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WO2024223740A1 - Traitement du psoriasis à l'aide de petites molécules inhibitrices du facteur de nécrose tumorale alpha - Google Patents

Traitement du psoriasis à l'aide de petites molécules inhibitrices du facteur de nécrose tumorale alpha Download PDF

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Publication number
WO2024223740A1
WO2024223740A1 PCT/EP2024/061394 EP2024061394W WO2024223740A1 WO 2024223740 A1 WO2024223740 A1 WO 2024223740A1 EP 2024061394 W EP2024061394 W EP 2024061394W WO 2024223740 A1 WO2024223740 A1 WO 2024223740A1
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Prior art keywords
compound
psoriasis
subject
score
treatment
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PCT/EP2024/061394
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English (en)
Inventor
Ohn CHOW
Nassr NASSR
Mai Anh NGUYEN
Laurent Perrin
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Sanofi SA
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Sanofi SA
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Priority to CN202480028154.3A priority Critical patent/CN121038791A/zh
Publication of WO2024223740A1 publication Critical patent/WO2024223740A1/fr
Priority to IL324175A priority patent/IL324175A/en
Priority to MX2025012780A priority patent/MX2025012780A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P17/06—Antipsoriatics

Definitions

  • a treatment for psoriasis in which patients are administered a defined amount of a small molecule inhibitor of soluble tumor necrosis factor alpha. This is based on the results of a clinical trial which showed that treatment with the inhibitor over 28 days was effective, safe, and well-tolerated by participants with mild-to-moderate psoriasis.
  • Tumor necrosis factor alpha is a cytokine with pleiotropic effects on both pathologic and homeostatic processes. TNFa is thought to have a key pathophysiological role in psoriasis (see, e.g., Mease, Ann Rheum Dis (2004) 63:755-758) and TNFa antagonists have become a cornerstone in modem management of psoriasis.
  • the TNFa is a member of the TNF superfamily of cytokines. It is produced by a variety of cell types, most notably, inflammatory cells. It is initially expressed as a transmembrane protein, also known as membrane-bound TNFa (mTNFa). At the cell surface, mTNFa may undergo cleavage by TNFa-converting enzyme to generate soluble TNFa (sTNFa). Structurally, both mTNFa and sTNFa exist as homotrimers which can bind three cognate receptors. This trimeric engagement is critical for receptor multimerization and subsequent signal transduction. sTNFa mainly signals via tumor necrosis factor receptor 1 (TNFR1), which is expressed on most cell types.
  • TNFR1 tumor necrosis factor receptor 1
  • TNFR2 tumor necrosis factor receptor 2
  • TNFR2 is expressed primarily on neurons, endothelial cells, and immune cells, with particular enrichment on certain subpopulations of regulatory T-cells (Tregs).
  • sTNFa and mTNFa play different roles in pathologic and homeostatic processes.
  • sTNFa engagement of TNFR1 leads to activation of pro-inflammatory and pro- apoptotic pathways, which play pivotal roles in the effect of TNFa in certain autoimmune conditions.
  • mTNFa signaling contributes to a variety of homeostatic functions, including tissue regeneration and cell survival. From an inflammatory standpoint, mTNFa has been shown to enhance function and proliferation of specific subsets of suppressive Tregs.
  • TNFR2 agonism has also been shown to promote death of autoreactive CD8+ T-cells.
  • mTNFa mice which express only a non-cleavable form of TNFa, have been generated to study the specific effects of mTNFa.
  • respiratory tuberculosis infection models multiple studies have demonstrated reduced mortality and bacterial burden in mTNFa mice compared with TNFa knockout mice. Similar results have been demonstrated in Listeria monocytogenes, Mycobacterium bovis bacilli Calmette-Guerin, and Leishmania major murine infection models.
  • sTNFa A naturally occurring, asymmetric trimeric form of sTNFa, which is normally a transient intermediate, has an impaired capacity to engage TNFR1 (see, e.g., O’Connell et al., Nat Commun (2019) 10:5795-5806).
  • O’Connell et al. used analytical size exclusion to demonstrate the impaired capacity of sTNFa; they further demonstrated that UCB-9260, a molecule having a trisubstituted benzimidazole structure, stabilizes the asymmetric sTNFa trimer and impairs TNFR1 signaling in vitro.
  • TNFR1 signaling as measured by Western Blot analysis of kinases, receptor-interacting protein kinase 1 (RIP-1) ubiquitination and nuclear factor kappa B (NF-KB) phosphorylation, was impaired in both the etanercept- and UCB-9260-treated samples as compared with the samples treated with sTNFa alone.
  • RIP-1 receptor-interacting protein kinase 1
  • NF-KB nuclear factor kappa B
  • the compound which is employed in the treatments of the present disclosure is (7R, 14R) ⁇ 11- [2-(l-aminocyclobutyl)pyrimidin-5-yl]-l-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- methanobenzimidazo[l,2-/>][2,5]benzodiazocin-5(1477)-one.
  • the structure of this compound, Compound 1, is shown below and it has a pentacyclic core structure:
  • PCT/EP2018/060489 (published as WO 2018/197503), which also describes the compound as belonging to a class of modulators of human TNFa activity which are useful for the treatment and/or prevention of various conditions, including a range of inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.
  • Psoriasis is a T cell-mediated disease with autoimmune characteristics modulated by genetic susceptibility along with environmental triggers. Inflammatory pathways marked with excessive production of cytokines interleukin- 12 (IL- 12) and interleukin-23 (IL-23), drive differentiation of pathogenic T cell responses resulting in TNF and interleukin- 17 (IL- 17) production. These cytokines are an integral part of the TNF/IL-23/IL-17 axis, which is responsible for maintaining inflammation in psoriatic skin (see, e.g., Bergen et al., Scand J Immunol. (2020) 92(4):el2946). Psoriasis is estimated to affect 1% to 3% of the world’s population.
  • psoriasis has been treated using topical formulations (e.g., creams and ointments, which may have just an emollient effect, or which may include active agents such as steroids and/or vitamin D analogues), phototherapy, and systemic therapeutic treatments (e.g., treatment with oral inflammatory suppressors such as methotrexate, or immunosuppressants such as ciclosporin).
  • topical formulations e.g., creams and ointments, which may have just an emollient effect, or which may include active agents such as steroids and/or vitamin D analogues
  • systemic therapeutic treatments e.g., treatment with oral inflammatory suppressors such as methotrexate, or immunosuppressants such as ciclosporin.
  • biologic therapies which inhibit TNFa have been developed, such as etanercept (Enbrel®, which is authorized in the EU for the treatment of conditions including moderate and severe plaque psoriasis).
  • Biologic therapies can be highly effective, but carry the risk of immunogenicity and development of neutralizing anti-drug antibodies, as well as side effects, some of which can be severe; they are also typically administered by injection and may require medical supervision or monitoring. There is, therefore, an acute need for new treatments for psoriasis which are effective, have an acceptable safety profile, and provide advantages in terms of ease of manufacture, storage, and suitability for oral administration.
  • the present disclosure provides results from a clinical trial in which Compound 1 was administered orally to patients with psoriasis.
  • the results suggest that the treatment described herein is not only effective at reducing clinical symptoms, but is also effective at reducing the levels of inflammatory mediators implicated in the progression of the disease.
  • There were no serious adverse effects identified during the course of the trial no safety concerns based on vital signs, ECG or laboratory results, and no signal for risks on liver function tests. No indication for risks on QTc prolongation was observed. This is believed to be the first successful clinical trial of a small molecule inhibitor of TNFa in patients with psoriasis.
  • the disclosure provides a compound for use in a method of treating psoriasis in a human subject, wherein the compound is (77?,147?)-ll-[2-(l-aminocyclobutyl)pyrimidin- 5-yl] - 1 -(difluoromethoxy )-6-methy 1-6, 7-dihy dro-7, 14-methanobenzimidazo[ 1 ,2-
  • Compound 1 6][2,5]benzodiazocin-5(1477)-one (Compound 1): or a pharmaceutically acceptable salt thereof, wherein the subject has mild to moderate psoriasis, and wherein the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as the free base).
  • the psoriasis is plaque psoriasis, e.g., chronic plaque psoriasis.
  • the severity of psoriasis in the subject is assessed using PASI scoring, and the subject has a total PASI score which is ⁇ 16.
  • the subject has a total PASI score which is > 10.
  • the subject has at least two lesions with TLS score > 4 (excluding the scalp).
  • the compound is administered to the subject orally.
  • the compound is administered in the form of an oral pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the oral pharmaceutical composition is a tablet.
  • the method comprises administering to the subject a dose of about 200 mg of the compound (calculated as the free base) twice daily.
  • the disclosure provides a method of treating psoriasis as defined hereinbefore, wherein a therapeutically effective amount of Compound 1 (or a pharmaceutically acceptable salt thereof) is administered to a human subject in need thereof, and wherein the therapeutically effective amount is a daily dose of about 400 mg (calculated as the free base).
  • the disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating mild to moderate psoriasis in accordance with a method as defined hereinbefore, wherein the medicament is adapted to provide a daily dose of about 400 mg of the compound (calculated as the free base).
  • Fig. 1 shows the mean ( ⁇ SEM) change in TLS score from baseline over 2 and 4 weeks of treatment in human subjects with psoriasis.
  • the solid line with filled circles is the placebo treatment arm, and the dashed line with open circles is the Compound 1 treatment arm.
  • Fig. 2 shows the mean ( ⁇ SEM) change in total PASI score from baseline over 2 and 4 weeks of treatment in human subjects with psoriasis.
  • the solid line with filled circles is the placebo treatment arm, and the dashed line with open circles is the Compound 1 treatment arm.
  • Fig. 3 shows the ratio from baseline over time for the serum levels of IL-17A, a systemic biomarker of psoriasis (data represent geometric mean ( X A) geometric SEM).
  • the light grey line (top) is the placebo treatment arm, and the dark grey line (bottom) is the Compound 1 treatment arm.
  • Fig. 4 shows the ratio from baseline over time for the serum levels of IL-17F, a systemic biomarker of psoriasis (data represent geometric mean ( X A) geometric SEM).
  • the light grey line (top) is the placebo treatment arm, and the dark grey line (bottom) is the Compound 1 treatment arm.
  • Fig. 5 shows the ratio from baseline over time for the serum levels of IL-22, a systemic biomarker of psoriasis (data represent geometric mean ( X A) geometric SEM).
  • the light grey line (top) is the placebo treatment arm, and the dark grey line (bottom) is the Compound 1 treatment arm.
  • Fig. 6 shows the percentage of patients achieving a static Investigators Global Assessment (sIGA) score category (determined as described herein) at baseline, week 2, and week 4.
  • sIGA Investigators Global Assessment
  • an amount of Compound 1 or a pharmaceutically acceptable salt thereof which is defined as being “about 400 mg (calculated as the free base)” may be an amount which is between 360 mg and 440 mg (calculated as the free base), i.e., 400 mg ⁇ 10%; alternatively, the variation may be ⁇ 5%, ⁇ 2%, or ⁇ 1% of the value. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.
  • an inhibitor includes a plurality of inhibitors, including mixtures thereof.
  • the term “or” is understood to be inclusive.
  • the term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but do not exclude others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass both “consisting essentially of’ and “consisting of’.
  • a “subject”, “individual”, or “patient” is used interchangeably herein, and refers to a human.
  • administering is defined herein as a means of providing an agent (e.g., active ingredient) or a composition containing the agent to a subject in a manner that results in the agent being inside the subject’s body.
  • agent e.g., active ingredient
  • compositions containing the agent e.g., a composition containing the agent to a subject in a manner that results in the agent being inside the subject’s body.
  • Such an administration can be by any route including, without limitation, oral administration.
  • Pharmaceutical preparations are, of course, given by forms suitable for each administration route.
  • the compositions and methods of the present disclosure are typically directed towards enteral, e.g. oral, administration.
  • Treating” or “treatment” of a disease includes: (1) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and/or (2) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.
  • Preventing” or “prevention” of a disease includes causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease.
  • the term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with the disease.
  • the term “suffering” as it relates to the term “prevention” refers to a patient or individual who is predisposed to the disease.
  • a patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease.
  • a patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.
  • an “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the severity of the particular disorder being treated, and the form of administration.
  • dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on suitable doses for patient administration.
  • one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with a disease or disorder described herein, ex vivo, in vitro, or in vivo.
  • the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • Pharmaceutical compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).
  • pharmaceutically acceptable salt means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.
  • a mass quantity (e.g., a dosage amount) of Compound 1 referred to herein corresponds, unless expressly stated otherwise, to a mass of the compound calculated as the free base.
  • a 400 mg dose of compound refers to an amount of 400 mg of Compound 1 free base, or to an amount of a salt of Compound 1 which provides an equivalent molar quantity of Compound 1 ; this is referred to herein as an amount “calculated as the free base”.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • IL interleukin e.g., IL-17A, IL-17F, IL-22
  • PASI psoriasis area and severity index (the following abbreviations are used in connection with PASI scoring: head (h), upper extremities (u), trunk (t), lower extremities (1), numerical score (A), erythema (E), thickness/induration (I), and desquamation/scaling (D), such that “Eh” would denote erythema of the head, “It” would denote induration of the trunk, etc.)
  • the present disclosure describes a clinical study which has been carried out to assess the impact of Compound 1 on patients with mild and moderate psoriasis.
  • Oral administration of 400 mg of Compound 1 per day was shown to be effective in improving clinical parameters in human patients, including Psoriasis Area and Severity Index (PASI) score, and Target Lesion Severity (TLS) score. Improvements in biomarkers for psoriasis were also observed, including serum levels of IL-17A, IL-17F and IL-22. No serious or severe adverse events were observed during the study, neither was any significant impact on cardiac parameters (e.g., QTcF interval) or liver parameters (e.g., AST, ALT, or bilirubin levels) observed.
  • cardiac parameters e.g., QTcF interval
  • liver parameters e.g., AST, ALT, or bilirubin levels
  • a first aspect of the present disclosure provides a compound for use in a method of treating psoriasis in a human subject, wherein the compound is (77?,147?)-ll-[2-(l- aminocy clobutyl)pyrimidin-5-yl]- 1 -(difluoromethoxy)-6-methyl-6,7-dihy dro-7, 14- methanobenzimidazo[l,2-/>][2,5]benzodiazocin-5(1477)-one (i.e., Compound 1): or a pharmaceutically acceptable salt thereof, wherein the subject has mild to moderate psoriasis, and wherein the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as the free base).
  • a related aspect provides a method of treating psoriasis in a human subject in need thereof, wherein the subject has mild to moderate psoriasis, and wherein the method comprises administering a therapeutically effective amount of (77?,147?)-ll-[2-(l- aminocy clobutyl)pyrimidin-5-yl]- 1 -(difluoromethoxy)-6-methyl-6,7-dihy dro-7, 14- methanobenzimidazo[l,2-6][2,5]benzodiazocin-5(1477)-one (i.e., Compound 1): or a pharmaceutically acceptable salt thereof to the subject, wherein the therapeutically effective amount is a daily dose of about 400 mg (calculated as the free base).
  • Another related aspect provides a compound for use in the manufacture of a medicament for treating psoriasis in a human subject, wherein the compound is (77?,147?)-ll-[2-(l- aminocy clobutyl)pyrimidin-5-yl]- 1 -(difluoromethoxy)-6-methyl-6,7-dihy dro-7, 14- methanobenzimidazo[l,2-6][2,5]benzodiazocin-5(1477)-one (i.e., Compound 1): or a pharmaceutically acceptable salt thereof, wherein the subject has mild to moderate psoriasis, and wherein the medicament is adapted to provide the subject with a daily dose of about 400 mg of the compound (calculated as the free base).
  • the psoriasis is plaque psoriasis. In embodiments, the psoriasis is chronic plaque psoriasis. In embodiments, the subject has mild psoriasis.
  • the disclosure provides a compound for use in a method of treating mild psoriasis in a human subject, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as the free base). In other embodiments, the subject has moderate psoriasis.
  • the disclosure provides a compound for use in a method of treating moderate psoriasis in a human subject, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as the free base).
  • the severity of psoriasis in the subject is assessed using PASI scoring, e.g. as described herein (see also, e.g., the EMA Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, November 18 th , 2004).
  • the subject may be classified as having mild to moderate psoriasis by virtue of having a total PASI score which is ⁇ 16.
  • the subject has a total PASI score which is ⁇ 16.
  • the subject may be classified as having mild psoriasis by virtue of having a total PASI score which is ⁇ 10.
  • the subject has a total PASI score which is ⁇ 10.
  • the subject may be classified as having moderate psoriasis if they have a total PASI score which is > 10.
  • the subject has a total PASI score which is > 10.
  • the disclosure provides a compound for use in a method of treating psoriasis in a human subject, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, wherein the subject has a total PASI score of > 10, and wherein the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as the free base).
  • the subject has a total PASI score which is > 10 and ⁇ 16.
  • the disclosure provides a compound for use in a method of treating psoriasis in a human subject, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, wherein the subject has a total PASI score of ⁇ 10, and wherein the method comprises administering to the subject a daily dose of about 400 mg of the compound (calculated as the free base).
  • the treatment results in a reduction in total PASI score (e.g., as compared to baseline, which may be assessed immediately before treatment commences).
  • the reduction is a reduction of at least 1 point, e.g. a reduction of about 1.5 points.
  • the reduction is a reduction of at least 2 points, e.g., a reduction of about 3 points.
  • the reduction in total PASI score is a reduction of at least 15%, e.g. a reduction of at least 25% or at least 35%.
  • the reduction is effected over a period of at least 2 weeks or at least 4 weeks.
  • the treatment results in a reduction in total PASI score of about 1.5 points over a period of about 2 weeks. In embodiments, the treatment results in a reduction in total PASI score of about 17% over a period of about 2 weeks. In embodiments, the treatment results in a reduction in total PASI score of about 3 points over a period of about 4 weeks. In embodiments, the treatment results in a reduction in total PASI score of about 35% over a period of about 4 weeks. In embodiments, the subject has a total PASI score of ⁇ 10 and the treatment results in a reduction in total PASI score of about 21% over a period of about 2 weeks, and/or a reduction in total PASI score of about 34% over a period of about 4 weeks.
  • the subject has a total PASI score of > 10 and the treatment results in a reduction in total PASI score of about 9% over a period of about 2 weeks and/or a reduction in total PASI score of about 33% over a period of about 4 weeks.
  • the presence (or severity) of psoriasis in the subject is assessed using TLS scoring, e.g. as described herein (see also, e.g., Fredriksson et al., Dermatologica (1978) 157(4):238-244; as well as Czamowicki et al., J Am Acad Dermatol. (2014) 71 (5): 954- 959.el).
  • TLS scoring e.g. as described herein (see also, e.g., Fredriksson et al., Dermatologica (1978) 157(4):238-244; as well as Czamowicki et al., J Am Acad Dermatol. (2014) 71 (5): 954- 959.el).
  • the subject has at least two lesions with TLS score > 4 (excluding the scalp).
  • the subject has at least two lesions with TLS score > 4 (excluding the scalp) and also has a total PASI score of ⁇ 16.
  • the treatment results in a reduction in TLS score of one or more lesions (e.g., as compared to baseline, which may be assessed immediately before treatment commences).
  • the TLS score is calculated as the average score from 2 lesions.
  • the reduction is a reduction of at least 1 point. In embodiments, the reduction is a reduction of about 1 point. In other embodiments, the reduction is a reduction of at least 1.5 points, e.g., a reduction of about 2.5 points. In embodiments, the reduction is a reduction of at least 15%, e.g., a reduction of at least 35%. In embodiments, the reduction is effected over a period of at least 2 weeks or at least 4 weeks.
  • the treatment results in a reduction in TLS score of about 1 point over a period of about 2 weeks. In embodiments, the treatment results in a reduction in TLS score of about 17% over a period of about 2 weeks. In embodiments, the treatment results in a reduction in TLS score of about 2.5 points over a period of about 4 weeks. In embodiments, the treatment results in a reduction in TLS score of about 38% over a period of about 4 weeks. In embodiments, the subject has a total PASI score of ⁇ 10 and the treatment results in a reduction in TLS score of about 21% over a period of about 2 weeks, and/or a reduction in TLS score of about 37% over a period of about 4 weeks. In embodiments, the subject has a total PASI score of > 10 and the treatment results in a reduction in TLS score of about 11% over a period of about 2 weeks and/or a reduction in TLS score of about 40% over a period of about 4 weeks.
  • the presence (or severity) of psoriasis in the subject is assessed using sIGA scoring, e.g. as described herein (see also, e.g., Langley et al., J Dermatolog. Treat. (2015) 26(l):23-31).
  • the subject may be classified as having mild to moderate psoriasis by virtue of having a mean sIGA score (e.g., the mean average calculated from the scoring for erythema, induration, and scaling as described below) which is less than 4.5.
  • a mean sIGA score which is > 0.0 and which is ⁇ 4.5, e.g.
  • a mean sIGA score which is > 1.5 and which is ⁇ 3.5 has a mean sIGA score which is > 0.0 and which is ⁇ 2.5, e.g. a mean sIGA score which is > 1.5 and which is ⁇ 2.5 (e.g., the subject is classified as having mild psoriasis).
  • the subject has a mean sIGA score which is > 2.5 and which is ⁇ 4.5, e.g. a mean sIGA score which is > 2.5 and which is ⁇ 3.5 (e.g., the subject is classified as having moderate psoriasis).
  • the sIGA scoring can also be used alongside other assessment measures, e.g. those described herein.
  • the subject has a mean sIGA score which is ⁇ 4.5, and has: (i) at least two lesions with TLS score > 4 (excluding the scalp); (ii) a total PASI score of ⁇ 16; or (iii) at least two lesions with TLS score > 4 (excluding the scalp) and a total PASI score of ⁇ 16.
  • the subject has a mean sIGA score which is ⁇ 3.5, e.g. a mean sIGA score which is ⁇ 2.5.
  • the subject may be classified as having mild to moderate psoriasis on the basis of an overall sIGA score (e.g., a sIGA score translated as described below into an integer from 0 to 5).
  • the subject has an overall sIGA score of 1, 2, 3, or 4.
  • the subject has an overall sIGA score of 1 or 2, e.g. an overall sIGA score of 2 (e.g., the subject is classified as having mild psoriasis).
  • the subject has an overall sIGA score of 3 or 4, e.g. an overall sIGA score of 3 (e.g., the subject is classified as having moderate psoriasis).
  • the treatment results in a reduction in mean sIGA score (e.g., as compared to baseline). In embodiments, the reduction is effected over a period of at least about 2 weeks or at least about 4 weeks.
  • the treatment results in a reduction in mean sIGA score of at least about 0.3, e.g. a reduction of at least about 0.6, 1.0, 1.3, or 1.6. In embodiments, the treatment results in a reduction in mean sIGA score of up to about 2.0, e.g. a reduction of up to about 1.7, 1.4, or 1.0. In embodiments, the reduction is a reduction of from about 0.3 to about 1.7. In embodiments, the treatment results in a reduction in mean sIGA score of from about 0.3 to about 1.7, e.g. from about 0.6 to about 1.4, such as about 1.0, over a period of about 2 weeks.
  • the treatment results in a reduction in mean sIGA score of from about 0.3 to about 1.7, e.g. from about 0.6 to about 1.4, such as about 1.0, over a period of about 4 weeks.
  • the subject has a mean sIGA score of less than 3.5 following treatment, e.g. mean sIGA score of less than about 2.5 or 1.5 following treatment.
  • the subject has a mean sIGA score of from 0 to about 2.5, e.g. from 0 to about 1.5, following treatment over a period of at least about 2 weeks or at least about 4 weeks.
  • the treatment results in a reduction in overall sIGA score (e.g., as compared to baseline). In embodiments, the reduction is effected over a period of at least 2 weeks or at least 4 weeks. In embodiments, the treatment results in a reduction in overall sIGA score of at least 1 point, e.g. a reduction in overall sIGA score of 1 point or more. In embodiments, the reduction is a reduction of 1 point. In embodiments, the treatment results in a reduction in overall sIGA score of 1 point over a period of about 2 weeks. In embodiments, the treatment results in a reduction in overall sIGA score of 1 point over a period of about 4 weeks.
  • the subject has an overall sIGA score of > 3 following treatment, e.g. an overall sIGA score of > 2 or > 1 following treatment. In embodiments, the subject has an overall sIGA score of 1 or 2 following treatment over a period of at least about 2 weeks. In embodiments, the subject has an overall sIGA score of 1 or 2 following treatment over a period of at least about 4 weeks. In embodiments, the subject has an overall sIGA score of 1 following treatment over a period of at least 4 weeks.
  • the treatment results in a reduction in the level of one or more biomarkers of psoriasis in the subject, e.g., a reduction in the level of IL-17A, IL-17F, and/or IL-22 in the blood (e.g., serum) of the subject.
  • the treatment results in a reduction in the level of IL-17A, e.g., a reduction in the level of IL-17A in the blood (e.g., serum) of the subject.
  • the treatment results in a reduction in the serum level of IL-17A of at least about 0.05 pg/mL (e.g., as compared to baseline, which may be assessed immediately before treatment commences), e.g., a reduction of at least about 0.15 pg/mL.
  • the treatment results in a reduction in the serum level of IL-17A of about 0.06 pg/mL at 2 weeks.
  • the treatment results in a reduction in the serum level of IL-17A of about 0.18 pg/mL at 4 weeks.
  • the treatment results in a reduction in the serum level of IL-17A of at least about 10% (e.g., as compared to baseline, which may be assessed immediately before treatment commences), e.g., at least about 25%. In embodiments, the treatment results in a reduction in the serum level of IL-17A of about 8% at 2 weeks. In embodiments, the treatment results in a reduction in the serum level of IL-17A of about 28% at 4 weeks. In embodiments, the treatment results in a reduction in the level of IL- 17F, e.g., a reduction in the level of IL-17F in the blood (e.g., serum) of the subject.
  • the treatment results in a reduction in the serum level of IL-17F of at least about 1.0 pg/mL (e.g., as compared to baseline, which may be assessed immediately before treatment commences), e.g., a reduction of at least about 1.2 pg/mL.
  • the treatment results in a reduction in the serum level of IL-17F of about 1.0 pg/mL at 2 weeks.
  • the treatment results in a reduction in the serum level of IL-17F of about 1.3 pg/mL at 4 weeks.
  • the treatment results in a reduction in the serum level of IL-17F of at least about 35% (e.g., as compared to baseline, which may be assessed immediately before treatment commences), e.g., at least about 50%. In embodiments, the treatment results in a reduction in the serum level of IL-17F of about 39% at 2 weeks. In embodiments, the treatment results in a reduction in the serum level of IL-17F of about 52% at 4 weeks. In embodiments, the treatment results in a reduction in the level of IL-22, e.g., a reduction in the level of IL-22 in the blood (e.g., serum) of the subject.
  • the treatment results in a reduction in the serum level of IL-22 of at least about 1.0 pg/mL (e.g., as compared to baseline, which may be assessed immediately before treatment commences), e.g., a reduction of at least about 1.5 pg/mL.
  • the treatment results in a reduction in the serum level of IL-22 of about 1.2 pg/mL at 2 weeks. In embodiments, the treatment results in a reduction in the serum level of IL-22 of about 1.6 pg/mL at 4 weeks.
  • the treatment results in a reduction in the serum level of IL-22 of at least about 30% (e.g., as compared to baseline, which may be assessed immediately before treatment commences), e.g., at least about 40%. In embodiments, the treatment results in a reduction in the serum level of IL-22 of about 34% at 2 weeks. In embodiments, the treatment results in a reduction in the serum level of IL-22 of about 43% at 4 weeks. In embodiments, the subject at the outset of treatment satisfies one or more (e.g., all) criteria selected from: (a) male or female (e.g., male) and aged between 18 and 65 years, inclusive;
  • the subject at the outset of treatment fails to satisfy any (e.g. all) of the criteria selected from: (a) pre-existing signs of skin atrophy, telangiectasia or striae in the affected area; (b) current evidence of non-plaque forms of psoriasis (e.g., erythrodermic, guttate or pustular) or psoriatic arthritis; (c) current evidence or suspicion of drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis from beta blockers, calcium channel blockers, or lithium); (d) presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician; (e) opportunistic infections within 6 months of the intended treatment start date; (f) any previous gastrointestinal surgery or recent (within 3 months prior to intended treatment start date) history of gastrointestinal disease that could impact the absorption of Compound 1; (g) history of drug or alcohol abuse within the 12 months prior to intended treatment
  • the present disclosure contemplates salt forms of Compound 1, e.g., Compound 1 in the form of a pharmaceutically acceptable salt. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P H. Stahl & C.G. Wermuth, Wiley- VCH, 2002.
  • the compound is a pharmaceutically acceptable salt of Compound 1.
  • the compound is a pharmaceutically acceptable salt of Compound 1 and the method comprises administering to the subject a daily dose of the salt which is equivalent to 400 mg of the free base, e.g. equivalent to 200 mg of the free base BID.
  • the compound is Compound 1 free base.
  • the compound is Compound 1 free base and the method comprises administering to the subject a daily dose of 400 mg, e.g. 200 mg BID.
  • the compound is administered to the subject orally.
  • the compound is administered in the form of an oral pharmaceutical composition (e.g., dosage form) comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • Pharmaceutical compositions of the compound may be prepared by conventional means known in the art including, for example, mixing with one or more pharmaceutically acceptable excipient.
  • the pharmaceutical composition may take the form of, e.g., tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropyl methyl cellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch, or sodium glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropyl methyl cellulose
  • fillers e.g., lactose, microcrystalline cellulose, or calcium hydrogenphosphate
  • lubricants e.g., magnesium stearate, talc, or silica
  • the treatment comprises administering to the subject a dose of about 200 mg of the compound (calculated as the free base) twice daily, e.g. 200 mg BID of Compound 1.
  • the compound is administered in the form of tablets, e.g. tablets comprising 50 mg of the compound (calculated as the free base).
  • the treatment comprises administering four tablets, each of which contains about 50 mg of the compound (calculated as the free base), twice a day, for a total daily dose of about 400 mg.
  • the treatment comprises administering the compound or pharmaceutically acceptable salt thereof to the subject with food, e.g., before, during, or immediately after a meal. In embodiments, the treatment comprises administering the compound or pharmaceutically acceptable salt thereof to the subject without regard to meals.
  • the present disclosure also provides a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is adapted to provide a daily dose of about 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base).
  • the pharmaceutical composition is adapted to provide a twice daily dose of about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base).
  • the pharmaceutical composition provides the Compound 1 or the pharmaceutically acceptable salt thereof in one or more (e.g., 1, 2, or 4) unit dosages.
  • the pharmaceutical composition provides a unit dosage of about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base), e.g., for administration of two unit dosages per day. In embodiments, the pharmaceutical composition provides a unit dosage of about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base), e.g., for administration of eight unit dosages per day, e.g., for administration of four unit dosages twice daily.
  • the present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in methods of treating psoriasis. It will be appreciated that the disclosure also provides methods of treating psoriasis as described herein, in which a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, as described herein is administered to a human subject in need thereof. It will also be appreciated that the disclosure further provides Compound 1 (or a pharmaceutically acceptable salt thereof) for use in the manufacture of a medicament for treating psoriasis in accordance with the methods disclosed herein. Having been generally described herein, the follow non-limiting examples are provided to further illustrate the disclosure.
  • Compound 1 was prepared according to Example 6 of international patent application No. PCT/EP2018/060489 (published as WO 2018/197503).
  • 7V-(cyclobutylidene)-2-methylpropane-2-sulfinamide (Intermediate 13) was prepared by reacting cyclobutanone with 2-methyl-2-propanesulfinamide followed by titanium(IV) isopropoxide and purified by flash chromatography.
  • Example 2 Clinical study of Compound 1 in patients with mild to moderate psoriasis
  • a double-blind, randomized, placebo-controlled phase 1 study was carried out in participants with mild to moderate psoriasis.
  • Study participants were randomized to 200 mg twice a day (BID) of Compound 1 or placebo in 2: 1 ratio (approximately 24 in the treatment group and 12 in the placebo group).
  • BID twice a day
  • the study comprised an up to 4-week screening period, and a 4- week treatment period with Compound 1 or placebo.
  • An end-of-study visit was carried out 10 ⁇ 3 days after the last investigational medicinal product (IMP) administration.
  • IMP investigational medicinal product
  • the primary objective of the study was to assess the safety, tolerability, and clinical efficacy of Compound 1 at 200 mg BID via oral administration. Also evaluated was the clinical effect of Compound 1 as compared to placebo on the percent change in PASI and TLS scores from baseline to week 2 and week 4. The percent change in PASI score from baseline to week 4 was determined. TLS score was also assessed over the same time period. Also assessed was the effect of Compound 1 on biomarkers of psoriasis. Blood samples collected at predetermined time points were processed to quantify serum levels of biomarkers, including interleukin (IL)-17A, IL-17F, and IL-22 by high sensitivity methods. IL-17A, IL-17F and IL- 22 are the main cytokines released by Thl7 cells. Plasma levels of Compound 1 were measured to assess pharmacokinetics in the study population. Planned study population
  • I 03. Participant must have at least two lesions with TLSS > 4 at both screening and baseline excluding the scalp.
  • Participant must be in good health (except for psoriasis) as judged by the Investigator, based on medical history, physical examination, vital signs, ECG, clinical laboratories, and urinalysis.
  • a postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
  • a high FSH level in the postmenopausal range is used to confirm a postmenopausal state in women (according to the local laboratory) not using hormonal contraception or HRT.
  • DBP diastolic blood pressure
  • systemic non-biologic psoriasis therapies including, but not limited to: psoralens and ultraviolet A (PUVA) therapy, cyclosporine, methotrexate, azathioprine, corticosteroids, apremilast, tofacitinib, oral retinoids, my cophenolate mofetil, sirolimus; or phototherapy (including ultraviolet B [UVB] or self-treatment with tanning beds or therapeutic sunbathing) or topical psoriasis therapy with psoralens.
  • PUVA ultraviolet A
  • E 18 Any participant receiving strong or moderate inducers or inhibitors of CYP3A4 and P-gp within 30 days or 5 half-lives from screening, whichever is longer, prior to enrolment. This also includes the consumption of grapefruit, grapefruit juice, or grapefruit containing products within 72 hours of starting Compound 1 administration.
  • E 19 Any participant receiving strong or moderate inducers of CYP1A1/CYP1A2 within 30 days or 5 half-lives from screening, whichever is longer, prior to enrolment. This also includes excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day).
  • E 20. Any participant enrolled or having participated in [this or] any other clinical study involving an IMP or in any other type of medical research and is still in the exclusion period according to applicable regulations.
  • E 22 Positive for hepatitis B surface antigen and/or Hepatitis B core antibody or positive for anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIVl and anti HIV2 Ab).
  • HCV hepatitis C virus
  • PCT Procalcitonin
  • the Compound 1 intervention comprised 4x tablets of Compound 1 50 mg twice daily, i.e. 200 mg BID, for 4 weeks.
  • the placebo intervention was 4x tablets of placebo twice daily for 4 weeks. Tablets were administered orally.
  • Arm 1 was the experimental arm and it involved participants receiving 200 mg of Compound BID for 4 weeks under fed conditions.
  • Arm 2 was the placebo arm and it involved participants receiving the matching placebo tablets for 4 weeks under fed conditions.
  • h Covid-19 test might be repeated during the study as needed according to the investigator ’s opinion and according to national and local regulations if applicable, the test at screening as nasopharyngeal swab will be analyzed by PCR, the PCR test can be also performed outside the study site, New covid-19 test may be used during the study according to available scientific knowledge and or local health authority recommendation.
  • RNA analysis from biopsies (3 mm punch): prior to first dosing
  • I TESS, PASI, sIGA should always be completed by the same physician for a given participant, if possible, in order to secure longitudinal comparison and avoid any bias
  • m Pre-dose at Day 28 (in case the site visit on Day 28) if the site visit on Day 29 or Day 30 it should be at the same dosing time of the treatment period.
  • ECG at post dose (3h ⁇ 1 h) q Triplicate digital ECGs to be recorded within 5 minutes with at least 1 min between 2 replicates for all ECGs.
  • r Medical history includes but are not limited to surgical history/Psoriasis history/Tonsillitis/periodontitis history/Smoking Status/concomitant disease(s) s Covid-19 test may be done on Day -1 in case of overnight stay from Day -1 to Day 1 Note: when several items take place at the same time, the following order should be respected: ECG, vital signs, questionnaires , pharmacodynamics , blood sampling, meal (if applicable), drug administration; the exact timing of pharmacokinetic samples, should be respected.
  • the PASI scoring system evaluates psoriasis based on the body surface area (BSA) involvement and morphological characteristics of the plaques (see, e.g., EMA Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, November 18 th , 2004).
  • BSA estimation was performed using the ‘palm’ (i.e., the subject’s flat hand and thumb together, fingers not included). The palm thus defined represented 1% of the total BSA.
  • the PASI combines assessments of four body areas: head (h, 10%), upper extremities (u, 20%), trunk (t, 30%) and lower extremities (1, 40%).
  • the proportion of skin affected by psoriasis in each area was given a numerical score (A) representing the proportion involved: 1 (0 to 9%); 2 (10 to 29%); 3 (30 to 49%); 4 (50 to 69%); 5 (70 to 89%) and 6 (90 to 100%).
  • A numerical score representing the proportion involved: 1 (0 to 9%); 2 (10 to 29%); 3 (30 to 49%); 4 (50 to 69%); 5 (70 to 89%) and 6 (90 to 100%).
  • E erythema
  • I thickness/induration
  • D desquamation/scaling
  • the PASI ranges from 0 to 72 and is calculated using the following formula:
  • PASI 0.1 (Eh + Ih + Dh)Ah + 0.2 (Eu + lu + Du) Au + 0.3 (Et + It + Dt)At + 0.4(El + Il + DI) Al
  • the sIGA employed in this study is a six-point ordinal scale used to assess the global severity of disease over the body as a whole, as measured by the overall degree of induration, scaling and erythema of a subject’s psoriatic lesions.
  • the scale was assigned scores of 0 to 5, for ‘clear’ to ‘very severe’, respectively.
  • Scoring was accorded to a subject on a scale of 0 to 5 for each of erythema, induration, and scaling; a mean sIGA score was calculated as the mean average of those individual scores and this was translated into an overall sIGA score (an integer between 0 and 5) as described in the tables below: Planned timepoints for all safety assessments are shown in the schedule of activities table above.
  • Standard 12-lead ECGs (safety ECGs) were recorded after at least 10 minutes in supine position using an electrocardiographic device. The electrodes were positioned at the same place for each ECG recording throughout the study (e.g., attachment sites of the leads were visualized on a transparent paper).
  • the Investigator’s medical opinion and automatic values were recorded in the eCRF. This printout was retained at the site. A second printout was performed also, if needed.
  • each digital file will be identified by theoretical time (day and time Dxx Txx Hxx), real date and real time (recorder time), Sponsor study code, participant number (i.e., 3 digits), and site and country numbers, if relevant.
  • the digital recording, data storage, and transmission (whenever requested) need to comply with all applicable regulatory requirements (i.e., FDA 21 code of federal regulations [CFR], Part 11).
  • Plasma/serum electrolytes sodium, potassium, chloride, calcium,
  • Liver function AST, ALT, alkaline phosphatase, GGT, total and conjugated bilirubin, Renal function: urea, creatinine,
  • Metabolism glucose, albumin, total proteins, total cholesterol, triglycerides,
  • C-reactive protein the CRP levels were evaluated by an independent investigator who is not involved in the study to protect the blinding of the study. CRP values were provided by the independent investigator to the investigator in case of medical need.
  • Urinalysis included specific gravity, proteins, glucose, blood, bilirubin, urobilinogen, leucocytes, ketone bodies, nitrite and pH:
  • Urine drug screening was done for amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates (only at screening).
  • Serology tests included hepatitis B antigen, anti-hepatitis B core antibodies (anti-HBc Ab), hepatitis C antibodies, anti-HIVl and anti-HIV2 antibodies.
  • a 15 mL (or three 5 mL) blood sample(s) were collected into a dry, red topped tube, kept upright at room temperature for 30 minutes and then centrifuged at approximately 1500 g for 10 minutes at 4°C; the serum was then transferred into 3 storage tubes, which were immediately capped and frozen in an upright position at 20°C.
  • This sample was to be used if any unexpected safety issue occurred to ensure that a pre-administration baseline value is available for previously non assessed parameters (e.g., serology). If this sample was not used, the Investigator would destroy it after the Sponsor’s approval.
  • a COVID-19 test could be repeated during the study as needed according to the Investigator’s opinion and according to national and local regulations if applicable.
  • the test at screening was a nasopharyngeal swab that was analyzed by PCR.
  • AEs Adverse events
  • An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
  • 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 intervention.
  • Any abnormal laboratory test results hematology, clinical chemistry, or urinalysis
  • other safety assessments e.g., ECG, radiological scans, vital signs measurements
  • ECG ECG, radiological scans, vital signs measurements
  • Medical or surgical procedure e.g., endoscopy, appendectomy: the condition that leads to the procedure is the AE.
  • SAE serious adverse event
  • hospitalization signifies that the participant 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.
  • 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.
  • Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
  • Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
  • Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking medications and not bedridden.
  • An event was defined as “serious” when it met at least 1 of the predefined outcomes as described in the definition of an SAE, not when it was rated as severe.
  • Pregnancy occurring in a female partner of a male participant included in the study was qualified as a SAE only if meeting one of the seriousness criteria.
  • IMP was discontinued. If pregnancy occurs during screening phase, it was reported only if it met one of the seriousness criteria.
  • Follow-up of pregnancy was mandatory until its outcome had been determined. If a pregnancy was reported, the Investigator recorded pregnancy information on the appropriate form and submitted it to the Sponsor within 24 hours of learning of the female participant. Cardiovascular events were reported if they met AE/SAE criteria. Events with fatal outcome events were reported as SAEs.
  • An adverse event of special interest is an AE (serious or non-serious) of scientific and medical concern, specific to the IMP or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. Such events may require further investigation in order to characterize and understand them.
  • the AESI may be added, modified or removed during a study by protocol amendment.
  • QT prolongation QTcF >500 milli seconds [ms]
  • a delta QTc change from baseline >60 ms (12-lead ECG).
  • prolongation of QTc interval automated measurement
  • the participant was placed under supervision in a specialized setting. Investigational medicinal product administration was stopped, and appropriate blood samples collected. Subsequent ECG monitoring of the participant was then performed on a regular and clinically responsible basis until the QTc interval returned to a safe value as determined by the Investigator in agreement with the Sponsor.
  • An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or spontaneously notified by the participant (not based on systematic pills count) and defined as at least twice the intended dose within the intended therapeutic interval, adjusted according to the tested drug.
  • Neutropenia characterized as neutrophils ⁇ 1500/mm 3 or according to ethnic group (recorded as an AE only if at least 1 of the criteria listed above was met)
  • Thrombocytopenia characterized as platelets ⁇ 100,000/mm 3 confirmed with or without bleeding (recorded as an AE only if at least 1 of the criteria listed above was met)
  • Acute renal impairment characterized as persistent increase from baseline in creatine of 0.3 mg/dL (-26.4 pmol/L) or 30%, whichever is less (recorded as an AE only if at least 1 of the criteria listed above was met)
  • Blood samples were processed for analysis of IL-17A, IL-17F and IL-22 in serum samples by high sensitivity methods. Samples were collected according to the schedule of activity described above.
  • the TLS score was assessed at baseline, 2 weeks and 4 weeks.
  • Table 2 presents the Least Square means (LSm) ⁇ Standard Error (SE) for each treatment and the Least Squares means difference (ALSm; Compound 1 minus placebo) ⁇ Standard Error (SE) with 90% confidence interval (CI) in percentage improvement from baseline in the TLS score (calculated as the average of the TLS score values collected from 2 lesions) at week 2 and week 4.
  • Table 2 Adjusted mean % improvement and 90% CI from baseline in TLS score between Compound 1 and placebo
  • Figure 1 shows the mean ( ⁇ SEM) change in TLS score from baseline over time.
  • the placebo treatment arm solid line with filled circles
  • the Compound 1 treatment arm shows a mean reduction of around 2.5 points over the same period.
  • Table 3 presents the mean ( ⁇ SEM) percentage improvement from baseline in the TLS score (calculated as the average of the TLS score values collected from 2 lesions) at week 2 and week 4 in the patient population with PASI ⁇ 10 (mild) or PASI > 10 (moderate) at baseline.
  • the PASI score was assessed at baseline, 2 weeks and 4 weeks.
  • Table 4 presents the LSm ( ⁇ SE) for each treatment and ALSm (Compound 1 minus placebo) with 90% confidence interval (CI) in percentage improvement from baseline in the total PASI score at week 2 and week 4.
  • Table 4 Adjusted mean % improvement and 90% CI from baseline in total PASI score between Compound 1 and placebo
  • Figure 2 shows the mean ( ⁇ SEM) change in total PASI score from baseline over time.
  • the placebo treatment arm (solid line with filled circles) shows a mean reduction of around 1.25 points at week 4, whereas the Compound 1 treatment arm (dashed line with open circles) shows a mean reduction of around 3.0 points over the same period.
  • Table 5 presents the mean ( ⁇ SEM) percentage improvements from baseline in the total PASI score at week 2 and week 4 in the patient population with PASI ⁇ 10 (mild) or PASI > 10 (moderate) at baseline.
  • the difference in percentage mean improvement of total PASI score at week 4 between Compound 1 and placebo was estimated to be 19.4% (90% CI [6.3%; 32.5%]).
  • the improvement in PASI score after 4 weeks of treatment with Compound 1 is clinically meaningful and is consistent with the improvement in the TLS score in mild-to- moderate psoriasis.
  • the sIGA score was assessed as described herein. As shown in Table 6 below, the proportion of patients achieving improvement by at least 1 severity level in sIGA score measured at week 4, as compared to sIGA measurement at baseline, was 58.3% in the treatment arm vs 0% in the placebo group.
  • Figure 6 shows the severity of psoriasis of patients as measured by sIGA score in the treatment arm vs placebo arm at baseline, week 2, and week 4.
  • Compound 1 at 200 mg BID showed a clinically important change in sIGA score after 4 weeks of treatment as compared with placebo.
  • Compound 1 showed a rapid and statistically significant improvement in psoriasis severity compared to placebo as early as week 2, and the improvement sustained through week 4.
  • the least square (LS) mean difference in percentage improvement of TLS score between Compound 1 and placebo was 10.77% at week 2 and 17.74% at week 4, indicating an overall improvement in TLS score with Compound 1 compared to placebo.
  • Comparison of the LS mean difference between the treatment arm and placebo arm in percentage improvement of TLS score at week 2 (mild: 20.9%; moderate: 10.9%) and week 4 (mild: 37.0%; moderate: 39.7%) shows improvement in TLS score despite disease severity.
  • the LS mean difference in percentage improvement of total PASI score at week 2 (13.61%) and week 4 (19.38%) also indicates an overall improvement in psoriasis severity with Compound 1 compared to placebo.
  • the proportion of patients achieving improvement by at least 1 severity level in sIGA was 58.3% in the Compound 1 group versus no effect (0%) in the placebo group.
  • sIGA score also demonstrated how a higher percentage of patients receiving Compound 1 improved from ‘moderate’ disease at baseline, to ‘mild’ or ‘almost clear’ at week 2 and week 4, in comparison to the placebo group. Patients from the placebo group showed an increase in sIGA from ‘mild’ to ‘moderate’.
  • Mean pre-dose and post-dose plasma concentrations of Compound 1 were consistent with analogous values observed at the same dose in a previous study in healthy participants. Mean pre-dose plasma levels of Compound 1 were similar from Day 8 through Day 29, indicating that steady state was achieved and maintained. Plasma concentrations of Compound 1 were below the limit of quantification in the placebo group.
  • TEAEs Treatment-emergent adverse events
  • SAEs serious AEs
  • AESI AEs of special interest
  • the most frequent TEAEs by primary system organ class (SOC) were nervous systems disorders [4 (33.3%) in placebo and 19 (73.1%) in Compound 1 treated groups], gastrointestinal disorders [2 (16.7%) in placebo and 8 (30.8%) in Compound 1 treated groups] and infections and infestations [4 (33.3%) in placebo and 4 (15.4%) in Compound 1 treated groups].
  • the most frequent TEAEs by preferred term (PT) were Dysgeusia [0 (0%) in placebo and 16 (61.5%) in Compound 1 treated groups], and headache [4 (33.3%) in placebo and 8 (30.8%) in Compound 1 treated groups]. All TEAEs were of grade 1 or grade 2 severity and participants fully recovered.
  • Compound 1 a specific inhibitor of TNFR1 signalling, showed consistent clinical efficacy in a 4-week treatment period. 200 mg BID of Compound 1 over 28 days was safe and well- tolerated by participants with mild-to-moderate psoriasis, with no serious AEs, severe treatment emergent AEs, or AESI being reported.
  • peripheral blood samples collected at predetermined time points were processed to quantify serum levels of biomarkers of psoriasis including IL-17A, IL-17F, and IL-22.
  • Levels of IL-17A and IL-17F were quantified using a single molecule counting sandwich immunoassay (SMCxProTM, Millipore - see also Hwang et al., Methods (2019) 158:69-76).
  • Levels of IL-22 were quantified using a single-molecule array ELISA (SIMOATM, Myriad RBM - see also Rissin et al., Anal Chem (2011) 83(6):2279-2285).
  • Serum levels of IL-17A, IL-17F and IL-22 were substantially decreased after treatment with
  • Compound 1 for 4 weeks in patients with mild-to-moderate psoriasis.
  • the biomarker decreases correlated with observed clinical improvement of patients receiving Compound 1.

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Abstract

L'invention concerne des traitements contre le psoriasis, consistant à administrer à un sujet humain une dose quotidienne de 400 mg du composé 1 ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/EP2024/061394 2023-04-26 2024-04-25 Traitement du psoriasis à l'aide de petites molécules inhibitrices du facteur de nécrose tumorale alpha Pending WO2024223740A1 (fr)

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CN202480028154.3A CN121038791A (zh) 2023-04-26 2024-04-25 使用肿瘤坏死因子α的小分子抑制剂治疗银屑病
IL324175A IL324175A (en) 2023-04-26 2025-10-23 Treating psoriasis with a small molecule that inhibits tumor necrosis factor alpha
MX2025012780A MX2025012780A (es) 2023-04-26 2025-10-24 Tratamiento de la psoriasis con un inhibidor de bajo peso molecular del factor de necrosis tumoral alfa

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US12384808B2 (en) 2022-11-23 2025-08-12 Forward Therapeutics, Inc. Modulators of TNF-α activity
US12410179B2 (en) 2023-08-16 2025-09-09 Raythera, Inc. Modulators of TNF alpha activity and uses thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12384808B2 (en) 2022-11-23 2025-08-12 Forward Therapeutics, Inc. Modulators of TNF-α activity
US12410179B2 (en) 2023-08-16 2025-09-09 Raythera, Inc. Modulators of TNF alpha activity and uses thereof

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MX2025012780A (es) 2025-12-01
TW202508596A (zh) 2025-03-01
IL324175A (en) 2025-12-01

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