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WO2024233379A1 - Inhibiteur de btk pour le traitement de la sclérose en plaques - Google Patents

Inhibiteur de btk pour le traitement de la sclérose en plaques Download PDF

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Publication number
WO2024233379A1
WO2024233379A1 PCT/US2024/027812 US2024027812W WO2024233379A1 WO 2024233379 A1 WO2024233379 A1 WO 2024233379A1 US 2024027812 W US2024027812 W US 2024027812W WO 2024233379 A1 WO2024233379 A1 WO 2024233379A1
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Prior art keywords
compound
subject
administered
daily dose
twice daily
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PCT/US2024/027812
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Inventor
Michael Soliman
Matthew P. SCARAMOZZA
Million Arefayene
Gab-Jin Park
Eris BAME
Michael Joseph PALTE
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Biogen MA Inc
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Biogen MA Inc
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Priority to AU2024267591A priority Critical patent/AU2024267591A1/en
Publication of WO2024233379A1 publication Critical patent/WO2024233379A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • MS Multiple sclerosis
  • CNS central nervous system
  • CIS clinically isolated syndrome
  • RRMS relapsing-remitting multiple sclerosis
  • SPMS active secondary progressive multiple sclerosis
  • MS primary progressive multiple sclerosis
  • SPMS non-relapsing SPMS
  • RIS radiologically isolated syndrome
  • tolerable MS therapies that are highly efficacious and include new options for treating the inflammatory component of MS seen across the spectrum of RMS through progressive multiple sclerosis (PMS) types, as well as effectively treating disability progression independent of relapse activity.
  • PMS progressive multiple sclerosis
  • the present disclosure provides methods of treating multiple sclerosis in a subject in need thereof comprising administering to the subject an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.
  • the disclosure provides safe and effective dosing 1 ME148355192v.1 123429-11420 regimens for Compound 1. More specifically, the disclosure provides a total oral daily dose of 200 mg to 1000 mg Compound 1 or a pharmaceutically acceptable salt thereof in an amount equivalent to 200 mg to 1000 mg of Compound 1 for use in the methods of the present disclosure.
  • the present disclosure provides a method of treating a subject with MS, comprising administering to the subject in need thereof orally an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.
  • FIG. 1 shows mean plasma concentration-time profiles for BIIB091 when administered as IR table with different regimens.
  • FIG.2 shows pre-dose plasma BIIB091 concentrations following administration of multiple oral doses of 250 mg IR tablets BID with MF meals.
  • FIG.3 shows CD69% inhibition on total B cells (CD19+) with a 250 mg BIIB091 IR tablet BID x 7 days (data up to Day 9).
  • the present disclosure provides therapies for treating MS in a subject in need thereof.
  • the methods comprise administering to the subject an effective amount of Compound 1, a BTK inhibitor.
  • Compound 1 is used as a monotherapy for treating MS.
  • BTK tyrosine kinase
  • TEC tyrosine kinase hepatocellular carcinoma
  • BTK is a key signaling node immediately downstream of the B-cell receptor (BCR) in B cells and Fc receptors (FcRs) in myeloid cells.
  • BCR B-cell receptor
  • FcRs Fc receptors
  • BTK inhibition blocks FcR dependent pro-inflammatory activities (including cytokine secretion by mast cells, monocytes, and macrophages; reactive oxygen species generation by neutrophils; and degranulation of basophils) triggered by binding of immune complexes to FcRs.
  • the BTK inhibitor is (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5- yl)-1H-1,2,3-triazole-4-carboxamide represented by the following structural formula: 3 ME148355192v.1 123429-11420 Compound 1, or a pharmaceutically acceptable salt thereof.
  • the BTK inhibitor is Compound 1 or a pharmaceutically acceptable salt thereof.
  • Methods of Treatment The present disclosure provides methods of treating a subject (e.g., a human patient) with MS, by administering Compound 1 to the subject..
  • the MS is relapsing form of MS (RMS).
  • the MS is relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS).
  • the MS is primary progressive MS (PPMS).
  • a “relapsing form of MS” includes clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease.
  • the methods can be used for treating MS selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), non-relapsing SPMS, primary progressive MS (PPMS), clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS).
  • RRMS relapsing-remitting MS
  • SPMS secondary progressive MS
  • PPMS primary progressive MS
  • CIS clinically isolated syndrome
  • RIS radiologically isolated syndrome
  • CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system.
  • the episode which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS.
  • CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS.
  • CIS When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS. 4 ME148355192v.1 123429-11420 [0022] RRMS, the most common disease course of MS, is characterized by clearly defined attacks of new or increasing neurologic symptoms.
  • RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity over a specified period of time) or not active, as well as worsening (a confirmed increase in disability following a relapse) or not worsening.
  • SPMS can be further characterized as either active (with relapses and/or evidence of new MRI activity during a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapses or new MRI activity) or without progression.
  • PPMS is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions.
  • PPMS can be further characterized as either active (with an occasional relapse and/or evidence of new MRI activity over a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapse or new MRI activity) or without progression.
  • Patients diagnosed with RIS do not present any overt symptoms of MS, but exhibit brain abnormality (e.g., observed by magnetic resonance imaging (MRI)) that are similar to what is seen in patients with MS. Diagnosis of RIS often occurs during a brain scan due to unrelated conditions, such as headache, migraines, head injury, stroke etc.
  • MRI magnetic resonance imaging
  • RIS RNA sulfate sulfate sulfate sulfate
  • MS recombinant protein
  • pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19.
  • the terms “subject” and “patient” may be used interchangeably, and mean a mammal in need of treatment, e.g., a human, companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • the term “treating” or ‘treatment” refers to obtaining desired pharmacological and/or physiological effect.
  • the effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
  • An “effective amount” of Compound 1 is an amount sufficient to provide a therapeutic benefit in the treatment of disease or disorder described herein or to delay or minimize one or more symptoms associated with the disorder or disease, is an amount sufficient to provide a therapeutic benefit in the treatment of a disorder or disease described herein or to delay or minimize one or more symptoms associated with the disorder or disease when combined with Compound 1.
  • therapeutically effective amount” and “effective amount” are used interchangeably.
  • an effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, an effective amount is an amount sufficient for eliciting therapeutic effects in the treatment of MS described herein.
  • the present disclosure provides a method of treating a human subject with multiple sclerosis (MS), comprising administering to the subject orally a total daily dose of 200 mg to 1000 mg of Compound 1: Compound 1; or a pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 200 mg to 1000 mg of Compound 1.
  • Compound 1 disclosed herein can be used in the form of a free base or as a salt.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al.
  • Compound 1 is administered as the free base. In some embodiments, in the methods of treatment disclosed herein, a pharmaceutically acceptable salt of Compound 1 is administered.
  • the stereochemical configuration at a chiral center in Compound 1 is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.
  • compositions of the disclosure comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and Compound 1, or a pharmaceutically acceptable salt thereof.
  • “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject.
  • Non- limiting examples of pharmaceutically acceptable carriers and/or diluents include NaCl, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethycellulose, fatty acid esters, polyvinyl pyrrolidine, and colors, and the like.
  • compositions of the disclosure optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • excipients such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • the carriers, diluents and/or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
  • Methods of Administration and Dosage Forms [0037] The precise amount of compound administered to provide an “effective amount” to the subject will depend on the type, and severity of the MS, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used.
  • Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of Compound 1 being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th Ed., 2003).
  • the subject in need thereof is administered a total daily dose of 300 mg to 900 mg of Compound 1. 8 ME148355192v.1 123429-11420 [0039]
  • the subject in need thereof is administered a total daily dose of 400 mg to 800 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 500 mg to 700 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, 600 mg to 800 mg, 700 mg to 900 mg, 800 mg to 1000 mg, 450 mg to 550 mg or 650 mg to 750 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 200 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 300 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 400 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 500 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 600 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 700 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 800 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 900 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 1000 mg of Compound 1.
  • the subject in need thereof is administered a total daily dose of 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 825 mg, 850 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg of Compound 1.
  • the subject in need thereof is administered Compound 1 once daily (QD) orally with the amount identified above.
  • the subject in need thereof is administered Compound 1 twice daily (BID) orally with the amount identified above.
  • the subject in need thereof is administered an amount of 100 mg to 500 mg of Compound 1 twice daily (BID).
  • the total daily dose is 200 mg to 1000 mg of Compound 1.
  • the subject in need thereof is administered an amount of 150 mg to 450 mg of Compound 1 twice daily (BID).
  • the total daily dose is 300 mg to 900 mg of Compound 1.
  • the subject in need thereof is administered an amount of 200 mg to 400 mg of Compound 1 twice daily (BID).
  • the total daily dose is 400 mg to 800 mg of Compound 1.
  • the subject in need thereof is administered an amount of 250 mg to 350 mg of Compound 1 twice daily (BID).
  • the total daily dose is 500 mg to 700 mg of Compound 1.
  • the subject in need thereof is administered an amount of 100 mg to 200 mg, 150 mg to 250 mg, 200 mg to 300 mg, 250 mg to 350 mg, 300 mg to 400 mg, 350 mg to 450 mg, 400 mg to 500 mg, 225 mg to 275 mg, or 325 mg to 375 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 200 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 250 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 275 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 300 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 325 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 350 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 375 mg of Compound 1 twice daily (BID). 10 ME148355192v.1 123429-11420 [0066] In some embodiments, the subject in need thereof is administered an amount of 400 mg of Compound 1 twice daily (BID). [0067] In some embodiments, the subject in need thereof is administered an amount of 450 mg of Compound 1 twice daily (BID). [0068] In some embodiments, the subject in need thereof is administered an amount of 500 mg of Compound 1 twice daily (BID).
  • the subject in need thereof is administered an amount of 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg or 500 mg of Compound 1 twice daily (BID).
  • BID Compound 1 twice daily
  • the subject in need thereof is administered Compound 1 with food (e.g., a regular meal, a moderate fat meal, a high fat meal, etc.).
  • the subject in need thereof is administered Compound 1 with a moderate fat meal.
  • the moderate fat meal has a total calorie of 500-800 Kcal.
  • the moderate fat meal has between 14 and 55g of fat, and/or between 25% and 50% by weight of the meal is fat, and/or total calorie for the fat content in the meal is between 125 and 500 Kcal.
  • the subject in need thereof is administered Compound 1 after food (e.g., a regular meal, a moderate fat meal, etc.).
  • the subject in need thereof is administered Compound 1 shortly after food (e.g., a regular meal, a moderate fat meal, etc.), for example, less than 4 hours, less than 2 hours, less than 1 hours or less than 30 minutes after food (e.g.,, a regular meal, a moderate fat meal, etc.). In some embodiments, the subject in need thereof is administered Compound 1 between 30 and 60 minutes after food (e.g., a regular meal, a moderate fat meal, etc.). [0071] In some embodiments, the subject in need thereof is administered Compound 1 in a fasted state. [0072] In some embodiments, an immediate release (IR) formulation of Compound 1 in tablets is used in the methods of the present disclosure.
  • IR immediate release
  • the tablets contain 50 mg, 150 mg or 250 mg of Compound 1.
  • the immediate release formulation of Compound 1 comprising one or more excipients selected from silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, and colloidal silicon dioxide.
  • the immediate release tablet comprises a 11 ME148355192v.1 123429-11420 film coating comprising titanium dioxide, hypromellose, macrogol, iron oxide yellow, and ferrosoferric oxide.
  • the subject is administered Compound 1 in the absence of a cytochrome P4503A4 (CYP3A4) inhibitor.
  • CYP3A4 cytochrome P4503A4
  • Administering “in the absence of a CYP3A4 inhibitor” means that the subject was never taking a CYP3A4 inhibitor or stopped taking a CYP3A4 inhibitor before treatment with Compound 1 or a pharmaceutically acceptable salt thereof was initiated or stopped taking a CYP3A4 inhibitor at the time treatment with Compound 1 or a pharmaceutically acceptable salt thereof was initiated.
  • a CYP3A4 inhibitor is a substance that decreases the activity of CYP3A4.
  • the CYP3A4 inhibitor is a strong inhibitor of CYP3A4, such as clarithromycin, indinavir, nefazodone, saquinavir, suboxone, telithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, and goldenseal. Intermediate strength inhibitors include aprepitant, erythromycin, fluconazole, grapefruit, verapamil, and diltiazem.
  • the CYP3A4 inhibitor is a weak inhibitor of CYP3A4, such as cimetidine.
  • exemplary CYP3A4 inhibitors include, but are not limited to amiodarone, boceprevir, chloramphenicol, ciprofloxacin, delaviridine, diethyl-dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, starfruit, telaprevir, and voriconazole.
  • the CYP3A4 inhibitor is itraconazole.
  • the subject is administered Compound 1 in the absence of a proton pump inhibitor (PPI).
  • PPI proton pump inhibitor
  • the subject is administered Compound 1 in the absence of a proton pump inhibitor (PPI) when the subject is in fasted state.
  • PPI proton pump inhibitor
  • the subject is administered Compound 1 and a proton pump inhibitor (PPI) with or shortly after food (e.g., a regular meal, a moderate fat meal, a high fat meal, etc.).
  • Administering “in the absence of a PPI” means that the subject was never taking a PPI or stopped taking a PPI before treatment with Compound 1 or a pharmaceutically acceptable salt thereof was initiated or stopped taking a PPI at the time treatment with Compound 1 or a 12 ME148355192v.1 123429-11420 pharmaceutically acceptable salt thereof was initiated.
  • a PPI is a class of drugs that cause a profound and prolonged reduction of stomach acid production by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump.
  • Exemplary PPIs include, but are not limited to omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.
  • the PPI is rabeprazole.
  • Exemplification Example 1. Phase 2 clinical study Study Design [0079] This is a multicenter, randomized, blinded, active controlled Phase 2 study to evaluate the safety and efficacy of Compound 1 in participants with RMS. The primary objective of the study is to investigate the safety and tolerability of BIIB091 monotherapy in participants with RMS with the primary endpoint for the study being incidence of adverse events (AEs) and SAEs.
  • AEs adverse events
  • the secondary object of the study is to evaluate the effects of BIIB091 monotherapy on the MRI measures of active CNS inflammation.
  • the study will include a 4-week screening period, a 16-week double-blind active- controlled treatment period, a 32-week blinded active controlled treatment period, and a 2- week post-treatment safety follow-up period.
  • Participants with absolute lymphocyte count (ALC) ⁇ lower limit of normal (LLN) at the 2 week safety Follow-Up Visit will return in 2 weeks for retesting and confirmation, and follow-up will be extended for those participants at intervals of every 8 weeks to monitor their lymphocyte counts until their ALC > LLN, or for a period up to 6 months, or until they commence another disease-modifying therapy, whichever occurs first.
  • IVMP intravenous methylprednisolone
  • Study Population This study will be conducted in participants who meet the following criteria: Aged 18 through 55 years old, inclusive, at the time of informed consent Time since MS symptom onset ⁇ 20 years Diagnosed with MS per the 2010 or 2017 McDonald’s criteria [Polman 2011; Thompson 2018] Must have Expanded Disability Status Scale (EDSS) score of 0 through 5.0 at Screening Must have at least 1 of the following occurring prior to Baseline (Day 1): ⁇ 2 clinical relapses in the last 24 months (but not within 30 days prior to Baseline [Day 1]) with at least 1 relapse during the last 12 months prior to randomization ⁇ 1 clinical relapse within the past 24 months (but not within 30 days prior to Baseline [Day 1]) and ⁇ 1 new brain MRI lesion (Gd positive and/or new or enlarging T2 hyperintense lesion) within the past 12 months prior to randomization.
  • EDSS Expanded Disability Status Scale
  • the baseline MRI could be used to satisfy this criterion (local MRI readings are allowed).
  • the reference scan cannot be > 12 months prior to randomization ⁇ 1 GdE lesion on brain MRI within 6 months prior to randomization
  • Number of Planned Participants Approximately 275 participants will be randomized.
  • Treatment Groups Participants will be randomized into treatment groups. The randomization will be stratified by intensive PK cohort (Yes/No) and region (Eastern Europe vs. Other). For stratification, Eastern Europe will include participants from countries such as Tru and the Czech Republic.
  • Sample Size Determination The planned sample size is 275 participants. Accounting for a 12% dropout rate, 275 participants are planned to be enrolled in the study.Of these 150 will be randomized in a separate Compound 1 combination therapy study. 15 ME148355192v.1 123429-11420 [0092] A sample size of 50 participants (44 evaluable) per treatment group will allow for an 80% or greater probability of observing at least 1 occurrence of an AE with an event rate of 3.6%.
  • Intensive PK will be collected in up to 25 participants (approximately 10 participants in each BIIB091 group and approximately 5 participants in the DRF group.
  • Visit Schedule Participants will have up to 12 scheduled visits during the study. Study assessments conducted at each visit are listed in the Schedule of Activities.
  • Visit days are calculated with respect to Day 1 (the date of first dose).
  • Duration of Study Participation The study duration for participants will be approximately 54 weeks and includes the following: 4-week screening period 16-week double-blind, active-controlled treatment period 32-week blinded, active-controlled treatment period 2-week post-treatment safety follow-up period Example 2.
  • PK pharmacokinetic
  • Cmax steady state C trough > 221 ng/mL while limiting the drug exposure (Cmax).
  • Part 1 IR tablet (50 mg) was tested in 19 healthy subjects at different dose levels (150, 250 and 350 mg) and in the fed (moderate fat and high fat) and fasted state and as a divided daily dose (12 h apart). Subject were treated with BIIB091 up to 4 periods. To facilitate comparisons between different regimens, subjects were randomized into 2 groups (Group 1 and Group 2) pre-dose on Day 1 in Periods 1, 3 and 4.
  • Period 2 was utilized as a reference period, where all subjects were dosed with the BIIB091 IR DiC (drug in capsule). 16 ME148355192v.1 123429-11420 [0098] IR tablet (150 mg) had higher exposure (129% Cmax and 138% AUCinf) and lower variability (CV%) ranging from 17.1% to 30.8% for Cmax and AUCinf, compared with 43.4% to 78.1% for the DiC 150 mg reference. Two doses of 250 mg (fasted) and 350 mg (with MF) IR tablets administered 12 h apart gave geometric mean C24 (CV%) of 282 (44.7%) and 411 (31.1%) ng/mL, respectively, both above the target Ctrough.
  • FIG.1 shows plasma concentration of BIIB091 over time.
  • a Moderate-fat breakfast comprised of 19 g protein, 87 g carbohydrates and 27 g (36%) fat
  • High-fat breakfast comprised of 35 g protein, 65 g carbohydrates and 61 g (57%) fat
  • Standard breakfast comprised of 16 g protein, 87 g carbohydrates and 17 g (27%) fat d
  • BIIB091 is a moderate CYP3A4 substrate.
  • CYP3A4 inhibitor co-administration increased BIIB091 exposure.

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Abstract

La présente invention concerne des méthodes de traitement de la sclérose en plaques (SEP) à l'aide du composé (1) tel que représenté par la structure ci-dessous ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2024/027812 2023-05-05 2024-05-03 Inhibiteur de btk pour le traitement de la sclérose en plaques Pending WO2024233379A1 (fr)

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AU2024267591A AU2024267591A1 (en) 2023-05-05 2024-05-03 Btk inhibitor for treating multiple sclerosis

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US202363464288P 2023-05-05 2023-05-05
US63/464,288 2023-05-05
US202363541965P 2023-10-02 2023-10-02
US63/541,965 2023-10-02

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