRs) being the most common adverse event. In the clinical trials, three (3) serious adverse events (SAEs) were observed in two (2) subjects: inflammatory bowel disease, an exclusionary criterion, in one (1) subject with pre-existing symptoms; and peri-colonic abscess/sepsis in another subject with preexisting symptoms and known diverticulosis. Moreover, there was no evidence of increased risk of infection and there were no Candida events reported through week 12.
[0155] The data demonstrated that izokibep achieved higher order responses, including HiSCRl 00 (z.e., complete clearance of abscesses and inflammatory nodules) in Hurley Stage II and III subjects. Izokibep may provide differentiated efficacy in HS. This is advantageous especially as compared to the other contemporary treatments for HS. These results warrant further investigation in clinical efficacy of izokibep in patients with diseases mediated through IL-17A, especially HS. [0156] As used herein, a "pure isomeric" compound or "isomerically pure" compound is substantially free of other isomers of the compound. The term "pure isomeric" compound or "isomerically pure" denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified structure. In certain embodiments, the weights are based upon total weight of all isomers of the compound.
[0157] As used herein, a "pure stereoisomeric" compound or "stereoisomerically pure" compound is substantially free of other stereoisomers of the compound. Thus, the composition is substantially free of isomers that differ at any chiral center. If the compound has multiple chiral centers, a substantial majority of the composition contains compounds having identical stereochemistry at all of the chiral centers. The term "pure stereoisomeric" compound or "stereoisomerically pure" denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified stereochemistry. In certain embodiments, the weights are based upon total weight of all stereoisomers of the compound.
[0158] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
[0159] Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; N may be any isotopic form, including 14N and 15N; O may be in any isotopic form, including 16O and 18O; and the like.
[0160] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
[0161] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
[0162] "Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.
[0163] " Solvate" refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate"), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the disclosure may be prepared e g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solutionphase and isolable solvates.
[0164] As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H orD), carbon- 13 (13C), nitrogen- 15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the disclosure may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon- 14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as nC, 18F,13O, and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the disclosure.
[0165] " Stereoisomers": It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers", and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, and an atom, such as a carbon atom, is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
[0166] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0167] A "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.
[0168] Disease, disorder, and condition are used interchangeably herein.
[0169] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment").
[0170] In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a cancer. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound, composition, or formulation of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.
[0171] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent, i.e., to produce a reduction in the amount and/or severity of the symptoms associated with that disorder. Therapeutically effective amounts vary with the type and extent of brain damage, and can also vary depending on the overall condition of the subject.
[0172] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
[0173] The izokibep compositions of the disclosure may be formulated for administration by a particular mechanism. The compositions may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration. The compositions may be formulated for administration by injection or on an implantable medical device (e.g., stent or drugeluting stent or balloon equivalents). Preferably, the compositions are formulated for subcutaneous administration.
[0174] The compositions may be formulated a single weekly, bi-weekly, or twice-weekly dosage. The compositions may be formulated to provide the weekly dose of izokibep split up in multiple daily doses, e.g., two, three, four, five, six or more daily doses. The compositions may be provided to the subject according to any dosing schedule, but is preferably once weekly as described herein. [0175] The methods of treating a subject of the present disclosure include providing an izokibep composition, as described above, to the subject. Providing may include administering the composition to the subject. The composition may be administered by any suitable route or means, such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
[0176] The composition may be provided as a single unit dosage. The composition may be provided as a divided dosage.
[0177] The composition may be provided under any suitable dosing regimen. For example, the composition may be provided as a single dose or in multiple doses. Doses may be provided once a week or twice a week over a duration of 1 week, 2 weeks, 3 weeks, 4 weeks, 4 weeks to 8 weeks, 8 weeks to 12 weeks, 12 weeks to 16 weeks, 16 weeks to 20 weeks, 20 weeks to 24 weeks, 24 weeks to 28 weeks, 28 weeks to 32 weeks, 32 weeks to 36 weeks, 36 weeks to 40 weeks, 40 weeks to 44 weeks, 44 weeks to 48 weeks, 48 weeks to 52 weeks, or more than 52 weeks. Multiple doses may be provided within a period of time. For example, multiple doses may be provided over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. The compositions may be provided repeatedly for a specified duration. For example and without limitation, the compositions may be provided for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months or more.
[0178] A pharmaceutical composition containing the izokibep, preferably at 160 mg/dose, may be in a form suitable for oral use, such as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No. 6,214,841 and U.S. Pub. No. 2003/0232877, the contents of which are incorporated herein by reference.
[0179] Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0180] An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the disclosure is encapsulated in an enteric coating.
[0181] Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0182] Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
[0183] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present.
[0184] The pharmaceutical compositions of the disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
[0185] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
EXAMPLES
[0186] The examples provided herein are representative for the dosing regimens disclosed in the disclosure. An exemplary clinical dosing in accordance with the present disclosure is provided below.
[0187] EXAMPLE 1 - treatment of HS axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis in patients that received a TNF-alpha inhibitor
[0188] Izokibep has been investigated in nonclinical and clinical studies including healthy subjects, and subjects with hidradenitis suppurativa (HS). The clinical development plan also includes axial spondyloarthritis, uveitis, psoriasis and psoriatic arthritis. This study investigates izokibep in subjects with active HS, including tumor necrosis factor alpha inhibitor (TNFi) naive subjects, and those who had an inadequate response or intolerance to TNFi, or for whom TNFi is contraindicated. The study is to be 1 of 2 adequate and well-controlled studies to support a claim of efficacy of izokibep in subjects with HS.
Overall Design:
[0189] An overall design of the Study is found in FIG. 3 and the Schedule of Activities (SoA) if shown below.
[0190] This is a Phase 3, pivotal, confirmatory, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of izokibep in subjects with moderate to severe HS. Subjects must have HS lesions present in >2 distinct anatomic areas, one of which must be Hurley Stage II or Hurley Stage III, and a total abscess and inflammatory nodule (AN) count of >5. Subjects with draining fistula count of > 20 at screening are excluded.
[0191] This study will be conducted at study sites globally in North America, Europe, and Asia Pacific. Additional sites and regions may be added during the study.
[0192] Brief Summary
[0193] Approximately 250 subjects with moderate to severe HS will be enrolled.
[0194] Subjects will be screened within 28 days of study drug administration. Subjects meeting eligibility criteria will be randomized 1 : 1 to 1 of 2 treatment groups on Day 1 , and will receive via subcutaneous injection:
[0195] Group 1 (n=125): placebo every week (QW) from Day 1/Week 0 to Week 15, then izokibep 160 mg QW from Week 16 to Week 51.
[0196] Group 2 (n=125): izokibep 160 mg QW from Day 1/Week 0 to Week 51. Randomization will be stratified by prior TNFi use for HS (Yes/No) and Hurley Stage (II or III). The AN count is the sum of inflammatory abscesses and inflammatory nodules. Subjects enrolled with stable concomitant antibiotic use (dosing regimen has been stable for > 4 weeks prior to the first dose of study drug) will be capped at approximately 30%.
[0197] The first dose of study drug (i.e., izokibep or placebo) will be administered on Day 1 (Week 0).
[0198] Randomization will be stratified by prior TNFi use for HS (Yes/No) and Hurley Stage (II or III). The AN count is the sum of abscesses and inflammatory nodules. Subjects enrolled with stable concomitant antibiotic use (dosing regimen has been stable for >4 weeks prior to first dose of study drug) will be capped at approximately 30%. [0199] Subjects will complete study assessments according to the study visits outlined in the SoA. The primary endpoint will be assessed at Week 16. The last dose of study drug will be administered on Week 51.
[0200] An End of Treatment Visit will be conducted at Week 52. A Safety Follow-up Visit will be conducted at Week 59. For subjects that early terminate, the End of Treatment visit should be completed 1 week after last dose of study drug (± 5 days), and Safety Follow-up Visit should be completed 8 weeks after last dose of study drug (± 5 days), where possible.
[0201] The final analysis of primary and secondary endpoints will be conducted after the last subject has had the opportunity to complete Week 16 assessments or early terminates from the study.
[0202] Analysis of data at later timepoints may occur after all subjects have had the opportunity to complete that timepoint.
[0203] Summaries of continuous variables will include mean, median, standard deviation, minimum, and maximum; change from baseline will additionally include standard error. Summaries of dichotomous, categorical, and ordinal variables will include counts and percentages.
[0204] Baseline characteristics and demographics will be summarized by randomized treatment group using the last value obtained before randomization. Efficacy and safety data will be summarized by randomized treatment group during the first 16 weeks of treatment; these data will also be summarized by randomized treatment group over 52 weeks for subjects randomized to receive izokibep during the first 16 weeks, and separately over the last 36 weeks for subjects randomized to receive placebo during the first 16 weeks. Efficacy variables (primary, secondary) will be summarized at each planned collection timepoint. Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs; percent of subjects reporting each TEAE and each SAE) will be summarized.
[0205] Comparisons of efficacy between doses test each dose group of izokibep versus placebo in a single analysis. Response rates will be compared with a stratified test for differences: the strata used for randomization [prior TNFi use for HS (Yes/No) and Hurley Stage (II or III)], using Cochran-Mantel-Haenszel weights. P-values for comparing izokibep versus placebo are reported, with a 2-sided 95% confidence interval on the difference in response rates. Continuous endpoints will be analyzed with a longitudinal model using values at each post-randomization timepoint.
[0206] The primary efficacy comparison of hidradenitis suppurativa clinical response (HiSCR75), which is a 75% reduction in AN count with no increase in the number of abscesses or the number of draining fistulae. The AN count is the sum of the number of abscesses and the number of inflammatory nodules. Testing will be reported at a = 0.05, 2-sided.
[0207] Secondary endpoints are tested analogously. The sequence will consider the secondary endpoints in a pre-specified order, comparing izokibep to placebo. As long as all prior tests showed statistically significant differences compared to placebo, testing will proceed using a = 0.05. If any comparison (primary or secondary) results in p > 0.05, p-values for subsequent comparisons will be reported but not considered conclusive.
[0208] The primary efficacy analyses will use the treatment policy estimands, using all available data from all randomized subjects regardless of treatment compliance. Subjects will be analyzed in the group to which they are randomized. Subjects who do not have an evaluation for a dichotomous endpoint at a given timepoint will be imputed as non-responders. Subjects who do not have a continuous measure at a given timepoint will have available data at other timepoints included in the longitudinal model, resulting in an analysis that is robust to data that are missing or completely at random. Sensitivity and supplementary analyses will be used to assess the impact of missing data assumptions.
[0209] Incidence of TEAEs over the first 16 weeks will be summarized by randomized treatment group. No p-values will be reported. Incidence will also be summarized over all 52 weeks for subjects randomized to receive izokibep, and summarized over the last 36 weeks for subjects randomized to receive placebo for the first 16 weeks. Serious adverse events will be summarized analogously. Subjects will be summarized for safety according to treatment actually received.
[0210] Available pharmacokinetic data will be summarized by dose group of izokibep.
[0211] At Week 16, HiSCR75 response rates are 15% for placebo and 35% for izokibep. With 125 subjects receiving placebo and 125 subjects receiving izokibep, this study has 94% power for the true difference in HiSCR75 response rates of 20 percentage points.
Benefit of disclosed compositions in treating HS in patients who received TNFi [0212] The potential benefit of izokibep is that it is designed to demonstrate whether treatment is associated with a reduction in the extent of inflammation in patients who have received a TNF-a inhibitor to treat a condition, such as those with moderate to severe HS manifested as a specific reduction in the number of inflammatory nodules and abscesses. As these inflammatory lesions are associated with considerable pain and impairment in quality of life, a reduction in the number of such lesions could directly benefit patients.
[0213] A 16-week, placebo-controlled period does not entail any additional risk of irreversible harm to subjects. Specified analgesics are permitted for HS-associated pain, and for subjects with increases in abscess and inflammatory node counts (2: 150% of Day 1 abscess and inflammatory nodule [AN] count), investigators may provide permitted antibiotic rescue therapy. Additionally, subjects with a draining fistula count > 20 at screening or Day 1 are excluded from enrolling in the study to exclude the most severe forms of the disease that may place subjects at a higher risk of disease-related complications.
Overall Benefit-Risk Conclusion
[0214] The following considerations are important for the benefit-risk assessment:
« Only subjects with moderate to severe HS will be enrolled. Subjects must have HS lesions present in at least 2 distinct anatomic areas one of which is Hurley Stage II or Hurley Stage III and AN count of 2 5. Subjects with draining fistula count of > 20 at screening or Day 1 will be excluded.
« The inclusion and exclusion criteria will ensure that patients who might be predisposed to a higher risk of drug-related TEAEs are either excluded or identified and treated with caution. Class effects seen with other IL- 17 inhibitors have been taken into account when designing the eligibility criteria. Subjects with active infections or with a history of autoimmune, chronic inflammatory, or connective tissue disease will be excluded from participating in the study.
® Subjects will be monitored at the study site for at least 1 hour after administration of izokibep at designated visits.
« After enrollment and through the end of the study if the subject's AN count is 2 150% of Day 1 AN count, antibiotic rescue medication is permitted. « Participation in the trial is voluntary. Each subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the patient is otherwise entitled.
[0215] Taking into account the measures taken to minimize risk to subjects participating in this study, and the lack of clear dose-limiting AEs associated with izokibep, the pre-existing data on the effects of IL-17 inhibitors in hidradenitis, the potential risks identified in association with izokibep are justified by the anticipated benefits that may be afforded to subjects with HS.
Scientific Rationale
[0216] The design of this clinical study was chosen to evaluate the efficacy of izokibep in the treatment of subjects with moderate to severe HS.
[0217] The primary aim of the study is to evaluate the efficacy of izokibep administered SC 160 mg QW for the treatment of active HS. The primary endpoint of HiSCR75 response will be evaluated after all subjects have the opportunity to complete the 16-week, placebo-controlled study period. After Week 16, subjects randomized to placebo will receive blinded active treatment (izokibep 160 mg QW) until Week 51. Long-term efficacy beyond Week 16 will be explored up to Week 52 and safety will be explored up to the End of Study visit at Week 59.
[0218] Standard statistical procedures will be utilized in this study. Efficacy measurements in this study have been selected or designed to assess disease activity in subjects with active HS. All clinical and laboratory procedures in this study are standard and generally accepted.
[0219] Males and females with HS who meet all inclusion criteria and who do not meet any of the exclusion criteria are eligible for this study. The population being studied is representative of that seen in clinical practice. This ensures the activity of izokibep can be evaluated across a distribution of disease severity in the study.
Predicted Exposure at Steady State for 160 mg Izokibep SC QW
Figure imgf000042_0001
Figure imgf000043_0002
[0220] The doses of izokibep used in this study supports the maximum likelihood of demonstrating the potential efficacy for izokibep in subjects with HS within an acceptable safety profile.
[0221] Measures have also been taken to ensure the well-being of subjects by applying appropriate inclusion and exclusion criteria to recruit a broad population that is most likely to benefit from treatment, while excluding subjects with an unacceptable risk to enter the study.
[0222] Further, during the study, measures are in place to monitor the safety of subjects on a regular dent DMC will also review the data on an ongoing basis.
[0223] The following table summarizes the objectives and endpoints of this study.
Figure imgf000043_0001
Figure imgf000044_0001
Primary Estimands
[0224] Estimands are discussed in greater detail herein.
[0225] The components of the estimand to address the primary objective are as follows: Treatment: izokibep versus placebo; Population of interest: subjects with HS who meet all inclusion/exclusion criteria; Variable of interest: achievement of HiSCR75 after 16 weeks of treatment; Summary measure: response rate, achievement of HiSCR75 (Yes/No); and Intercurrent event (ICE) handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
Secondary Estimands
[0226] The 5 components of the estimand to address each secondary objective are as follows.
[0227] First secondary objective:
• Treatment: izokibep versus placebo.
• Population of interest: subjects with HS who meet all inclusion/exclusion criteria.
• Variable of interest: Percentage of subjects achieving HiSCR90 at Week 16. Summary measure: response rate, achievement of Hi SCR90 at Week 16 (Yes/No).
• ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0228] Second secondary objective:
• Treatment: izokibep versus placebo.
• Population of interest: subjects with HS who meet all inclusion/exclusion criteria.
• Variable of interest: Percentage of subjects achieving HiSCRIOO at Week 16. Summary measure: response rate, achievement of HiSCRIOO at Week 16 (Yes/No). • ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0229] Third secondary objective:
[0230] Treatment: izokibep versus placebo.
• Population of interest: subjects with HS who meet all inclusion/exclusion criteria
• Variable of interest: Percentage of subjects achieving HiSCR50 at Week 16
• Summary measure: response rate, achievement of HiSCR50 at Week 16 (Yes/No).
• ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0231] Fourth secondary objective
• Treatment: izokibep versus placebo.
• Population of interest: subjects with HS who meet all inclusion/exclusion criteria
• Variable of interest: change in HS flares after 16 weeks of treatment.
• Summary measure: response rate, improvement in HS flare occurrence (Yes/No).
• ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0232] Fifth secondary objective
• Treatment: izokibep versus placebo.
• Population of interest: subjects with HS who meet all inclusion/exclusion criteria
• Variable of interest: change in Dermatology Life Quality Index (DLQI) after 16 weeks of treatment.
• Summary measure: mean change from baseline in DLQI
• ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0233] Sixth secondary objective:
• Treatment: izokibep versus placebo. • Population of interest: subjects with HS who meet all inclusion/exclusion criteria and with baseline Hurley Stage II.
• Variable of interest: achievement of AN count of 0, 1, or 2 at Week 16. Summary measure: response rate, achievement of AN count of 0, 1, or 2 at Week 16 (Yes/No). ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0234] Seventh secondary objective:
• Treatment: izokibep versus placebo.
• Population of interest: subjects with HS who meet all inclusion/exclusion criteria and have a baseline numeric rating scale (NRS) >4.
• Variable of interest: change in NRS score after 16 weeks of treatment.
• Summary measure: response rate, reduction in NRS scores, specifically, at least a 3- point reduction from baseline in NRS in Patient Global Assessment of Skin Pain at its worst, at Week 16 (Yes/No).
• ICE handling: treatment policy strategy, with all subjects included in the analysis regardless of treatment discontinuation, concomitant medication/rescue medication, protocol deviations, or other actions.
[0235] The study will include the following parts:
[0236] Part A: Single-arm, open-label, proof-of-concept investigation to explore preliminary efficacy and safety of izokibep in adult subjects with moderate to severe hi dradenitis suppurativa (HS).
[0237] Part B: Randomized, double-blind, placebo-controlled, parallel group, dose-finding investigation to evaluate the efficacy, safety, and immunogenicity of izokibep in subjects with moderate to severe HS.
[0238] Inclusion Criteria
1. Subject or legally authorized representative has provided signed informed consent including consenting to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Subject must be > 18 (or the legal age of consent in the jurisdiction in which the study is taking place) and < 75 years of age, at the time of signing the informed consent. Diagnosis of hidradenitis suppurativa (HS) for > 1 year prior to first dose of study intervention. Hidradenitis suppurativa lesions present in > 2 distinct anatomic areas (e.g., left and right axilla; or left axilla and left inguino-crural fold), one of which is Hurley Stage II or Hurley Stage III at screening and Day 1 prior to enrollment/randomization. A total abscess and inflammatory nodule (AN) count of > 5 at screening and Day 1 prior to enrollment/randomization. Subject must have had an inadequate response to oral antibiotics (defined as > 3-month treatment with an oral antibiotic for treatment of HS) OR exhibited recurrence after discontinuation to, OR demonstrated intolerance to, OR have a contraindication to oral antibiotics for treatment of their HS as assessed by the investigator through subject interview and review of medical history. Must agree to use daily (throughout the duration of the study) one of the following over- the-counter topical antiseptics on their body areas affected with HS lesions: chlorhexidine gluconate, triclosan, benzoyl peroxide, or diluted bleach in bathwater or as otherwise deemed acceptable by a medical monitor. Subject must be willing to complete a daily skin pain diary 7 consecutive days prior to Day 1; if skin pain diaries are not completed for at least 3 of the 7 consecutive days prior to the Day 1 visit, the subject may not be enrolled/randomized. No known history of active tuberculosis (TB). Subject has a negative TB test at screening, as defined by1:
Negative QuantiFERON test OR Negative purified protein derivative (PPD) test (< 5 mm of induration at 48 to 72 hours after the test is placed). Subjects with a positive PPD test and a history of Bacillus Calmette-Guerin vaccination will be allowed with a negative QuantiFERON test.
Subjects with a positive QuantiFERON test are allowed if all of the following is satisfied: No symptoms of TB as determined by the investigator.
Documented history of adequate prophylaxis initiation prior to receiving study drug per local guidelines.
No known exposure to a case of active TB after most recent prophylaxis (if previously treated). No evidence of active TB on chest radiograph within 3 months prior to first
For indeterminate QuantiFERON test, subjects are permitted to retest once. If retest determines indeterminate, subject may be randomized if all of the following is satisfied:
No symptoms of TB as determined by the investigator.
No known exposure to a case of active TB after most recent prophylaxis.
No evidence of active TB on chest radiograph within 3 months prior to first dose of study drug.
Deemed to be low risk per risk determination questionnaire and medical monitor review
1 T-SPOT TB test may be used to establish eligibility if agreed upon with the medical monitor.
11. Male and female subjects:
Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male subjects: Male subjects are eligible to participate if they agree to the following during the study drug period and for at least 8 weeks after the last dose of study drug:
Refrain from donating semen, plus either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
Must agree to use contraception/barrier as detailed below:
Agree to use a male condom (and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.
Female subjects: A female subject is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
Is a woman of nonchildbearing potential as defined in the protocol.
OR
Is a WOCBP and uses a contraceptive method that is highly effective, with a failure rate of < 1%, as described in the protocol during the study drug period and for at least 8 weeks after the last dose of study drug. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study drug.
A WOCBP must have a negative highly sensitive serum pregnancy test at screening and a negative urine pregnancy test on Day 1 prior to the first dose of study drug.
[0239] Exclusion Criteria
1. Draining fistula count of > 20 at screening or Day 1 prior to enrollment/randomization.
2. Outpatient surgery < 8 weeks prior or inpatient surgery < 12 weeks prior to enrollment/randomization.
3. Other active skin disease or condition (e.g., bacterial, fungal or viral infection) that could interfere with study assessments.
4. History of active IBD.
OR
Any of the following symptoms (of unknown etiology) or any signs or symptoms within the last year that in the opinion of the investigator may be suggestive of IBD, with fecal calprotectin > 500 pg/g; OR if fecal calprotectin > 150 to < 500 pg/g without confirmed approval from a gastroenterology consultation that an IBD diagnosis is clinically unlikely when the following clinical signs and symptoms are present: a. prolonged or recurrent diarrhea b. prolonged or recurrent abdominal pain c. blood in stool
5. Chronic pain not associated with HS (e g., fibromyalgia).
6. History of major autoimmune, chronic inflammatory, or connective tissue disease (e.g., rheumatoid arthritis, psoriasis, psoriatic arthritis, axial spondyloarthritis, system lupus erythematosus, inflammatory bowel disease (IBD)) other than HS.
7. History of demyelinating disease (including myelitis) or neurological symptoms suggestive of demyelinating disease.
8. Malignancy within 5 years except treated and considered cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer, or in situ breast ductal carcinoma. The subject is at risk of self-harm or harm to others as evidenced by past suicidal behavior or endorsing items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) assessed at screening. Subjects with major depressive disorder are permitted in the study if they are considered by the investigator to be stable and are taking no more than 1 medication. If on medication for major depressive disorder, subjects must have been on a stable antidepressant dose for at least 3 months prior to the first dose of study drug and agree to continue for the duration of the study or as indicated by their treating psychiatrist. History or evidence of any clinically significant disorder (including psychiatric), condition, or disease that, in the opinion of the Investigator, may pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. Active infection or history of infection as follows:
• Any active infection for which oral anti-infectives (antibiotics, antivirals, antifungals) were used < 14 days prior to first dose of study intervention (except for the use of a stable dose allowable antibiotics [doxycycline or minocycline only] for HS).
• A serious infection requiring hospitalization or IV anti-infectives (antibiotics, antivirals, antifungals) < 30 days prior to first dose of study intervention.
• Recurrent or chronic infections or other active infections that in the opinion of the investigator might cause this study to be detrimental to the subject. Candida infection requiring systemic treatment within 3 months prior to first dose of study drug. Tuberculosis or fungal infection seen on available chest x-ray taken < 3 months of screening or at screening (Exception: documented evidence of completed treatment and clinically resolved). Known history of human immunodeficiency virus (HIV) or positive HIV test at screening. Previous exposure to izokibep or any other IL- 17 inhibitor and IL- 17 receptor inhibitors (e.g., secukinumab, ixekizumab, bimekizumab, brodalumab). Prior exposure to biologies that had a potential or known association with progressive eukoencephalopathy (i.e., natalizumab [Tysabri], rituximab [Rituxan], orefalizumab [Raptiva]). Exposure to TNF-a inhibitors, TL-1, IL-12, IL-23, or IL-12/23 receptor inhibitors within 5 half-lives prior to first dose of study drug 18. Exposure to any of the following:
• Exposure to the following < 12 weeks prior to first dose of study drug
• Other experimental or commercially available biologic or biosimilar therapies (within 12 weeks or 5 half-lives, whichever is longer).
• IV gamma-globulin or Prosorba column therapy.
• Exposure to the following < 4 weeks prior to first dose of study drug
• Janus-kinase (JAK) inhibitors (e.g., tofacitinib, upadacitinib)
• Oral or injectable corticosteroids (including intralesional injections)
• Cyclosporine, azathioprine, tacrolimus
• Other systemic treatments for autoimmune/inflammatory conditions not listed above or below (e.g., mycophenolate mofetil, retinoids, fumarates, apremilast, or phototherapy [e.g., psoralen plus ultraviolet-A radiation ultraviol et-A radiation, ultraviol et-B radiation]), except for allowable stable dose antibiotics (doxycycline or minocycline).
• Laser or intense pulse light therapy in anatomic areas of HS lesions
19. Exposure of the following < 2 weeks prior to first dose of study drug: Prescription topical therapies; Opioid analgesics; Non-oral concomitant analgesics (e.g., IV, SC).
[0240] For subjects entering study with a permitted oral antibiotic treatment (doxycycline or minocycline only) for HS: not on a stable dose for > 4 weeks prior to first dose of study drug.
[0241] For subjects entering study with oral, non-opioid analgesics: not on a stable dose for >5 days prior to first dose of study drug. Exception is acetaminophen is allowed <2 g per day.
[0242] Required or is expected to require, opioid analgesics for any reason (excluding tramadol) during the study.
[0243] History of hypersensitivity or allergy to izokibep or its excipients.
[0244] Received live vaccination <12 weeks prior to dosing or scheduled to receive a live vaccine < 12 weeks following the last dose of study drug.
[0245] Participating in another clinical study or participated in a clinical study involving administration of an IMP within the following time period prior to dosing: 12 weeks, five halflives, or twice the duration of the biological effect of the IMP (whichever is longer). [0246] Positive hepatitis B surface antigen or detected sensitivity on the hepatitis B virus DNA polymerase chain reaction qualitative test for hepatitis B core antibodies/Hepatitis B surface antibodies positive subjects OR positive Hepatitis C virus antibody test at screening.
[0247] Laboratory abnormalities at screening:
• Hemoglobin < 9 g/dL
• Platelet count < 100 000/mm3
• White blood cell count < 3000 cells/mm3
• Aspartate aminotransferase and/or alanine aminotransferase > 2.5 times the upper limit of normal
• Moderate or severe renal impairment (i.e., creatinine clearance < 60 mL/min) (Modification of Diet in Renal Disease formula)
• Note: Laboratory assessments due to value(s) out of range due to sampling error or that could be within range with repeat sampling may be repeated up to 2 times.
[0248] Any other laboratory abnormality that in the opinion of the investigator will pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
[0249] Previously enrolled, randomized to or withdrawn from this study.
[0250] Active substance abuse (drug or alcohol) within 24 weeks prior to first dose of study drug, as determined by the investigator.
[0251] Any condition that compromises the ability of the subject to give written informed consent, or the subject’s unwillingness or inability to comply with study procedures.
[0252] Lifestyle C onsiderations: The investigator should encourage subject to limit alcohol consumption to < 2 per day, < 7 alcoholic drinks per week. An alcoholic drink is defined as a 6 oz (175 mL) glass of wine, a 1 oz (30 mL) glass of hard liquor (e.g., whiskey), or an 8 oz (250 mL) glass of beer.
[0253] Screen Failures: Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently enrolled/randomized to the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs. [0254] Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened up to 2 times (i.e., total of 3 screens including initial screen).
[0255] Criteria for Temporarily Delaying Dosing: Subject should be dosed within the window as detailed in the SoA. All missed or delayed doses should be documented. If the investigator determines a subject should not be dosed within the defined window for a safety reason (e g., an AE, SAE), then a missed dose should be recorded.
[0256] COVID-19-related Precautions: Risk mitigation measures, including COVID-19-related precautions and procedures (including SARS-CoV-2 testing/screening) will be implemented based on the prevailing situation during the study conduct, at the investigator’s discretion, and in accordance with local and institutional guidelines as applicable. Subjects should be routinely monitored for any AEs at every visit, including signs or symptoms of infection. Should subjects demonstrate any symptoms or AEs (including known COVID-19 symptoms or tested positive for COVID-19), the symptoms or AEs will be reported to the site as per study procedures and assessed by the investigator. As with any AEs, AE data will be collected on the appropriate electronic case report form (eCRF).
[0257] If a subject has received, or is planning to receive, COVID-19 vaccination, the investigator should refer to vaccine considerations in eligibility criteria and concomitant medications requirements in the protocol.
Study Drug(s) and Concomitant Therapy
[0258] Study drugs are all pre-specified, investigational and non-IMPs, medical devices and other interventions (e.g., surgical and behavioral) intended to be administered to the study subjects during the study conduct.
Figure imgf000053_0001
Figure imgf000054_0001
Dosage, Administration and Schedule
[0259] Study drug (izokibep 160 mg QW or placebo) are dosed by SC injection as described below. Study drug vials for placebo and izokibep are visually indistinguishable. Study drug doses are fixed and are not adjusted for individual subjects during the study. Throughout treatment period, 2 SC injections are given for each study drug administration. The anatomical sites for administration of study drug are the upper arm, upper thigh, or abdomen.
[0260] At the study site, only authorized investigational site study staff members administer study drug. Subjects are monitored for 1 hour after the first 2 study drug administrations at Visits Day Week 0, Week 1, Week 16, and Week 17.
Group 1: placebo QW from Day 1/Week 0 to Week 15, then izokibep 160 mg QW from Week 16 to Week 51
Group 2: izokibep 160 mg QW from Day 1/Week 0 to Week 51
Preparation, Handling, Storage, and Accountability
[0261] The investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all study drug received, and any discrepancies are reported and resolved before use of the study drug. Only subjects randomized in the study may receive study drug. All study drug must be stored prior to dispensing in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff.
[0262] The investigator, institution, or the head of the medical institution (where applicable) is responsible for study drug accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition records).
Measures to Minimize Bias: Randomization and Blinding
[0263] Before subjects begin participation in any study-specific activities/procedures, the sponsor or
[0264] designee requires a copy of the site’s written Institutional Review Board (IRB)/Independent
[0265] Ethics Committee (IEC) approval of the protocol, ICF, and all other subject information and/or recruitment material, if applicable. All subjects must personally sign and date the ICF before the commencement of study-specific activities/procedures.
[0266] A subject is considered enrolled when the investigator decides that the subject has met all eligibility criteria and registered the subject as enrolled/randomized within the Interactive Voice/Web Response System (IXRS). The investigator is to document this decision and date in the subject’s medical record. The screening period starts when the subject signs and dates the ICF and ends when the subject is enrolled/randomized, or screen failed. The screening period is up to 28 days. Certain initial screening period procedures may be repeated during the original initial screening period. (Note: Repeating procedures during the original initial screening period is a part of screening and is not considered “rescreening.”) These procedures include laboratory assessments due to value(s) out of range due to potential sampling error or that could be within range with repeat sampling. [0267] Laboratory value(s) out of range due to sampling error or that might be within range after medically appropriate supplementation may be repeated up to 2 times within the screening window before the subject is considered a screen failure.
[0268] All subjects entering the screening period for the study receive a unique subject identification number assigned by the IXRS system. This number identifies the subject throughout the clinical study and is used on all study documentation related to that subject. The subject identification number remains constant throughout the entire clinical study; it is not changed after initial assignment, including if a subject is rescreened.
[0269] The subject identification number consists of 12 digits that correspond to the site number (9 digits) plus the sequential number (3 digits) as follows:
[0270] Site number (first 9 digits)
First 3 digits correspond to the last 3 digits of the study protocol number (i.e., 103 in the example below)
Middle 3 digits correspond to the 3-digit ISO 3166-1 number code for the country (e.g., US country code = 840; for country codes with only 2 digits, a lead “0” is added)
Last 3 digits are sequential numbers given to sites within a country (e.g., for a US site = 103840001)
[0271] Sequential numbering of subjects within a site (last 3 digits)
The last 3 digits are sequential numbers assigned by IXRS within a site (e.g., for US Site 103840001, their first subject = 103840001001)
[0272] A subject who is determined to be ineligible is registered as a screen fail in the IXRS system.
Rescreening
[0273] Investigators may rescreen a subject if the investigator is reasonably certain that reasons for screen failure will be resolved prior to or during a repeat screening attempt. Reasons to rescreen may include but are not limited to the following:
[0274] Laboratory value(s) out of range due to sampling error or that might be within range after medically appropriate supplementation. (Note: Before screen failing and then rescreening the subject, efforts should be made to repeat the laboratory assessment(s) during the original initial screening period). [0275] The subject has a medical condition that can be stabilized or resolved prior to the repeat screening/rescreening attempt, or
[0276] Additional time is required following the subject’s last dose of an excluded medication.
[0277] Investigators are encouraged to consult with the medical monitor prior to rescreening subjects for other reasons.
[0278] A subject provides informed consent prior to the initiation of any rescreening procedures only if 30 or more days have elapsed since the date of the subject’s initial informed consent. The subject enters into rescreening in the IXRS system, and all screening procedures are repeated except as noted in the inclusion/exclusion criteria. A subject is screened up to 3 times (i.e., no more than 2 rescreens). Near to the end of study enrollment, sites are or may be notified when no additional subjects will be screened or rescreened.
[0279] If a subject rescreens, a chest x-ray does not need to be repeated if a previous chest x-ray was performed < 3 months prior to day 1.
[0280] If a subject rescreens, hepatitis, TB, HIV, urinalysis, and electrocardiogram (ECG) tests do not need to be repeated if a previous test was performed < 60 days prior to day 1.
Treatment A ssignment/ Randomization
[0281] Subjects are randomized to the study drug or placebo (in a 1 : 1 ratio) on Day 1 by the IXRS system. The subject, site personnel, and sponsor/Contract Research Organization (CRO) study personnel and designees are blinded to the randomization treatment group assignment (i.e., izokibep or placebo). The randomization dates are documented in the subject’s medical record. [0282] Randomization is stratified by prior TNFi use for HS (Yes/No) and Hurley Stage (II or III). Izokibep and matching placebo is visually indistinguishable to prevent unblinding during preparation or administration of study material.
Site Personnel Access to Individual Treatment Assignments
[0283] A subject’s treatment assignment should be unblinded only when knowledge of the treatment is essential for the further management of the subject in this study. Unblinding at the study site for any other reason is considered a protocol deviation. The investigator is strongly encouraged to contact the medical monitor before unblinding any subject’s treatment assignment but must do so within 1 working day after the unblinding event. If an SAE requires an expedited regulatory report to be sent to 1 or more regulatory agencies, sponsor/designee’s safety staff may unblind the intervention assignment for the subject. A copy of the report, identifying the subject’s intervention assignment, may be sent to that regulatory agency in accordance with local regulations.
Study Drug Compliance
[0284] When subjects are dosed at the site, they receive study drug directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic is recorded in the source documents.
[0285] After Week 4, qualified subjects may perform home dosing of study drug. Site staff administer the first 2 doses of study drug and train the subject on handling and self-administration of study drug during those study visits. Prior to beginning self-administration, the subject needs to self-administer the following 2 doses of study drug at the site and demonstrate competency prior to being allowed to perform home dosing. Subject’s caregiver or designee can also be trained on home dosing based on subject’s preference. Only those subjects/caregivers or designees who demonstrate competency to perform home dosing are allowed to do so; otherwise, the subject needs to return to the site for all study drug administrations.
[0286] When study drug(s) is administered at home by the subject/caregiver, compliance with study drug is assessed at each visit. Compliance will be assessed by review of the subject dosing diary during the site visits and documented in the source documents and relevant form. Deviation(s) from the prescribed dosage regimen should be recorded and reported to sponsor (or designee).
[0287] A record of the quantity of study drug dispensed and administered to each subject is maintained and reconciled with study drug and compliance records. Study drug dose dates, including study drug delays are also recorded. Partial dose administration will be explained.
Dose Modification
[0288] No dose modifications are allowed in the study.
Continued Access to Study Drug after the End of the Study
[0289] There is no plan to continue access to study drug after the end of study. The choice of further therapy for HS at the end of the clinical trial depends on the patient's individual needs and is left at the physician's discretion.
Overdose
[0290] Excessive dosing (beyond that prescribed in this protocol and including overdose) should be recorded in the case report form (CRF). Any SAE or non-serious AE associated with excessive dosing must be followed as any other SAE or non-serious AE. These events are only considered AEs or SAEs if there are associated clinical signs and symptoms or if the act of taking the excess medicine itself is an AE or SAE (e.g., suicide attempt).
Prior and Concomitant Therapy
[0291] Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the patient is receiving at the time of enrollment or receives during the study is recorded along with: z. reason for use ii. dates of administration including start and end dates
Hi. dosage information including route, dose and frequency.
[0292] Concomitant medications should be used in alignment with the approved label in the respective country, and per doses as outlined below.
[0293] The medical monitor should be contacted if there are any questions regarding concomitant or prior therapy.
Prior Therapies
[0294] Any treatments for HS since initial diagnosis (as determined through medical history records or through subject interview) prior to study entry are recorded in the source documents and on the CRF, along with the reason for discontinuation. A detailed history of prior antibiotic and biologic (including but not limited to TNF-alpha inhibitors, IL-1, IL-12, IL-23, or IL-12/23 receptor inhibitors) use, response and reason for discontinuation is collected.
Concomitant Therapies
[0295] Upon initiation or discontinuation of investigational product, investigators should consider potential effects on metabolism of cytochrome P450 substrates with narrow therapeutic indices including, but not limited to, methotrexate, tacrolimus, cyclosporine, certain tricyclic antidepressants (including amitriptyline and nortriptyline), baricitinib, warfarin and tamoxifen. The concomitant medications/treatments in the following sections are permitted during the study. Antiseptic Therapy
[0296] Subjects are required to use an antiseptic wash on their HS lesions daily or at a minimum of 3 days a week. Antiseptic wash use should be consistent during the study. Allowable antiseptic washes are limited to one of the following: chlorhexidine gluconate, triclosan, benzoyl peroxide, or dilute bleach in bathwater. If a different antiseptic wash is required during the study, the medical monitor should be consulted.
Wound Care
[0297] Concomitant use of wound care dressings on HS wounds is allowed; however, options are limited to alginates, hydrocolloids, and hydrogels. If a different option for wound care is required during the study, the medical monitor should be consulted.
Analgesic Therapy
[0298] For a subject entering the study on oral non-opioid analgesic, the dose must be stable for >5 days. For a non-HS medical condition (e.g., osteoarthritis), the subject may continue the analgesic, provided the dose is stable for 5 days prior to the first dose of study drug and is anticipated to remain stable throughout study participation. If a subject's pain (HS-related or non- HS-related) worsens after Day 1, they may initiate analgesic therapy at any time as follows:
[0299] For HS-related pain, permitted analgesics are limited to: i. Ibuprofen (at a dose of up to 800 mg by mouth every 6 hours) not to exceed 2.0 grams/per 24 hours; AND/OR acetaminophen/paracetamol as per local labeling. ii. If HS-related pain is uncontrolled with ibuprofen or acetaminophen/paracetamol at the above dosing regimens after the Day 1 visit, subjects can be prescribed tramadol (at a dose of up to 100 mg po every 4 hours), not to exceed 400 mg per 24 hours. iii. From screening through Week 16, subjects complete a daily diary of their analgesic use. From Week 16 through Week 59, subjects are required to tell site staff if they took any analgesics within 24 hours of their study site visit. All analgesics and dose adjustments are captured in the source and on the appropriate CRF. iv. Subjects are encouraged not to take analgesics 12 hours prior to a study visit.
[0300] For non-HS-Related Pain: i. Opioid analgesics are prohibited. ii. All other analgesics (including tramadol) are allowed at the recommended or prescribed dose.
Antibiotic Therapy [0301] In approximately 30% of subjects, concomitant antibiotic use is permitted if dosing regimen has > 4 weeks prior to first dose of study drug, and dosing regimen is maintained through the placebo-controlled period (Week 16 assessment). Antibiotics taken on an ‘as-needed’ basis are not considered a stable dose.
[0302] Permitted oral concomitant antibiotics include: i. Oral: doxycycline (at a dose of up to 100 mg twice daily [BID]); minocycline (at a dose of up to 100 mg, BID). z/. If another oral concomitant antibiotic for HS is medically necessary at the time of enrollment/randomization, the medical monitor must be contacted for approval. If systemic antibiotics are used concomitantly, the dose should remain stable and constant.
[0303] For non-HS-related AEs requiring antibiotic use:
Hi. Concomitant antibiotic use for the treatment of an AE other than HS may be permitted per standard of care (e.g., for treatment of pneumonia, tonsillitis) and should be captured and documented appropriately.
Lesion Intervention
[0304] In the event that an acutely painful lesion occurs that requires an immediate intervention, the investigator will have the option to perform protocol-allowed interventions. Only 2 types of interventions are allowed: injection with intralesional triamcinolone acetonide suspension (at a concentration of up to 5 mg/mL, up to 1 cc) and incision and drainage.
[0305] If incision and drainage is performed, the required over-the-counter antiseptic wash should continue to be used. New systemic and topical therapies following incision and drainage (including antibiotics), are prohibited. Concomitant use of wound care dressings is allowed; however, options are limited to alginates, hydrocolloids, and hydrogels.
[0306] Subjects should continue using any ongoing oral and topical therapies (including antibiotics, with the constraints as described herein) during the study.
[0307] Concomitant medications associated with the lesion intervention(s) must be captured in the source and on the appropriate CRF.
[0308] A total of 2 protocol-allowed interventions are permissible up until Week 16 visit. An intervention can occur on maximally 2 different lesions at the same or different visits or on the same lesion at 2 different study visits. The same lesion cannot be treated 2 times at the same visit. If a subject requires more than 2 interventions within the first 16 weeks, then they must be discontinued from study drug. After Week 16, maximally 2 interventions every 4 weeks are permitted. If a subject requires more than 2 interventions within a 4-week period or has 2 of the same interventions on the same lesion within that period, then he or she must be discontinued from the study drug.
[0309] All study visit evaluations must occur before any interventions are performed. Any lesion that undergoes an intervention will be documented in the source documents. The site will be required to count any lesion that undergoes an intervention as permanently present from the date of the intervention and must account for it in the source documents and on the appropriate CRF.
Prohibited Medications
[0310] The following medications are prohibited from enrollment through 2 weeks after the last dose of study drug:
• All other biologic therapies with a potential therapeutic impact on HS including but not limited to TNF-alpha inhibitors, IL-1, IL- 12, IL- 17, IL-23, or IL- 12/23 inhibitors Any other immunomodulatory therapy (e.g., cyclosporine, azathioprine, tacrolimus, IV gamma-globulin or Prosorba column therapy)
• JAK inhibitors (e.g., tofacitinib, upadacitinib)
• Other systemic treatments for HS including but not limited to antibiotics (except as specified in herein), methotrexate, cyclosporine, retinoids, and fumaric acid esters
• Prescription topical therapies, unless prescribed for other indication (other than HS) AND approved by medical monitor
• Oral analgesics for HS not listed in herein
• Oral opioid analgesics
• Non-oral concomitant analgesics (e.g., IV, SC)
• Live vaccines (during the study and for 12 weeks after the last dose of study drug)
• Oral or injectable corticosteroids (except as allowed as described herein)
• Phototherapy
• Any investigational agents
• Over-the-counter topical antiseptic washes, creams, soaps, ointments, gels and liquids containing antibacterial agents to treat HS not listed herein • Surgical or laser intervention for an HS lesion except as outlined herein.
Rescue Medicine
[0311] If a subject experiences an increase in the AN count such that the total count is > 150% of their Day 1 AN count, antibiotic rescue medication may be initiated.
[0312] Subjects who qualify may initiate treatment with minocycline or doxycycline up to 100 mg BID. The dosing regimen must remain stable throughout study participation. In the case that a subject was previously intolerant or has a contraindication to both minocycline and doxycycline for the treatment of HS, the medical monitor should review to determine whether another rescue medication would be more appropriate. Rescue antibiotic therapy should be captured in the source and on the appropriate electronic CRF. The date and time of rescue medication administration as well as the name and dosage regimen of the rescue medication must be recorded.
Discontinuation of Study Drug
[0313] In rare instances, it may be necessary for a subject to permanently discontinue study drug. The reason for permanent discontinuation of drug will be documented. If study drug is permanently discontinued, the subject should, if at all possible, remain in the study to be evaluated for safety and efficacy. Subjects should continue to complete study assessments as outlined in the SoA where possible, with the exception of study drug administration. Reasons for removal from study drug include any of the following: i. subject request ii. death
Hi. lost to follow-up iv. protocol-specified reasons:
7. A subject that requires more than 2 lesion interventions within the first 16 weeks of the study must be discontinued from study drug.
2. After Week 16, a subject that requires more than 2 lesion interventions within a v. 4-week period or has 2 of the same interventions on the same lesion within that period must be discontinued from study drug. vi. termination of study by sponsor vii. emergency unblinding viii. liver chemistry stopping criteria ix. serious infections (e.g., sepsis) which cannot be adequately controlled within 4 weeks by anti -infective treatment or would put the subject at risk for continued participation in the trial as determined by the investigator x. The subject becomes pregnant while on study drug. xi. malignancy, except for localized non-melanoma skin cancer or carcinoma in-situ of the cervix xii. Subject develops Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3 or higher cardiovascular AE(s) that would put the subject at risk for continued participation in the trial as determined by the investigator or medical monitor. xiii. Any CTCAE version 5.0 grade 4 AE (life-threatening consequences; urgent intervention indicated considered by the investigator to be related to the study treatment). xiv. Subject develops an illness that, in the opinion of the investigator, would interfere with his or her continued participation, if the risk of continuing with study drug outweighs the potential benefit. xv. Subject uses prohibited concomitant medications, as defined herein, that may present a risk to the safety of the subject in the opinion of the investigator following discussion and agreement with the medical monitor. xvi. Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time during the study. xvii. Subj ect is significantly non-compliant with study procedures which would put the subj ect at risk for continued participation in the trial as determined by the investigator or medical monitor. xviii. Subjects with disease progression or not responding to treatment are to be withdrawn from study drug treatment based on investigator’s discretion.
[0314] Subjects with newly diagnosed IBD during the study must: (i) discontinue study drug and be followed-up until resolution of active IBD symptoms; and (ii) be referred, as appropriate, to a health care professional treating IBD, such as a gastroenterologist.
[0315] Study drug must be interrupted in case of any SAE or AE with a CTCAE version 5.0 grade 3 or above, unless obviously unrelated to study medication (e.g., motor vehicle accident). The option to restart study drug after interruption, if felt warranted by the investigator, should be discussed with, and cannot be implemented before agreement from, the medical monitor. [0316] If the subject has a clinical laboratory value meeting any of the following criteria, study drug must be interrupted. The laboratory test must be repeated in 1 to 2 weeks at a scheduled or unscheduled visit. The option to restart study drug after interruption, if felt warranted by the investigator, should be discussed with, and cannot be implemented, before agreement from the medical monitor: i. neutrophil count <1.0 x 109/L ii. platelets < 50 000/mm3
Hi. hemoglobin < 8.5 g/dL with decrease of at least 2 g/dL from baseline iv. creatinine >2 x baseline v. any other laboratory abnormality that in the investigator’s judgment could indicate a medical condition that puts the subject’s safety at risk and that cannot be readily treated (e.g., hyperkalemia).
[0317] If sponsor medical monitor approval to restart study drug after interruption is not granted, then the subject must permanently discontinue study drug and may continue in the study for protocol-specified study assessments.
Liver Chemistry Stopping Criteria
[0318] Discontinuation of study drug for abnormal liver tests is required by the investigator when a subject meets one of the conditions outlined in the algorithm or in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the investigator believes that it is in the best interest of the subject (Fig. 4). The investigator may consider rechallenge if a reasonable alternative explanation is identified and after consultation with the medical monitor.
[0319] Study Drug Restart or Rechallenge After Liver Stopping Criteria Are Met
[0320] Study drug restart/rechallenge after liver chemistry stopping criteria are met is allowed in this study. If the subject meets liver chemistry stopping criteria, there is no restart/rechallenge for the subject with study drug unless:
• Liver tests have returned to subj ect’ s baseline values.
• Sponsor medical monitor approval is granted; and
• Ethics and/or IRB approval is obtained, if required.
NOTE: If study drug was interrupted for suspected study drug-induced liver injury, the subject is informed of the risk of death, liver transplantation, hospitalization and jaundice before resumption of dosing. [0321] Refer to Liver Safety: Required Actions and Follow-up Assessments and Study drug Restart/Rechallenge Guidelines for details on the restart/rechallenge process, as provided herein. [0322] If sponsor medical monitor approval to restart/rechallenge the subject with study drug is not granted, then the subject must permanently discontinue study drug and may continue in the study for protocol-specified study assessments.
Subject Discontinuation/Withdrawal from the Study
[0323] Reasons for removal of a subject from the study are:
• Decision by sponsor
• Decision by investigator (following discussion with sponsor)
• Death
• Withdrawal of consent from study
• Lost to follow-up
[0324] Withdrawal of consent from study:
• A subject may withdraw from the study at any time without jeopardizing subsequent medical care.
• At the time of discontinuing from the study, if possible, an early discontinuation visit should be conducted, as shown in the SoA. See SoA for data to be collected at the time of study discontinuation and follow-up and for any further evaluations that need to be completed.
• The subject will be permanently discontinued from the study drug and the study at that time.
• If the subject withdraws consent for disclosure of future information, the sponsor may retain and continue to use any data collected before such a withdrawal of consent.
• If a subject withdraws from the study, he/she may request destruction of any samples taken and not tested, and the investigator must document this in the site study records and notify the sponsor or its designee.
Lost to Follow-up
[0325] A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site.
[0326] The following actions must be taken if a subject fails to return to the clinic for a required study visit: • The site must attempt to contact the subject and reschedule the missed visit as soon as possible, counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether the subject wishes to and/or should continue in the study.
• Before a subject is deemed lost to follow-up, the investigator or designee must make every effort to regain contact with the subject (where possible, 3 attempts at known effective points of contact [eg, phone, email, text], and if necessary, a certified letter to the subject’s last known mailing address or local equivalent methods). These contact attempts should be documented in the subject’s medical record.
• Should the subject continue to be unreachable, he/she will be considered lost to followup.
Study Assessments and Procedures
[0327] Informed consent must be obtained before any study-related procedures are performed. In regions where the legal age of consent is older than 18 years, informed consent must be obtained from and signed by the subject.
[0328] Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions are not allowed.
[0329] Day 1 corresponds to the date of the first dose of study drug.
[0330] Visit/dosing windows of ± 3 days on either side of the scheduled visits/dosing are permitted; however, the investigator should try to keep the subjects on the original visit/dosing schedule. The window of ± 3 days is relative to Day 1 and applicable for all subsequent visits/dosing. For QW dosing, the minimum of time between doses should be no less than 4 days and no more than 10 days.
[0331] All assessments are to be completed before study drug administration, unless otherwise specified. It is recommended that patient-reported outcome assessments be completed first.
[0332] Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or awareness to determine if the subject should continue or discontinue study drug.
[0333] Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct.
[0334] All screening evaluations must be completed and reviewed to confirm that potential subjects meet all eligibility criteria. The investigator will maintain a screening log to record details of all subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.
[0335] Procedures conducted as part of the subject’s routine clinical management (e.g., x-rays) and obtained before signing of the ICF may be utilized for screening or baseline purposes provided the procedures met the protocol-specified criteria and were performed within the timeframe defined in the SoA.
[0336] Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.
Efficacy Assessments
[0337] Planned timepoints for all efficacy and/or immunogenicity assessments are provided in the SoA. The study site should make every attempt to have the same investigator conduct efficacy assessments throughout the study for each subject.
Hidradenitis Suppurativa Clinical Response
[0338] The HiSCR was developed to address issues with available HS scoring systems and is a validated measure that is responsive to improvement in disease activity, simplifies the scoring process, and increases the sensitivity to detect HS-specific lesions (Kimball et al. 2014; Kimball et al. 2016). The HiSCR50 is defined as at least a 50% reduction from baseline in the total AN count, with no increase from baseline in abscess or draining fistula count. HiSCR75, HiSCR90, HiSCRIOO are defined as at least 75%, 90% or 100% reduction respectively from baseline in the total AN count, with no increase from baseline in abscess or draining fistula count.
Lesion and AN Count
[0339] The number of inflammatory and non-inflammatory nodules, abscesses, draining and nondraining fistulas, and hypertrophic scars, as well as the physical location (e.g., right/left axilla, right/left inframammary, intermammary, right/left buttock, right/left inguino-crural fold, perianal, perineal, other) will be recorded at the designated study visits listed in SoA. The AN count is the sum of abscesses and inflammatory nodules. In addition, lesions counts will be performed at any time if the subject experiences a disease flare. The longest distance between 2 relevant lesions (if only 1 lesion, measure diameter of lesion) and whether the lesions are clearly separated by normalappearing skin (yes or no) will be measured. The calculation of the HiSCR, International Hidradenitis Suppurativa Severity Score System (IHS4), and modified Sartorius score will be performed by the sponsor or designee based on the lesion counts entered by the study investigate^ s) on the appropriate CRFs. In addition, the sponsor or designee will utilize the lesions counts entered by the investigator on the CRF to establish the rate of flares.
[0340] Treatment decisions made during the conduct of the study will not be based on the HiSCR. Hurley Stage
[0341] The Hurley Stage is a severity classification for HS that was developed in 1989 and is widely used for the determination of the severity of HS (Hurley, 1989). The Hurley Stage is defined by the following criteria:
• Stage I: Abscess formation, single or multiple, without sinus tracts and cicatrization (scarring).
• Stage II: Recurrent abscesses with tract formation and cicatrization, single or multiple, widely separated lesions.
• Stage III: Diffuse or near-diffuse involvement, or multiple interconnected tracts and abscesses across the entire area.
[0342] The study investigator will determine the Hurley Stage in each affected anatomical region at the designated study visits listed in the SoA. If more than 1 stage is present in a region, the worst state in each region should be entered.
Numeric Rating Scale Patient Global Assessment of Skin Pain
[0343] The NRS Patient Global Assessment of Skin Pain will be completed on a daily diary by subjects from screening through Week 16, listed in SoA. If pain diaries are not completed for at least 3 of the 7 consecutive days prior to the Day 1 visit, the subject may not be randomized.
[0344] The Patient Global Assessment of Skin Pain is a unidimensional NRS that allows for rapid (often 1 item) measures of pain that can be administered multiple times with minimal administrative burden. The NRS consists of scores from 0 to 10 with 0 indicating “no skin pain” and 10 indicating “pain as bad as you can imagine”. The pain will be described as “skin pain at its worst in the last 24 hours” and “skin pain on average in the last 24 hours”.
[0345] The subject should complete the questionnaire before site personnel perform any clinic assessments and before any interaction with the site personnel has occurred to avoid biasing the subject’s response.
Dermatology Life Quality Index
[0346] Subjects will complete the DLQI questionnaire at the designated study visits listed in SoA. The DLQI will be used to assess the symptoms and the impact of skin problems on quality of life. The DLQI can be used to evaluate 6 areas: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment (Finlay and Khan 1994). Subjects will be asked to respond to the 10 items of the DLQI based on a recall period of “the last week”. Decreased scores indicate improved health-related quality of life. The subject should complete the questionnaire before site personnel perform any clinic assessments and before any interaction with the site personnel has occurred to avoid biasing the subject’s response.
Safety Assessments
[0347] Planned timepoints for all safety assessments are provided in the SoA.
Medical and Medication History
[0348] A complete medical and medication history, as well as history of alcohol and nicotine use, will be obtained from each subject during the screening visit. An updated medical history will be obtained at the Day 1 visit prior to study drug administration and updated as necessary throughout the study.
[0349] A HS history obtained at screening will capture date of onset of HS.
[0350] Any systemic treatment for HS since diagnosis will be recorded. Any other treatment used for any other reasons (including contraception) prior to randomization will be recorded as per eCRF Completion Guidelines.
[0351] Any changes in concomitant medication will be recorded throughout the study, from Day 1 until End of Study at Week 59.
Physical Examinations
[0352] A complete physical examination will include, at a minimum, assessments of the dermatological, cardiovascular, respiratory, gastrointestinal, and neurological systems. Clinically significant findings observed prior to first dose of study drug should be listed as medical history in the CRF and reported as AEs if observed after first dose of study drug.
Vital Signs
[0353] Vital signs will be measured in a sitting position after 5 minutes rest and will include temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.
Physical Measurements
[0354] Height and weight measurements are to be performed at the timepoints indicated in the SoA and data will be recorded in centimeters and kilograms respectively. Height and weight are to be measured without shoes. Electrocardiograms
[0355] Triplicate 12-lead ECGs will be obtained after subject has been supine for at least 5 minutes as outlined in the SoA using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals.
Chest X-ray
[0356] Only subjects with a positive or indeterminate QuantiFERON® test will undergo a chest x-ray (posterior/anterior or anterior/posterior). A subject must not be included in the study if his/her chest x-ray reveals evidence of active TB. Women of childbearing potential must have a negative pregnancy test before an x-ray is performed.
Clinical Safety Laboratory Tests
[0357] See below for the list of clinical laboratory tests to be performed and the SoA for the timing and frequency.
[0358] The investigator must review the laboratory results, document this review, and record any clinically significant changes occurring during the study as an AE. The laboratory results must be retained with source documents.
[0359] Abnormal laboratory findings associated with the underlying disease are not considered clinically significant unless judged by the investigator to be more severe than expected for the subject’s condition.
[0360] All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 8 weeks after the last dose of study drug should be repeated until the values return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor. i. If clinically significant values do not return to normal/baseline within a period of time judged reasonable by the investigator, the etiology should be identified, and the sponsor notified. ii. All protocol -required laboratory tests, as defined herein, must be conducted in accordance with the laboratory manual and the SoA.
Hi. If laboratory values from non-protocol-specified laboratory tests performed at institution’s local laboratory require a change in subject management or are considered the clinically significant by the investigator (e.g., SAE or AE or dose modification), then the results must be recorded within source documents. Pregnancy Testing
[0361] Pregnancy testing in WOCBP is conducted throughout the study. A serum pregnancy test will be performed at screening and urine pregnancy testing is performed at subsequent visits as detailed in the SoA.
[0362] Additional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation or regulatory agency, to establish the absence of pregnancy at any time during the subject’s participation in the study.
[0363] The investigator is responsible for review of medical history, menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. IBD Screening
[0364] Given that subjects with HS appear to have a higher lifetime risk of IBD compared to the general population and given that approved IL- 17 inhibitors have reported worsening or new onset IBD in clinical trials, all subjects will be screened for IBD by history and a subset will undergo additional laboratory screening. i. During screening, all subjects will be assessed for the following symptoms within the last year: ii. prolonged or recurrent diarrhea without established etiology
Hi. prolonged or recurrent abdominal pain without established etiology iv. blood in stool without established etiology v. any other symptoms in the opinion of the investigator that may be suggestive of IBD. If any are marked affirmative, a fecal calprotectin test must be performed. vi. If the resulting fecal calprotectin level is > 150 to 500 pg/g, the subject must undergo a GI consultation and obtain documented approval from the GI consultation to enroll in the clinical trial before continuing with the screening process. If the consultation cannot be completed within the screening window, the subject will be screen failed but may rescreen. vii. Fecal calprotectin levels > 500 ug/g will be exclusionary.
Suicidal Ideation and Behavior Risk Monitoring
[0365] Subjects with HS may occasionally develop suicidal ideation or behavior. Furthermore, suicidal ideation and behavior has been an identified, potential risk with other IL- 17 class products. [0366] Suicidal ideation and behavior will be assessed during the study by trained study personnel using the C-SSRS. The visits at which the C-SSRS assessments will be performed are specified in the SoA. The C-SSRS is a standardized and validated instrument developed for the assessment of the severity and frequency of suicidal ideation and behavior (Posner et al. 2011). Subjects respond to standardized clinical questions that are presented in a uniform fashion. The C-SSRS defines 5 subtypes of suicidal ideation and behavior in addition to self-injurious behavior with no suicidal intent. The C-SSRS takes approximately 3 to 10 minutes to complete.
[0367] Subjects should be monitored appropriately and observed closely for suicidal ideation and behavior or any other unusual changes in behavior, especially at the beginning and end of the course of study drug. Subjects who experience signs of suicidal ideation and behavior should undergo a risk assessment which may or may not include examination by a mental health care professional. All factors contributing to suicidal ideation and behavior should be evaluated and consideration should be given to discontinuation of the study drug.
Home Study Drug Administration Diary
[0368] Study site staff will administer study drug at the first 2 visits. Thereafter, if home dosing is a consideration, the subject or subject’s caregiver or designee must administer and demonstrate competency for at least 2 visits prior to being allowed to dose at home. Otherwise, the patient will need to return to the site for all injections. The subject (or caregiver/designee) will complete a diary for every study dose taken outside of the study site (i.e., at home). The study drug should be administered on the dates as directed by the site staff. Information regarding the study drug administration (e.g., date and time of study drug administration, if the full dose was administered) will be recorded on the study drug administration diary. Instructions on proper study drug administration will be provided to the subject (caregiver/designee). Subjects will be instructed to call the study site if they are having problems administering the study drug or have missed or delayed administering a dose. Subjects will be instructed to bring the study drug administration diary to each study visit.
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting
[0369] The definitions of AEs and SAEs can be found herein.
[0370] Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the subject’s legally authorized representative). [0371] The investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE. The investigator is responsible for following up on all AEs that are serious, considered related to the study drug or study procedures, or that caused the subject to discontinue the study drug.
[0372] Currently all SAEs require immediate reporting by the investigator to ACELYRIN. There are no SAEs that do not require immediate reporting. If this changes during the course of the study, the protocol will be amended, as appropriate.
[0373] The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for completing and transmitting SAE reports are provided herein.
Time Period and Frequency for Collecting AE and SAE Information
[0374] All SAEs will be collected from the signing of the ICF until the 8-week follow-up visit as specified in the SoA.
[0375] All AEs will be collected from the first dose of study drug until 4 weeks after the last dose of study drug as specified in the SoA.
[0376] Medical occurrences that begin before the start of study drug but after obtaining informed consent will be recorded as medical history/current medical conditions, not as AEs.
[0377] All SAEs will be recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours from investigator’s knowledge of the event, as indicated herein The investigator will submit any updated SAE data to the sponsor within 24 hours of it being available.
[0378] Investigators are not obligated to actively seek information on AEs or SAEs after the conclusion of the study participation. However, if the investigator learns of any SAE, including death, at any time after a subject has been discharged from the study, and he/she considers the event to be reasonably related to the study drug or study participation, the investigator must promptly notify the sponsor or its designee.
Method of Detecting AEs and SAEs
[0379] Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrences.
Regulatory Reporting Requirements for SAEs [0380] Prompt notification by the investigator to the sponsor of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of subjects and the safety of a study drug under clinical investigation are met.
[0381] The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study drug under clinical investigation. The sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. This includes reporting of events that meet SUSAR criteria via Eudravigilance, as applicable.
[0382] An investigator who receives an investigator safety report describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local requirements.
[0383] Investigator safety reports must be prepared for SUSARs according to local regulatory requirements and sponsor policy and forwarded to investigators as necessary.
Pregnancy
[0384] Details of all pregnancies in female subjects and, if indicated, female partners of male subjects will be collected after the start of study drug and until 8 weeks after the last dose of study drug.
[0385] If a pregnancy is reported, the investigator will record pregnancy information on the appropriate form and submit it to the sponsor or designee within 24 hours of learning of the female subject or female partner of male subject (after obtaining the necessary signed informed consent from the female partner) pregnancy.
[0386] While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.
[0387] Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.
[0388] The subject/pregnant female partner will be followed to determine the outcome of the pregnancy. The investigator will collect follow-up information on the subject/pregnant female partner and the neonate, and the information will be forwarded to the sponsor or designee.
[0389] Any post-study pregnancy-related SAE considered reasonably related to the study drug by the investigator will be reported to the sponsor or designee as herein. While the investigator is not obligated to actively seek this information in former study subjects/pregnant female partner, he or she may learn of an SAE through spontaneous reporting.
[0390] Any female subject who becomes pregnant while participating in the study will discontinue study drug.
Adverse Events of Special Interest
[0391] Based on the class effects or potential risks with IL- 17 inhibitors, the following events of special interest will be monitored: i. Candida infection ii. IBD iii. Suicidal ideation iv. Malignancies v. Major cardiovascular and cerebrovascular events vi. Tuberculosis vii. Infections (including opportunistic infections and serious infections) viii. Cytopenias (anemia, neutropenia, lymphopenia, monocytopenia, thrombocytopenia) ix. Hypersensitivity reactions.
Overdose
[0392] These events are only considered AEs or SAEs if there are associated clinical signs and symptoms or if the act of taking the excess medicine itself is an AE or SAE (e.g., suicide attempt). [0393] If an overdose occurs associated with an SAE in the course of the study, then the investigator follows the immediate safety reporting requirement for SAE with describing the overdose in an SAE description.
Statistical Considerations
[0394] This section is a summary of the planned statistical analyses of the most important endpoints including primary and secondary endpoints.
Statistical Hypotheses
[0395] The primary objective of this study is to demonstrate that izokibep is superior to placebo in the proportion of subjects achieving HiSCR75 at Week 16 of the study. The statistical null and alternative hypotheses to be used to assess the primary objective are:
HO: 7tABY -nPBO = 0 HA: 7iABY - TTPBO 0 where ABY and 7tPBO are the proportion achieving HiSCR75 at Week 16 among subjects randomly assigned to receive izokibep and placebo, respectively.
[0396] Analogous statistical hypotheses will be used for the secondary objective of assessing the percentage of subjects who achieve HiSCR90 at Week 16, who achieve HiSCRIOO at Week 16, who achieve HiSCR50 at Week 16, who experience a flare through Week 16, who achieve an AN count of 0, 1, or 2 at Week 16, or who achieve a 3-point reduction in pain NRS at Week 16. For the last secondary objective, to demonstrate that izokibep is efficacious compared to placebo, as measured by change in DLQI, the statistical null and alternative hypotheses are:
HO: pABY - pPBO = 0
HA: pABY - pPBO 0 where pABY and pPBO are the mean changes in DLQI from baseline to Week 16 among subjects randomly assigned to receive izokibep and placebo, respectively.
Multiplicity Adjustment and Type I Error Rate
[0397] Hypotheses tested will be adjusted to control the familywise error rate in the strong sense at a = 0.050, 2-sided.
[0398] As described herein an adjustment of 0.0001 will be made to account for the unblinded data summaries reviewed by the DMC. The hypotheses will therefore be tested at a = 0.0499.
[0399] The statistical comparisons for the primary efficacy endpoint and the secondary endpoints, all at Week 16, will be carried out in sequential order. The primary endpoint, comparing izokibep to placebo, will be tested first, with significance concluded if p < 0.0499. Testing of secondary endpoints will only be carried out if all prior tests, including the test of the primary endpoint, first show significance with p < 0.0499. As long as all prior tests are significant, testing will proceed in the following order:
[0400] The first secondary endpoint, proportion of subjects achieving HiSCR90 at Week 16. [0401] The second secondary endpoint, proportion of subjects achieving HiSCRIOO at Week 16. [0402] The third secondary endpoint, proportion of subjects achieving HiSCR50 at Week 16.
[0403] The fourth secondary endpoint, proportion of subjects who experience flares through Week 16.
[0404] The fifth secondary endpoint, change in DLQI from baseline to Week 16. [0405] The sixth secondary endpoint, achieving AN count of 0, 1, or 2 at Week 16 among subjects with baseline Hurley Stage II.
[0406] The seventh secondary endpoint, proportion of subjects who achieve a reduction in pain NRS of at least 3 points from baseline to Week 16, among subjects with a pain NRS of at least 4 at baseline.
[0407] If a null hypothesis is not rejected, p-values for subsequent hypotheses in the sequence will be reported as nominal and will not be used to assess objectives or make determinations of efficacy.
Analysis Sets
[0408] The following analysis sets will be used for reporting.
Full Analysis Set (FAS)
[0409] For assessing the primary and secondary efficacy objectives, all subjects randomized will be included in the analyses as FAS. Intercurrent events such as missed assessments, missed or discontinued treatment, and protocol deviations, will be addressed as described in the definition of the Estimands herein. Subjects will be included according to randomized treatment.
[0410] For assessment of the sixth secondary endpoint, the proportion of subjects who achieve AN of 0, 1, or 2 at Week 16, only the subset of subjects in the FAS who have Hurley Stage II at baseline will be included in the assessment. For the seventh secondary endpoint, achievement of a reduction in pain NRS of at least 3 points, only the subset of subjects in the FAS who have pain NRS of at least 4 at baseline will be included in this assessment. Both will be called the FAS for reporting purposes.
Safety Analysis Set
[0411] For assessing the safety objectives, all subjects randomized who receive at least 1 administration of test material will be included in the summaries and analyses. In the event that a subject receives incorrect study treatment, that subject will be grouped according to treatment received. If a subject receives both treatments, the subject will be grouped with the treatment received most often.
Statistical Analyses
General Considerations [0412] All data collected will be summarized by planned timepoint without imputation. Continuous data will be summarized with count, mean, median, standard deviation, minimum, and maximum. Change from baseline will additionally include standard error. Categorical data will be summarized with count and percent. Time to event data will be summarized with productlimit estimators of median and quartiles.
[0413] All hypothesis tests will be reported with 2-sided p-values. All Cis will be 2-sided with nominal 95% coverage.
[0414] Data will be summarized by part and planned timepoint, using data collected at the visit. Study day will be calculated as post-baseline date minus randomization date, plus 1 (except that study day for pre-randomization dates will not include the plus 1). Day range windows will not be applied for summaries (but may be applied for protocol deviations). Baseline values will be the last value collected before randomization and change from baseline will be calculated as postbaseline value minus baseline value.
[0415] Stratified tests will use the 4 strata from the randomization process. If a subject is incorrectly classified during the randomization process, the analysis will use the correct classification, not the classification used during randomization.
[0416] Any deviation from the planned analyses made after breaking the blind will be documented in the clinical study report.
Primary Endpoint and Estimand
[0417] The primary endpoint is HiSCR75, the proportion of subjects who achieve at least a 75% reduction from baseline in the total AN count, with no increase from baseline in abscess or draining fistula count, as defined herein. The primary timepoint for analysis is Week 16.
[0418] The treatment policy strategy approach for the estimand will be used in general, so subjects will be included using observed data at Week 16 regardless of treatment compliance, use of rescue medications except as noted below, or any other protocol deviations. Subjects with missing HiSCR75 assessments at Week 16 will be imputed as non-responders (non-response imputation or NRI). A composite strategy will be used for ICEs of receiving oral antibiotic therapy that could affect HS: a list of all oral antibiotic therapy that results in such imputation will be finalized after review of all oral antibiotic therapy received by any subject and before unblinding of the study, and will include tetracycline, clindamycin, and possibly other products. Such subjects will be imputed using NRI. The number of subjects imputed with NRI will be tabulated with reasons for imputation at Week 16.
[0419] The null hypothesis of equal response rates will compare the izokibep to the placebo group. A stratified test of response rates will be used. Within each of the 4 strata used for randomization, the response rate for each treatment group and corresponding standard error will be calculated. The difference in response rates (risk difference) will be calculated for each stratum. The common risk difference among the 4 strata and associated standard error will be estimated by combining the observed risk differences using Cochran— Mantel -Haenszel weighting. The estimated risk difference divided by the standard error will be used as the test statistic and a p- value calculated assuming that the test statistic follows a standard normal distribution under the null hypothesis. Analyses at earlier timepoints when data to calculate the HiSCR75 scores are collected will also be presented using the same methodology. P— values from earlier timepointswill be presented for descriptive purposes, not part of the alpha-preserving multiple testing strategy.
[0420] Supportive analyses using other assumptions about ICEs will also be reported. These will be defined before the database is locked and treatment assignments are unblinded.
Secondary Endpoints and Estimands
[0421] The secondary endpoints are HiSCR90, HiSCRIOO, HiSCR50, percentage of subjects who experience flare through Week 16, percentage of subjects with baseline Hurley Stage II who achieved an AN count of 0, 1, or 2, percentage of subjects with a decrease in pain score of at least 3 points at Week 16, and change in DLQI at Week 16. The treatment policy strategy will be used to construct estimands for each secondary endpoint except as noted below.
[0422] The secondary endpoint of experiencing flare will be analyzed using multiple imputation for subjects who have missing assessments. All subjects with missing abscess, inflammatory nodule, and draining tunnel counts will be included using multiple imputation. The imputation dataset will be created from placebo subjects who have complete data. The imputed counts will be used to determine which subjects meet the criteria for flare, and the primary analysis methodology applied. This will be repeated and the various outcomes will be combined using Rubin’s rule.
[0423] The secondary endpoint of pain score will use a hybrid estimand, with treatment policy strategy used for most ICEs and hypothetical strategy used to account for use of prohibited pain medications. All pain scores after the use of prohibited pain medication will be omitted from the dataset and replaced via multiple imputations. The imputation dataset will be created from the placebo subjects who have complete data. The imputed pain scores will be used to determine which subjects meet the criteria of a decrease of at least 3 points. This will be repeated and the various outcomes will be combined using Rubin’s rule. Sensitivity analyses will include a nonlinear mixed effects model with repeated measures (MMRM), using observed change in pain score at all scheduled post-baseline assessments.
[0424] The secondary endpoints of percentage of subjects who experience flare and percentage of subjects with baseline Hurley Stage II who achieved AN count of 0, 1, or 2 will be analyzed analogously to the primary endpoint. Subjects who have missing data at Week 16 or who received an oral antibiotic that could impact HS will be included in the analysis with NRI (did experience flare, or did not achieve AN count of 0, 1, or 2). Only subjects with Hurley Stage II at baseline will be included in the hypothesis test for AN count, while other subjects will be summarized, and a p-value reported for descriptive use only.
[0425] The secondary endpoint of change in DLQI will use MMRM to account for subjects with missing data. The factors used for stratification will be included as covariates in the model, as will baseline DLQI score.
Safety Analyses
[0426] Safety data will include summaries of exposure, AEs, SAEs, and laboratory data. No inferential statistics (p-values) will be reported for safety data.
[0427] Exposure will include the number of doses administered (including complete and incomplete doses) and reasons for missed or incomplete doses. Exposure will be reported through the planned collection of the primary endpoint and for the entire study. For subjects assigned to receive placebo who later receive izokibep, exposure will further be summarized by placebo and izokibep.
[0428] Adverse events and SAEs reported before first administration of study drug will be listed. All summaries will include only treatment-emergent events. The number of subjects who report 1 or more AEs, the number who report 1 or more severe AEs, the number who report 1 or more SAEs, and the number who report 1 or more AEs that leads to discontinuation of study intervention will be summarized by treatment during the primary phase of the study and overall. Subjects who receive placebo during the primary phase will additionally be summarized by phase (placebo-controlled and after crossing over to active).
[0429] Laboratory data and vital signs will be summarized at each planned collection timepoint.
Supporting Documentation and Operational Considerations
Regulatory, Ethical and Study Oversight Consideration
Regulatory and Ethical Considerations
[0430] This study is conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences international ethical guidelines; Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines; and Applicable laws and regulations.
[0431] The protocol, protocol amendments, ICF, Investigator’s Brochure and other relevant documents (e.g., advertisements) are submitted to an IRB/1EC by the investigator and reviewed and approved by the IRB/IEC before the study is initiated.
[0432] Any amendments to the protocol require IRB/IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study subjects.
[0433] Any amendments to the protocol require IRB/IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study subjects.
[0434] Approval for protocols and any substantial amendments to the protocol that require health authority approval prior to initiation will be obtained except for changes necessary to eliminate an immediate hazard to study subjects.
[0435] The investigator is responsible for the following:
• Providing written summaries of the status of the study to the IRB/IEC annually or more frequently in accordance with the requirements, policies and procedures established by the IRB/IEC;
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC procedures; and • Providing oversight of the conduct of the study at the site and adherence to requirements of 21 Code of Federal Regulations, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable) and all other applicable local regulations.
Financial Disclosure
[0436] Investigators and subinvestigators provide the sponsor or designee with sufficient, accurate financial information as requested to allow the sponsor to submit complete and accurate financial certification or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for providing information on financial interests during the course of the study and for 1 year after completion of the study.
[0437] Informed Consent Process
[0438] The investigator or his/her representative explain the nature of the study, including the risks and benefits, to the subject and answer all questions regarding the study.
[0439] Subjects are informed that their participation is voluntary. Subjects are required to sign a statement of informed consent.
[0440] The medical record must include a statement that written informed consent was obtained before the subject was enrolled in the study and the date the written consent was obtained. The authorized person obtaining the informed consent must also sign the ICF.
[0441] Subjects are reconsented to the most current version of the ICF(s) during their participation in the study.
[0442] A copy of the ICF(s) is provided to the subject.
[0443] A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 30 days from the previous ICF signature date.
Data Protection
[0444] Subjects are assigned a unique identifier by the sponsor. Any subject records or datasets that are transferred to the sponsor contain the identifier only; subject names or any information which would make the subject identifiable are not be transferred.
[0445] The subject is informed that the subject’s personal study -related data will be used by the sponsor in accordance with local data protection law. The level of disclosure must also be explained to the subject who is required to give consent for their data to be used as described in the informed consent. [0446] The subject is informed that the subject’s medical records may be examined by Clinical Quality Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC members and by inspectors from regulatory authorities.
[0447] The sponsor and investigator implement appropriate measures to monitor and identify any breach of security leading to accidental or unlawful destruction, loss, alteration, unauthorized disclosure or access to that data. In the event of a personal data breach, the sponsor and investigator will take appropriate measures to address the breach, including measures to mitigate its adverse effects. The investigator will notify the sponsor without undue delay after having become aware of the breach. Such notification will contain the details of a contact point where more information can be obtained, a description of the nature of the breach (including, where possible, categories and approximate number of data subjects and personal data records concerned), its likely consequences and the measures taken or proposed to address the breach including, where appropriate, measures to mitigate its possible adverse effects. Upon becoming aware of any data breach, the sponsor will notify all competent data protection authorities of the breach, where required by local regulations. Where feasible and permissible by applicable law, such notification will occur within 72 hours of becoming aware of the breach. Such notification will contain the details of a contact point where more information can be obtained, a description of the nature of the breach (including, where possible, categories and approximate number of data subjects and personal data records concerned), its likely consequences and the measures taken or proposed to address the breach including, where appropriate, measures to mitigate its possible adverse effects. [0448] Taking into account the nature, scope, context and purpose of the processing, and the risks for the rights and freedoms of natural persons, the investigator will implement technical and organizational measures to ensure adequate security and confidentiality of the data. Such measures will include without limitation pseudonymization and data encryption in transit and at rest, identity and access management procedures to restrict physical and logical access to the data, network perimeter and endpoint protection using firewalls and other intrusion detection systems, documented policies taking account of the state of the art, and regular training of all personnel responsible for the processing of personal data. Dissemination of Clinical Study Data
[0449] The results of the study are reported in a clinical study report generated by the sponsor and will contain CRF data from all study sites that participated in the study. Recruitment performance or specific expertise related to the nature and the key assessment parameters of the study is used to determine a coordinating investigator. Study subject identifiers are not be used in publication of results. Any work created in connection with the performance of the study and contained in the data that can benefit from copyright protection (except any publication by the investigator) is the property of the sponsor as author and owner of copyright in such work.
[0450] Registration of Clinical Studies and Disclosure of Results
[0451] The sponsor registers and/or discloses the existence of and the results of clinical studies as required by law including posting company-sponsored study information in the US National Institutes of Health website www.clinicaltrials. ov.
Monitoring and Data Quality Assurance
[0452] Qualified, assigned monitors from the sponsor (or designee) conduct regular on-site and remote monitoring visits to monitor various aspects of the study. These visits and communications, along with regular inspection of the electronic CRTs, are conducted to assess subject enrollment, compliance with protocol procedures, completeness and accuracy of data entered on the electronic CRFs, verification of data against source documents, and occurrence of AEs, etc. The investigator provides the monitor with full access to all source and study documents.
[0453] All subject data relating to the study is recorded on CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is responsible for verifying that data entries are accurate and correct by signing the CRF.
[0454] Guidance on completion of CRFs is provided.
[0455] The investigator or site staff promptly report to the sponsor (or designee) all deviations that occur at their clinical site, and report protocol deviations to their IRB/IEC according to local requirements.
[0456] The sponsor (or designee) may audit investigator sites regarding, but not limited to, the informed consent process, presence of required documents, adherence to protocol, accountability and storage of drug supplies, comparison between electronic CRF with source documents, etc. All medical records and study related documents must be available for audit, and the investigator and study staff agree to participate and cooperate in audits conducted in a reasonable manner.
[0457] Government regulatory authorities and ethics committees may also inspect the investigator site during or after the study. The investigator or designee should contact the sponsor (or its designee) immediately if this occurs. The investigator must cooperate fully with regulatory authorities or other audits conducted in a reasonable manner.
[0458] The sponsor or designee is responsible for the data management of this study, including quality checking of the data.
[0459] The sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). [0460] Records and documents, including signed ICFs, pertaining to the conduct of this study must be retained by the investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the study drug. These documents should be retained for a longer period, however, if required by the applicable regulatory requirements or by an agreement with the sponsor.
[0461] No records may be destroyed during the retention period without the written approval of the sponsor. No records may be transferred to another location or party without written notification to the sponsor.
[0462] Quality Tolerance Limits will be defined before the start of the study and monitored by the CRO and sponsor during the course of the study. They will also be reported in the clinical study report.
Source Documents
[0463] Source documents provide evidence for the existence of the subject and substantiate the integrity of the data collected. Source documents are filed at the investigator’s site.
[0464] Source documents contain the results of original observations and activities of a clinical investigation. Source documents include, but are not limited to, medical records (progress notes), computer printouts, screening logs and recorded data from automated instruments. Information from medical records and other source documents will be promptly transcribed to the appropriate section of the electronic CRF. The electronic CRF is not considered and should not be used as source documentation. [0465] Data reported on the CRF that are transcribed from source documents must be consistent with the source documents or the discrepancies must be explained. The investigator may need to request previous medical records or transfer records, depending on the study. Also, current medical records must be available.
[0466] The investigator must maintain accurate documentation (source data) that supports the information entered in the CRF.
[0467] Study monitors will perform ongoing source data verification to confirm that data entered into the CRF by authorized site personnel are accurate, complete and verifiable from source documents; that the safety and rights of subjects are being protected; and that the study is being conducted in accordance with the currently approved protocol and any other study agreements, ICH GCP and all applicable regulatory requirements.
Study and Site Start and Closure
Study Start
[0468] The study start date is the date on which the first subject is enrolled into the study. Study/Site Termination
[0469] The sponsor reserves the right to close the study site or terminate the study at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A study site is considered closed when all required documents and study supplies have been collected and a study-site closure visit has been performed.
[0470] The investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination.
[0471] Reasons for the early closure of a study site by the sponsor or investigator may include but are not limited to:
[0472] For study termination: Discontinuation of further study drug development
[0473] For site termination: a. Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local health authorities, the sponsor’s procedures or GCP guidelines b. Inadequate or no recruitment (evaluated after a reasonable amount of time) of subjects by the investigator c. Total number of subjects included earlier than expected [0474] If the study is prematurely terminated or suspended, the sponsor shall promptly inform the investigators, the lECs/IRBs, the regulatory authorities and any CRO(s) used in the study of the reason for termination or suspension, as specified by the applicable regulatory requirements. The investigator shall promptly inform the subject and should assure appropriate subject therapy and/or follow-up.
Publication Policy
[0475] The results of this study may be published or presented at scientific meetings. If this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. This allows the sponsor to protect proprietary information and to provide comments. The clinical study agreement/site contract will cover additional details regarding publications.
[0476] The sponsor will comply with the requirements for publication of study results. In accordance with standard editorial and ethical practice, the sponsor will generally support publication of multi -center studies only in their entirety and not as individual site data. In this case, a coordinating investigator will be designated.
[0477] Authorship will be determined by mutual agreement and in line with International Committee of Medical Journal Editors authorship requirements.
Clinical Laboratory Tests
[0478] The tests detailed in the table below are performed by the central laboratory.
[0479] Protocol-specific requirements for inclusion or exclusion of subjects are detailed hereinabove as part of the subject protocol.
[0480] Additional tests may be performed at any time during the study as determined necessary by the investigator or required by local regulations. All study-required laboratory tests will be performed by a central laboratory, with the exception of i. urine pregnancy test ii. PPD test.
[0481] Investigators must document their review of each laboratory safety report.
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
AEs and SAEs: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting Definition of AE
AE Definition
[0482] An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug.
[0483] Note, an AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug.
Events Meeting the AE Definition
[0484] Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the investigator (i .e ., not related to progression of underlying disease, or more severe than expected for the subject’s condition)
[0485] Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition
[0486] New condition detected or diagnosed after study drug administration even though it may have been present before the start of the study.
[0487] Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
[0488] Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae.
[0489] Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
Events NOT Meeting the AE Definition
[0490] Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the first dose of study drug that do not worsen; such events should be recorded as medical history eCRF.
[0491] Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition.
[0492] The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.
[0493] Medical or surgical procedure (e.g., endoscopy, appendectomy): The condition that leads to the procedure is the AE.
[0494] Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).
[0495] Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.
[0496] An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed:
[0497] a Results in death
[0498] b. Is life threatening
[0499] The term life threatening in the definition of serious refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.
[0500] c. Requires inpatient hospitalization or prolongation of existing hospitalization x In general, hospitalization signifies that the subject has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not considered an AE.
[0501] d. Results in persistent or significant disability/incapacity. The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption. [0502] e. Is a congenital anomaly /birth defect
[0503] f. Other situations:
[0504] Medical or scientific judgment should be exercised by the investigator in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should usually be considered serious.
[0505] Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions not resulting in hospitalization, or development of intervention dependency or intervention abuse.
Recording and Follow-up of AE and/or SAE
AE and SAE Recording
[0506] When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event.
[0507] The investigator will then record all relevant AE/SAE information in the required eCRF and SAE Report Form (if applicable).
[0508] It is not acceptable for the investigator to send photocopies of the subject’s medical records to the sponsor or designee of in lieu of completion of the required eCRF and SAE Report Form (if applicable). [0509] There may be instances when copies of medical records for certain cases are requested by sponsor or designee. In this case, all subject identifiers, with the exception of the subject number, should be fully redacted on the copies of the medical records before submission.
[0510] The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Severity
[0511] The investigator is responsible for assessing the severity for each AE and SAE according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 5.0):
[0512] Mild (Grade 1): Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
[0513] Moderate (Grade 2): Minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental activities of daily living (ADL). Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
[0514] Severe (Grade 3): Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
[0515] Life-threatening (Grade 4): Life-threatening consequences; urgent intervention indicated.
[0516] Death (Grade 5): Events that result in death.
[0517] Many common AEs are able to be graded according to CTCAE. Adverse events that do not have a corresponding CTCAE term will be assessed according to the general guidelines for grading used in CTCAE version 5.0 as stated above. Additional considerations when assessing severity are outlined below:
[0518] The seriousness of an AE should not be confused with its severity. Severity is a measure of intensity (e.g., Grades 1 through 5 or mild, moderate, severe), whereas seriousness is based on subject/event outcome as defined by the criteria provided herein.
[0519] It is important to distinguish between category (AE versus SAE) and intensity (Grades 1 to 5) of AEs. Seriousness, not severity, serves as a guide for defining regulatory reporting obligations. [0520] An AE of severe intensity is not necessarily considered serious. For example, nausea that persists for several hours may be considered grade 3 nausea, but not an SAE. On the other hand, minor cardiac chest pain results in hospitalization may be considered grade 1 but would be an SAE.
Assessment of Causality
[0521] The investigator is obligated to assess the relationship between study drug and each occurrence of each AE/SAE. The investigator will use clinical judgment in the assessment of causality according to the following categories:
[0522] Not related: Another documented cause of the AE is most plausible; and/or the administration of study drug and occurrence of AE are not reasonably related in time; and/or causal relationship is considered biologically implausible.
[0523] Related: There is clear evidence to suggest that the AE is more likely explained by the study drug and other possible contributing factors can be ruled out; a causal relationship is clinically/biologically plausible, and there exists a plausible time sequence between onset of the AE and administration of the study drug.
[0524] Additional factors in the assessment of causality include the following:
[0525] A reasonable possibility of a relationship conveys that there are facts, evidence, and/or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
[0526] Alternative causes, such as underlying disease(s), concomitant therapy, and other risk as the temporal relationship of the event to study drug administration, will be considered and investigated.
[0527] The investigator will also consult the Investigator’s Brochure and/or product information, for marketed products, in his/her assessment.
[0528] For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the AE/SAE and has provided an assessment of causality.
[0529] There may be situations in which an SAE has occurred and the investigator has minimal information to include in the initial report to the sponsor or designee. However, it is very important that the investigator always make an assessment of causality for every event before the initial transmission of the SAE data to the sponsor or designee.
[0530] The investigator may change his/her opinion of causality in light of follow-up information and send an SAE follow-up report with the updated causality assessment. [0531] The causality assessment is one of the criteria used when determining regulatory reporting requirements.
Follow-up of AEs and SAEs
[0532] The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as medically indicated or as requested by the sponsor or designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.
[0533] If a subject dies during participation in the study or during a recognized follow-up period, the investigator will provide the sponsor or designee with a copy of any postmortem findings including histopathology.
[0534] New or updated information will be recorded in the originally submitted documents.
[0535] The investigator will submit any updated SAE data to the sponsor/ designee within 24 hours of receipt of the information.
Reporting of SAEs
SAE Reporting to Sponsor Designee via the SAE Report Form
[0536] The primary mechanism for reporting an SAE to the sponsor/designee will be the SAE Report Form.
[0537] All SAEs will be recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours from investigator’s knowledge of the event.
[0538] Email transmission of the SAE Report Form is the preferred method to transmit this information to the sponsor/designee.
[0539] In the rare circumstance email is not available, the SAE Report Form may be sent by facsimile as a back-up reporting method.
[0540] Investigator signature is required to be collected on the SAE Report Form prior to submission. With rare exception, the form may be sent without signature in order to meet the reporting deadline; however, investigator signature is required to be obtained as soon as possible after submission.
[0541] Contacts for SAE reporting can be found on the SAE Report Form.
Figure imgf000096_0001
Figure imgf000097_0002
Liver Safely: Required Actions and Follow-up Assessments
[0542] Phase 2 Liver Chemistry Stopping Criteria and Follow-up Assessments are provided in FIG. 4.
[0543] Phase 2 liver chemistry stopping criteria are designed to assure subject safety and to evaluate liver chemistry stopping criteria are designed to assure subject safety and to evaluate liver event etiology. The guidelines provided below are based on the EASL Clinical Practice Guidelines: Drug Induced Liver Injury (2019) and Food and Drug Administration 2009 Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation.
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Abbreviation: ALT = alanine transaminase; AST = aspartate transaminase; eCRF = electronic case report form; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of normal.
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.
2. All events of ALT or AST t3 x ULN and total bilirubin t2 x ULN (> 35% direct bilirubin) or ALT or AST t3 x ULN and INR > 1.5 may indicate severe liver injury (possible “Hy’s Law”) and must be reported to sponsor in an expedited manner and as an SAE. The INR stated threshold value will not apply to subjects receiving anticoagulants.
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia).
4. Record the date/time of the PK blood sample draw and the date/time of the last dose of study drug prior to the blood sample draw on the eCRF. If the date/time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the Study Laboratory Manual.
Results from Placebo-Controlled Clinical Trial of Izokibep for Moderate-to-Severe
Hidradenitis Suppurativa [0544] The following are results of Part B of a Phase 2b trial evaluating izokibep for the treatment of moderate-to-severe Hidradenitis Suppurativa (HS).
[0545] The study was a randomized double-blind, placebo-controlled, multi-center trial evaluated the safety and efficacy of izokibep dosed 160 mg weekly (QW) and every two weeks (Q2W), versus placebo, in 175 patients with moderate-to-severe HS (Hurley Stage II and III). The trial was conducted at 50 sites globally and assessed various efficacy endpoints, including the primary endpoint of HiSCR75 (Hidradenitis Suppurativa Clinical Response) at 16 weeks utilizing a nonresponder imputation (NRI) analysis method.
[0546] A schematic of the study is provided in FIG. 5.
[0547] FIG. 5 provides a schematic of the Phase 2b study for use of Izokibep in treating HS and FIG. 6 provides an overview of the subjects in the study. Results and conclusions of the study are provided in FIGS. 7-20.
[0548] The data shown in FIG. 7 reveals that any discontinuation of subjects in the study was not related to adverse events. FIG. 8 provides an overview of results from the study. FIG. 9 shows the HiSCR response at week 16. FIG. 10 describes the drug exposure as consistent with observed dose response. FIG. 11 provides a last observation carried forward sensitivity analysis. FIG. 12 shows study discontinuations over time. FIG. 13 shows HiSCR responses over time. FIG. 14 shows results of a pre-planned interim analysis a week 12. FIG. 15 shows izokibep performed closely between Part A & B Pre-planned interim. FIG. 16 provides results of an independently conducted part B interim analysis demonstrating greater & deeper izokibep responses compared to Bimekizumab. FIG. 17 provides part B pre-planned interim over time. FIG. 18 provides data for the pre-planned part B interim with NRI at week 12. FIG. 19 provides data of a modified NRI approach to the part B interim data set revealing a high statistical significance. FIG. 20 provides a summary of the results of the phase 2b study.
[0549] The results of the study show that HiSCR response rates of izokibep 160mg weekly (QW) were consistent with Part A open label results, demonstrating early onset of HiSCRIOO at week 4, increasing through week 12 to 38% of patients in the Independently Conducted Pre-Planned Interim Analysis (FIG. 13).
[0550] The interim result data show that patient response to the therapy was dose ordered, and safety was consistent with prior izokibep experience and not dose-limiting. The results demonstrate that Izokibep provides early and high orders of response without safety or tolerability limitation. [0551] Further, as shown in the data (e g., FIGS. 14-20) show the consistency of Part A open label results relative to the Part B placebo-controlled interim analysis, which was pre-specified to be an as observed analysis at week 12.
[0552] Results of the study using a modified-NRI (mNRI) approach demonstrate the therapeutic performance of izokibep (FIG. 19).
[0553] The safety profile for izokibep was consistent with prior studies and the anti-IL-17A class. There were no events of Candida in the high dose 160mg QW arm and there were two discontinuations across the trial due to injection site reactions (3.5%).
Long-term 32-Week Data from the Phase 2b Trial of Izokibep in Hidradenitis Suppurativa Demonstrating Sustained Responses and Deepening Clinical Benefit - Improving Quality of Life for Patients
[0554] The following includes results from the same Phase 2b trial above. These results include data through week 32 for the long-term Phase 2b clinical trial of izokibep in hidradenitis suppurativa (HS) as set forth above. This Phase 2b clinical trial (NCT05355805) is a global, multicenter, randomized double-blind, placebo-controlled, trial evaluating the safety and efficacy of izokibep dosed 160 mg every week (QW) or every two weeks (Q2W) versus placebo. At week 16, patients who received placebo were randomized to either the weekly or every two-week active treatment arm and all patients were assessed through week 32. Follow up assessments also occur at weeks 39 and 45. The objective of the study was to determine the effect of izokibep versus placebo on various measures of clinical impact and determine the appropriate dose(s) for further clinical development in hidradenitis suppurativa.
[0555] An overview of the Phase 2b trial through week 32 (and the subsequent follow ups at weeks 39 and 45) is provided in Fig. 21. Fig. 22 provides the disposition of the trial participants through week 32, while Fig. 23 provides the participants’ baseline characteristics.
[0556] As shown in Fig. 24, through week 32, the measured HiSCR75 responses with 160 mg QW in HS patients provided a positive HiSCR75 response. Furthermore, when patients receiving a placebo were switched to the 160 mg QW izokibep dose, they likewise attained comparable positive HiSCR75 responses.
[0557] As shown in Fig. 25, high orders of HiSCR responses were observed for patients receiving izokibep 160 mg QW or Q2W, with almost one-third of participants achieving HiSCRIOO. Similarly, as shown in Fig. 26, patients who received a placebo for 16 weeks and then switched to a 160 mg izokibep dose (QW or Q2W) achieved clinically meaningful and comparable HiSCR responses as the patients who received the sustained izokibep dosages.
[0558] Surprisingly, as shown in Fig. 27, the 160 mg QW or Q2W izokibep dosages reaches HiSCRIOO responses at a rate that far surpasses currently-marketed IL-17A agents or comparable with currently-marketed IL-17A/F agents, but with a far improved safety profile.
[0559] As shown in Fig. 28, draining tunnel resolution with 160 mg QW continued to improve through week 32 of the trial. Further, as provided in Fig. 29, patients receiving the 160 mg QW dosage reported marked reductions in skin pain through week 32. Similarly, Fig. 30 provides data indicating that in patients receiving the 160 gm QW dose, marked improvements in DLQI were observed with a corresponding, clinically meaningful improvement in QOL.
[0560] The long-term data demonstrates that continued treatment with izokibep led to deepening of response over time without evidence of the safety liabilities observed with targeting IL- 17 more broadly than selectively targeting LL-17A. Patients who switched from placebo to izokibep at week 16 achieved a similar magnitude of response - within the same timeframe - as those who began treatment with izokibep at baseline for HiSCR, draining tunnels, skin pain and Dermatology Life Quality Index (DLQI). High orders of HiSCR were achieved with the majority of patients achieving HiSCR75 and about a third achieving HiSCRIOO through 32 weeks. These results are from an open label extension with all subjects through week 32.
[0561] The magnitude and depth of responses for signs and symptoms of Hidradenitis Suppurativa in this long-term study are consistent with izokibep’ s mechanism of action. These results are corroborated by the appreciable clinical responses observed in the placebo cross-over cohort, which demonstrate rapid, HiSCR response. These consistent and robust results in HS point to the future potential for izokibep to deliver differentiated clinical benefits for patients. Izokibep was well -tolerated with a favorable safety profile consistent with previous experience and the IL-17A class.
[0562] Potential for differentiation was demonstrated with higher clinical responses than reported by the currently-marketed IL-17A and IL-17A/F agents without evidence to date for increased risk of infection, especially fungal or suicidal ideation and behavior, in a patient population predisposed to infection and clinical depression.
[0563] The pain and discomfort that people living with HS experience on a daily basis is extremely debilitating, and these data are impressive, showing izokibep dose ordered, fast speed of onset across endpoints. The consistency and speed of responses in resolution of abscesses and nodules, reduction in draining tunnels, and improvement in pain, impact overall quality of life and indicate that izokibep provides a significant therapeutic benefit for patients with HS, while also providing a positive benefit risk in addressing an unmet need.
[0564] Interim Data at Weeks 12 and 16 of Phase 3 Trial of Izokibep in Hidradenitis Suppurativa Demonstrating Sustained Responses and Deepening Clinical Benefit - Improving Quality of Life for Patients
[0565] The following includes results from a Phase 3 clinical trial to further assess use of izokibep in hidradenitis suppurativa (HS). This Phase 3 clinical trial is a global, multi-center, randomized double-blind, placebo-controlled, trial evaluating the safety and efficacy of izokibep dosed 160 mg every week (QW) versus placebo. At week 16, patients who received the placebo are assigned to the weekly active treatment arm. All patients are assessed through week 52 after which, at week 59, there is a followup assessment. The objective of the study is to determine the effect of izokibep versus placebo on various measures of clinical impact and confirm the appropriate dose for further clinical development in hidradenitis suppurativa. The switch from placebo to active at week 16 helps to validate the first 16 weeks of data in the active treatment arm.
[0566] An overview of the Phase 3 trial through week 59 is provided in Fig. 31. Fig. 32 provides the baseline characteristics (left) and the patient disposition of trial participants (right) as assessed at week 12 of the Phase 3 clinical trial. The trial initially included 129 patients randomly selected for each of the placebo and Izokibep arms of the study. As shown, patient dropouts were mostly equivalent between both arms of the study. However, while the placebo arm lost a participant due to disease progression, no such dropout occurred in the active treatment arm.
[0567] As shown in Fig. 33, through week 12, the measured HiSCR75 responses with 160 mg QW in HS patients were positive, statistically relevant, and surpassed the placebo. Fig. 34 provides the HiSCR75 through week 16. As shown, both relative to the placebo arm, and from a quantitative perspective, the HiSCR75 values continued to increase in the active treatment arm through week 16, with 40% of participants meeting HiSCR75 on the 160 QW dose.
[0568] Fig. 35 shows the HiSCR90 (left) and HiSCRIOO responses at week 12. Fig. 36 shows HiSCR90 (left) and HiSCRIOO responses at week 16. As shown, over 20% of patients met HiSCRIOO at week 12, with 25% of participants meeting HiSCRIOO by week 16. [0569] Fig. 37 summarizes the HiSCR50, HiSCR75, HiSCR90, andHiSCRIOO responses through week 12 for the Phase 3 trial. Fig. 38 summarizes the HiSCR50, HiSCR75, HiSCR90, and HiSCRIOO responses through week 16. Fig. 39 summarizes the higher order responses (HiSCR90, and HiSCRIOO) for both the phase 3 trial through 12 weeks and across the Phase 2b trial (discussed above) and the Phase 3 trial. With approximately 1 in 4 patients achieving HiSCR90/100 by week 16, the data demonstrate high order HiSCR responses. This rate of HiSCR90/100 response surpasses known IL-17A targeting agents.
[0570] Further, as provided in Fig. 40, through week 12 of the Phase 3 trial, the 160 mg QW dosage produced marked reductions in skin pain. Fig. 40 also provides DLQI data (right) indicating that through week 12, patients in the active treatment arm showed marked improvements in DLQI, which were observed with a corresponding, clinically meaningful improvement in QOL. As provided in Fig. 41, through week 16, the 160 mg QW dosage produced increased reductions in skin pain (left) and maintained the improved DLQI (right).
[0571] Fig. 42 provides the safety results through week 12 of the Phase 3 trial. As shown, the only 1 serious TEAE was reported in the active treatment arm, with four times that number reported in the placebo arm. Overall, the results are consistent with those from the earlier trials, which helps confirm the safety profile of the tested treatment dose.
[0572] The interim Phase 3 study data met primary endpoint ofHiSCR75 at week 12 with statistical significance, which continues to confirm that continued treatment with izokibep provides a deepening of response over time without evidence of safety liabilities. These responses included high order HiSCR responses, with HiSCRIOO achieved by 22% of patients by week 12 of treatment. Treatment response in the trial also showed consistent improvement in resolution of abscesses and nodules as early as week 8 and a robust reduction in skin pain, and remarkable improvement in overall quality of life.
[0573] The Phase 3 trial also provides a differentiated profile. The rapidity, magnitude and depth of responses support the hypothesis that the characteristics of izokibep - including small size and highly potent and selective inhibition of IL-17A - provide differentiated clinical benefits. This is evident as resolution of abscesses and inflammatory nodules (HiSCRIOO) achieved twice as fast in twice as many patients compared to current, approved IL-17A agents. Moreover, there was no reported increased risk of fungal infection, which is a serious side effect of the IL-17A&F agents. Equivalents
[0574] Various modifications of the disclosure and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this disclosure in its various embodiments and equivalents thereof.
Incorporation by Reference
[0575] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.
[0576] Select abbreviations used herein:
ADL means activities of daily living
AE means adverse event
AN means abscess and inflammatory nodule
AUG means area under the concentration-time curve
AUCO-oo means area under the plasma concentration time curve extrapolated to infinity AUCO-T means area under the plasma concentration time curve over a dosing interval BID means twice daily
CFR means Code of Federal Regulations
CI means confidence interval
Cmax means maximum observed plasma concentration
COVID- 19 means coronavirus disease of 2019
CRF means case report form
CRO means Contract Research Organization
C-SSRS means Columbia-Suicide Severity Rating Scale
CTCAE means Common Terminology Criteria for Adverse Events
CV% means percent coefficient of variation
DLQI means Dermatology Life Quality Index
DMC means data monitoring committee
DNA means deoxyribonucleic acid
ECG means electrocardiogram eCRF means electronic case report form
EudraCT means European Union Drug Regulating Authorities Clinical Trials
FAS means Full Analysis Set
FSH means follicle-stimulating hormone
GCP means Good Clinical Practice HiSCR50 means hidradenitis suppurativa clinical response 50 is defined as at least a 50% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count
HiSCR75 is defined as at least a 75% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count HiSCR90 is defined as at least a 90% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count HiSCRIOO is defined as a 100% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscesses or draining fistula count.
HIV means human immunodeficiency virus.
HRT means hormonal replacement therapy
HS means hidradenitis suppurativa
IBD means inflammatory bowel disease
ICE means intercurrent event
ICH means International Council for Harmonisation
ICF means informed consent form
IEC means Independent Ethics Committee
IL means interleukin
IL-17A means interleukin 17A
IMP means investigational medicinal product IRB means Institutional Review Board ISR means injection site reaction
IV means intravenous(ly)
IXRS means Interactive Voice/Web Response System
JAK means Janus-kinase
MMRM means nonlinear mixed effects model with repeated measures
NOAEL means no observed adverse effect level
NRI means non-response imputation
NRS means numeric rating scale
PASI means Psoriasis Area and Severity Index
PASI90 means Psoriasis Area and Severity Index response of 90%
PK means pharmacokinetic(s)
PPD means purified protein derivative
PsA means psoriatic arthritis
QW means every week
Q2W means every other week
SAE means serious adverse event
SARS-CoV-2 means severe acute respiratory syndrome coronavirus
SC means subcutaneous(ly)
SoA means Schedule of Activities
SUS AR means suspected unexpected serious adverse reaction tU means half-life
TB means tuberculosis
TEAE means treatment-emergent adverse events Th 17 means T-helper 17 cell tmax means time to maximum observed concentration TNF-a means tumor necrosis factor-a
US means United States
USPI means United States prescribing information
WOCBP means women of childbearing potential
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Figure imgf000108_0001
Figure imgf000109_0002
Figure imgf000109_0001
Figure imgf000110_0002
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
References
Izokibep [Investigator’s Brochure] ACELYRIN INC., Version 8.0, 2022
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Claims

1. A method of treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor by administration to the patient a composition comprising izokibep or a salt thereof.
2. The method of claim 1, wherein the composition comprises between about 100 and about 200 mg of izokibep or a salt thereof.
3. The method of claim 1 or claim 2, wherein the composition comprises between about 150 and about 170 mg of izokibep or a salt thereof.
4. The method of any one of claims 1-3, wherein the composition comprises about 160 mg of izokibep or a salt thereof.
5. The method of any one of claims 1-4, wherein the composition comprises 160 mg of izokibep or a salt thereof.
6. The method of any one of claims 1-5, wherein the composition further comprises one or more of sodium phosphate, NaCl, and EDTA.
7. The method of any one of claims 1-6, wherein the composition is administered to the patient subcutaneously.
8. The method of claim 7, wherein the composition is administered in an arm, upper thigh, and/or abdomen of the patient.
9. The method of any one of claims 1-8, wherein the composition is administered to the patient once weekly.
10. The method of any one of claims 1-8, wherein the composition is administered to the patient twice weekly.
11. The method of any one of claims 1-10, wherein the composition is administered to the patient for between 1 and 52 weeks.
12. The method of claim 11, wherein the composition is administered to the patient for 16 weeks.
13. The method of any one of claims 1-12, wherein the condition is selected from one or more of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, hemolytic anemiajuvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or panuveitis, thyroiditis, and/or vasculitis.
14. The method of claim 13, wherein the condition is or comprises hidradenitis suppurativa (HS).
15. The method of claim 14, wherein the HS is a severe or a moderate HS.
16. The method of claim 14 or claim 15, wherein the HS presents as lesions in at least 2 anatomic areas of the patient, wherein the patient is Hurley Stage II or Hurley Stage III, wherein the patient has an abscess and inflammatory nodule (AN) count of > 5 prior to treatment.
17. The method of any one of claims 1-16, wherein prior to the administration, the patient has received a TNF-a inhibitor to treat the condition.
18. The method of any one of claims 1-17, wherein prior to the administration the patient exhibited an inadequate response to > 3 month treatment with an oral antibiotic for treatment of the condition, exhibited recurrence of the condition after discontinuing an antibiotic treatment, and/or the patient demonstrated intolerance to and/or exhibits a contraindication to oral antibiotics for treatment of the condition.
19. The method of any one of claims 1-18, wherein the condition affects areas of the patient’s skin, and wherein during the administration with composition, the patient applies topical antiseptics to the affected areas.
20. The method of any one of claims 1-19, wherein the condition is HS and wherein the administration of the composition provides to the patient at least a 75% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
21. The method of claim 20, wherein the 75% reduction occurs before or at a sixteenth week of the administration of the composition.
22. The method of any one of claims 1-21, wherein the condition is HS and wherein the administration of the composition provides to the patient at least a 90% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
23. The method of claim 22, wherein the 90% reduction occurs before or at a sixteenth week of the administration of the composition.
24. The method of any one of claims 1-23, wherein the condition is HS and wherein the administration of the composition provides to the patient an AN count of 0, 1, or 2.
25. The method of any one of claims 1-24, wherein the condition is HS and wherein the administration of the composition provides to the patient at least a 3-point reduction from baseline in an NRS Patient Global Assessment of Skin Pain.
26. The method of any one of claim 1-25, wherein the treatment reduces IL- 17 expression in the patient.
27. A medicament for the treatment of a condition in a human subject that has received prior treatment with a TNF-a inhibitor comprising izokibep or a salt thereof.
28. The medicament of claim 26, comprising between about 100 and about 200 mg of izokibep or a salt thereof.
29. The medicament of claim 26 or claim 27, comprising between about 150 and about 170 mg of izokibep or a salt thereof.
30. The medicament of any one of claims 26-28, comprising about 160 mg of izokibep or a salt thereof.
31. The medicament of any one of claims 26-29, comprising 160 mg of izokibep or a salt thereof.
32. The medicament of any one of claims 26-30, further comprising one or more of sodium phosphate, NaCl, and EDTA.
33. The medicament of any one of claims 26-32, wherein the medicament is formulated for subcutaneous administration.
34. The medicament of claim 33, wherein the subcutaneous administration is in an arm, upper thigh, and/or abdomen of the subject.
35. The medicament of any one of claims 26-34, wherein the medicament is administered to the subject one weekly.
36. The medicament of any one of claims 26-34, wherein the medicament is administered to subject twice weekly.
37. The medicament of any one of claims 26-36, wherein the medicament is administered to a subject for between 1 and 52 weeks.
38. The medicament of claim 37, wherein the medicament is administered to the patient for 16 weeks.
39. The medicament of any one of claims 26-37, wherein the condition is selected from one or more of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel syndrome or disease, multiple sclerosis, Addison's disease, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, diabetes type 1, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hidradenitis suppurativa, hemolytic anemiajuvenile arthritis, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, including plaque psoriasis, psoriatic arthritis, refractory asthma, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, uveitis, including non-infectious-, intermediate-, and/or panuveitis, thyroiditis, and/or vasculitis.
40. The medicament of claim 39, wherein the condition is or comprises hidradenitis suppurativa (HS).
41. The medicament of claim 40, wherein the HS is a severe or a moderate HS.
42. The medicament of claim 40 or claim 41, wherein the HS presents as lesions in at least 2 anatomic areas of the patient, wherein the patient is Hurley Stage II or Hurley Stage III, and/or wherein the patient has an abscess and inflammatory nodule (AN) count of > 5 prior to administration.
43. The medicament of any one of claims 26-42, wherein the patient has received a TNF-a inhibitor to treat the condition.
44. The medicament of any one of claims 26-43, wherein prior to receiving the medicament the patient exhibited an inadequate response to > 3 month treatment with an oral antibiotic for treatment of the condition, exhibited recurrence of the condition after discontinuing an antibiotic treatment, and/or the patient demonstrated intolerance to and/or exhibits a contraindication to oral antibiotics for treatment of the condition.
45. The medicament of any one of claims 26-44, wherein the condition affects areas of the patient’s skin, and in conjunction to receiving the medicament the patient applies a topical antiseptic to the affected areas.
46. The medicament of any one of claims 26-45, wherein the condition is HS and wherein administration of the medicament provides to the patient at least a 75% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
47. The medicament of claim 46, wherein the 75% reduction occurs before or at a sixteenth week of the administration of the medicament.
48. The medicament of any one of claims 26-47, wherein the condition is HS and wherein administration of the medicament provides to the patient at least a 90% reduction from baseline in the patient’s total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining fistula count.
49. The medicament of claim 48, wherein the 90% reduction occurs before or at a sixteenth week of the administration of the medicament.
50. The medicament of any one of claims 26-49, wherein the condition is HS and wherein administration of the medicament to the patient provides to the patient an AN count of 0, 1, or 2.
51. The medicament of any one of claims 26-50, wherein the condition is HS and wherein the administration of the medicament to the patient provides to the patient at least a 3-point reduction from baseline in an NRS Patient Global Assessment of Skin Pain.
52. A composition comprising izokibep or a salt thereof for use in the treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor.
53. A composition for use according to claim 52, wherein the composition comprises between about 100 and about 200 mg of izokibep or a salt thereof.
54. A composition for use according to claim 52 or claim 53, wherein the composition comprises between about 150 and about 170 mg of izokibep or a salt thereof.
55. A composition for use according to any one of claims 52-54, wherein the composition comprises about 160 mg of izokibep or a salt thereof.
56. A composition for use according to any one of claims 52-55, wherein the composition comprises 160 mg of izokibep or a salt thereof.
57. A composition for use according to any one of claims 52-56, wherein said treatment is as defined in any one of claims 7-26.
58. Use of a composition comprising izokibep or a salt thereof in the manufacture of a medicament for the treatment of one or more condition in a patient who has received a tumor necrosis factor alpha (TNF-a) inhibitor.
59. Use according to claim 58, wherein the composition comprises between about 100 and about 200 mg of izokibep or a salt thereof.
60. Use according to claim 58 or claim 59, wherein the composition comprises between about 150 and about 170 mg of izokibep or a salt thereof.
61. Use according to any one of claims 58-60, wherein the composition comprises about 160 mg of izokibep or a salt thereof.
62. Use according to any one of claims 58-61, wherein the composition comprises 160 mg of izokibep or a salt thereof.
63. Use according to any one of claims 58-62, wherein said treatment is as defined in any one of claims 7-26.
PCT/US2024/045651 2023-09-08 2024-09-06 Methods of treating hidradenitis suppurativa Pending WO2025054498A1 (en)

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Citations (2)

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