Therapeutic tyrosine kinase inhibitors for multiple sclerosis and myasthenia gravis

Abstract

The present disclosure relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase ("BTK") inhibitors, for use in the treatment of patients suffering from MG or MS.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 357,465, filed on June 30, 2022, and U.S. Provisional Application No. 63 / 433,866, filed on December 20, 2022, which are incorporated herein by reference in their entirety for any purpose. introduction

[0002] The present disclosure relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase ("BTK") inhibitors, for the treatment of multiple sclerosis (MS) and myasthenia gravis (MG). Multiple sclerosis (MS) is a neurological disease that affects more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has significant physical, psychological, social and economic impacts on subjects and their families. MS involves an immune-mediated process in which an abnormal response of the body's immune system is directed against the central nervous system (CNS). During the disease process, sclerosis, i.e., lesions or scars, occur in the myelin sheath of nerve cells, disrupting the transmission of electrical signals. Sclerosis accumulates over time and causes MS patients to experience debilitating symptoms.

[0003] MS patients usually experience one of four clinical courses, each of which may be mild, moderate or severe: clinically isolated syndrome, relapsing-remitting, secondary progressive (non-relapsing secondary progressive multiple sclerosis (NRSPMS)) and primary progressive (PPMS). About 85% of MS patients suffer from the disease in the form of relapsing-remitting forms, in which they experience well-defined relapses (also referred to as flare-ups or exacerbations), which are episodes of acute deterioration of neurological function, followed by a partial or complete recovery period (remission) in which there is no disease progression. Within the scope of the present disclosure, "relapsing multiple sclerosis", "relapsing MS" or "RMS" may include clinically isolated syndrome ("CIS"), relapsing-remitting multiple sclerosis ("RRMS") and relapsing secondary progressive multiple sclerosis ("R-SPMS"). See, for example, Lublin et al., Defining the clinical course of multiple sclerosis; 2013 revised edition, Neurology 2014; 83: 278-286. Immunomodulatory drugs have become the mainstay of MS therapy. Results of the latest clinical studies have confirmed the efficacy of agents targeting B lymphocytes, especially B cell depleting agents like ocrelizumab (anti-CD20) (Hauser et al., N Engl J Med. 2017; 376(3): 221-34).

[0004] Targeting B cells represents a violation of the prevailing dogma based on animal models showing therapeutic benefit from modulating T cell activity and the position of B cells as the center of current MS drug development (Lehmann-Horn K et al., Int J Mol Sci. 2017; 18(10): 2048). The importance of immune cells resident in the CNS is also well known and needs to be considered in MS pathogenesis (Hemmer B et al., Nat Clin Pract Neurol. 2006; 2(4): 201-11).

[0005] MG is a chronic autoimmune neuromuscular disease that causes skeletal muscle weakness, which worsens after an active period and improves after a rest period. These muscles are responsible for functions including breathing and moving body parts, including arms and legs. The hallmark of myasthenia gravis is muscle weakness, which worsens after an active period and improves after a rest period. Certain muscles are usually (but not always) involved in the disorder, such as those that control eye and eyelid movement, facial expression, chewing, talking and swallowing. The onset of the disorder may be sudden, and symptoms are usually not immediately recognized as myasthenia gravis. The degree of muscle weakness involved in myasthenia gravis varies significantly with the individual. People with myasthenia gravis may experience the following symptoms: eye muscle weakness (called eye muscle weakness), drooping of one or both eyelids (ptosis), blurred vision or visual confusion (diplopia), changes in facial expression, difficulty swallowing, shortness of breath, speech disorders (dysarthria), weakness in arms, hands, fingers, legs and neck.

[0006] MG is an autoimmune disease, which means that the immune system, which normally protects the body from foreign organisms, mistakenly attacks itself. Myasthenia gravis is caused by errors in the transmission of nerve impulses to muscles. It occurs when normal communication between nerves and muscles is interrupted at the neuromuscular junction (the place where nerve cells connect to the muscles they control). Neurotransmitters are chemicals that neurons or brain cells use to communicate information. Normally when an electrical signal or impulse travels along a motor nerve, the nerve ending releases a neurotransmitter called acetylcholine, which binds to sites on the muscle called acetylcholine receptors. The binding of acetylcholine to its receptor activates the muscle and causes it to contract. In myasthenia gravis, antibodies block, alter, or destroy the acetylcholine receptors at the neuromuscular junction, making it impossible for the muscle to contract. This is most often caused by antibodies against the acetylcholine receptors themselves, but antibodies against other proteins such as the MuSK (muscle-specific kinase) protein may also impair transmission at the neuromuscular junction.

[0007] Tolebrutinib is a BTK inhibitor being studied for both MG and MS. The Bruton's tyrosine kinase pathway is critical for signaling in B lymphocytes and myeloid cells, including CNS microglia. Each of these cell types is implicated in the pathophysiology of multiple sclerosis. In addition, since BTK signaling is critical for the maturation of B cells into antibody-secreting plasma cells, BTK inhibition can modulate both cellular and humoral immunity.

[0008] Thus, inhibitors of BTK signaling represent a dual mechanism targeting two aspects of the immune system.

[0009] Therefore, compounds that inhibit BTK that can both inhibit antigen-induced B cell activation leading to neuroinflammation and modulate maladaptive microglia associated with neuroinflammation in the brain and spinal cord may be used to treat MS and MG with superior benefit when compared to currently available therapies.

[0010] Drug-induced liver injury has been identified in an ongoing phase 3 trial of tolebrutinib. The reported events occurred between months 2 and 3 after initiation of tolebrutinib administration, and the elevations in liver enzymes appeared to be reversible after discontinuation of tolebrutinib. Therefore, there is a need to reduce the risk of liver injury and provide safe treatments for patients with MS or MG. Summary of the invention

[0011] The present disclosure relates to methods of treating MS in a patient in need thereof, the methods comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels, and when the patient is found not to have elevated transferrin levels or elevated ferritin levels, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0012] The present disclosure relates to methods of treating MS comprising administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient in need thereof, wherein the patient does not have elevated transferrin levels or elevated ferritin levels.

[0013] The present disclosure relates to methods of treating MG in a patient in need thereof, the methods comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels, and when the patient is found not to have elevated transferrin levels or elevated ferritin levels, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0014] The present disclosure relates to methods of treating MG comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient does not have elevated transferrin levels or elevated ferritin levels.

[0015] The present disclosure relates to methods of treating MS in a patient in need thereof, the methods comprising determining the patient's iron status (iron panel), and upon finding that the patient has suitable iron status, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0016] The present disclosure relates to methods of treating MS comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient has suitable iron status.

[0017] The present disclosure relates to methods of treating MG in a patient in need thereof, the methods comprising determining the patient's iron status and, upon finding that the patient has suitable iron status, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. The present disclosure relates to methods of treating MG comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient has suitable iron status.

[0018] The present disclosure relates to methods of treating MS in a patient in need thereof, the methods comprising determining the patient's alcohol consumption, and when the patient is found to have an appropriate alcohol consumption, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0019] The present disclosure relates to methods of treating MS comprising administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient in need thereof, wherein the patient has a suitable alcohol level.

[0020] The present disclosure relates to methods of treating MG in a patient in need thereof, the methods comprising determining the patient's alcohol consumption, and when the patient is found to have an appropriate alcohol consumption, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0021] The present disclosure relates to methods of treating MG, comprising administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient in need thereof, wherein the patient has a suitable alcohol consumption.

[0022] The present disclosure relates to methods of treating MS in a patient in need thereof, the methods comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and upon finding that the patient does not have an inducer of CYP3A or an inhibitor of CYP3C8, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0023] The present disclosure relates to methods of treating MS comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient does not have inducers of CYP3A or inhibitors of CYP3C8 in the patient's system.

[0024] The present disclosure relates to methods of treating MG in a patient in need thereof, the methods comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and upon finding that the patient does not have an inducer of CYP3A or an inhibitor of CYP3C8, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0025] The present disclosure relates to methods of treating MG comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient does not have an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system.

[0026] The present disclosure relates to methods of treating MS in a patient in need thereof, the methods comprising determining whether the patient has elevated ALT enzyme, and if the patient is found not to have elevated ALT enzyme, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0027] The present disclosure relates to methods of treating MS comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient does not have elevated ALT enzyme.

[0028] The present disclosure relates to methods of treating MG in a patient in need thereof, the methods comprising determining whether the patient has elevated ALT enzyme, and if the patient is found not to have elevated ALT enzyme, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0029] The present disclosure relates to methods of treating MG comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient does not have elevated ALT enzyme.

[0030] In some embodiments, a dose of about 5 mg to about 60 mg of the BTK inhibitor is administered.

[0031] In some embodiments, the dose is 5 mg.

[0032] In some embodiments, the dose is 15 mg.

[0033] In some embodiments, the dose is 30 mg.

[0034] In some embodiments, the dose is 60 mg.

[0035] In some embodiments, the dosage is once daily.

[0036] In some embodiments, the dose is administered once daily with food.

[0037] In some embodiments, the dose is 60 mg and is administered once daily with food.

[0038] In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0039] In some embodiments, the subject or patient is a human.

[0040] In some embodiments, the subject or patient is a human subject or patient ranging in age from 12 to 55 years old.

[0041] The present disclosure also relates to a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one for use in a method of treating MG or MS in a patient in need thereof.

[0042] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) testing the patient's blood or serum for iron status; (b) detecting a level of said iron status test within a normal range; and (c) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient, wherein the iron status test measures any one or more of iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum, and wherein the normal range for the iron status test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of ≤500 μg / L, (iii) a transferrin saturation level of ≤50% in male patients or ≤40% in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0043] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) detecting a transferrin saturation level in the patient's blood or serum within a normal range; and (b) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient, wherein the transferrin saturation level in the blood or serum of the male patient within the normal range is ≤50% of transferrin saturation, and the transferrin saturation level in the blood or serum of the female patient within the normal range is ≤40% of transferrin saturation.

[0044] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) detecting a ferritin level in the patient's blood or serum within a normal range; and (b) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient, wherein the patient's ferritin level in the blood or serum is within the normal range and is ≤500 μg / L.

[0045] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) Perform liver function tests in patients; (b) detecting adequate liver function in said patient; and (c) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient, wherein the liver function test measures one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein, and wherein patients with suitable liver function have one or more of the following: ALT ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

[0046] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >8x upper limit of normal (ULN) were detected; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; and (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0047] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >5x upper limit of normal (ULN) detected during a period of at least two weeks; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; and (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0048] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; (e) one or more of total bilirubin >2 x ULN and INR >1.5 was detected; (f) ceasing administration of the compound to the patient; and optionally (g) monitoring ALT levels in said patient; and (h) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0049] The present disclosure also relates to a method of treating MS, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) stopping administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally (e) monitoring ALT levels in said patient; and (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0050] In some embodiments, the ALT level in step (b) is determined at least monthly.

[0051] In some embodiments, the ALT level in step (d) is monitored at least weekly.

[0052] In some embodiments, the ALT level in step (d) is monitored every 2 to 3 days.

[0053] The present disclosure also relates to methods of treating MS in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not currently receiving strong and moderate inducers of cytochrome P450 3A (CYP3A) or strong inhibitors of the CYP2C8 liver enzyme.

[0054] The present disclosure also relates to a method of treating MS in a patient in need thereof, the method comprising the steps of: (a) advising the patient to limit alcohol consumption during treatment; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is female and is advised to limit alcohol consumption to 14 grams per day or less, or wherein the patient is male and is advised to limit alcohol consumption to 28 grams per day or less.

[0055] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) testing the patient's blood or serum for iron status; (b) detecting a level of said iron status test within a normal range; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the iron status test measures any one or more of the iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum, and wherein the normal range of the iron status test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of ≤500 μg / L, (iii) a transferrin saturation level of ≤50% in male patients or ≤40% in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0056] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) detecting a transferrin saturation level in the patient's blood or serum within a normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, Wherein the transferrin saturation level in the blood or serum of a male patient within a normal range is ≤50% of transferrin saturation, and the transferrin saturation level in the blood or serum of a female patient within a normal range is ≤40% of transferrin saturation.

[0057] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) detecting a ferritin level in the patient's blood or serum within a normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, The ferritin level in the patient's blood or serum is within the normal range and is ≤500 μg / L.

[0058] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) Perform liver function tests in patients; (b) detecting adequate liver function in said patient; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the liver function tests measure one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein, and wherein patients with adequate liver function have one or more of the following: ALT ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

[0059] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >8x upper limit of normal (ULN) were detected; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; and (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0060] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >5x upper limit of normal (ULN) detected during a period of at least two weeks; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; and (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0061] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; (e) one or more of total bilirubin >2 x ULN and INR >1.5 was detected; (f) ceasing administration of the compound to the patient; and optionally (g) monitoring ALT levels in said patient; and (h) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0062] The present disclosure also relates to a method of treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) stopping administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally (e) monitoring ALT levels in said patient; and (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0063] In some embodiments, the ALT level in step (b) is determined at least monthly.

[0064] In some embodiments, the ALT level in step (d) is monitored at least weekly.

[0065] In some embodiments, the ALT level in step (d) is monitored every 2 to 3 days.

[0066] The present disclosure also relates to methods of treating MG in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not currently receiving strong and moderate inducers of cytochrome P450 3A (CYP3A) or strong inhibitors of the CYP2C8 liver enzyme.

[0067] The present disclosure also relates to a method of treating MG in a patient in need thereof, the method comprising the steps of: (a) advising the patient to limit alcohol consumption during treatment; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is female and is advised to limit alcohol consumption to 14 grams per day or less, or wherein the patient is male and is advised to limit alcohol consumption to 28 grams per day or less. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1A The study design of Example 1 is provided.

[0069] Figure 1B The study design for Example 2 is provided.

[0070] Figure 1C The study design for Example 3 is provided.

[0071] Figure 1D The study design for Example 4 is provided.

[0072] Figure 2 Provides suggested activities and follow-up assessments in the event of neutropenia.

[0073] Figure 3 Provides suggested activities and follow-up assessments in the event of thrombocytopenia.

[0074] Figure 4A Provides recommended activities and follow-up assessments in the event of increased alanine aminotransferase (ALT) algorithm.

[0075] Figure 4B Provides recommended activities and follow-up assessments in the event of increased alanine aminotransferase (ALT) algorithm.

[0076] Figure 5 Provide suggested activities and follow-up assessments in the event of elevated serum creatinine.

[0077] Figure 6 Provides recommended activities and follow-up evaluations when progressive multifocal leukoencephalopathy (PML) is suspected.

[0078] Figure 7 Provides a description of the Expanded Disability Status Scale (EDSS) score according to level of disability.

[0079] Figure 8 Provides recommended activities and follow-up assessments in the event of an increase in CPK that is non-cardiac in origin and not related to vigorous physical activity. DETAILED DESCRIPTION

[0080] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying drawings. Although the present disclosure provides illustrative embodiments, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications and equivalents that may be included in the present disclosure defined by the appended claims.

[0081] The section titles used herein are only for organizational purposes and should not be interpreted as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined in this specification, this specification shall prevail. Although the present invention has been described in conjunction with various embodiments, it is not intended that the present invention is limited to such embodiments. On the contrary, as will be appreciated by those skilled in the art, the present invention encompasses various substitutions, modifications, and equivalents. I. Definitions

[0082] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.

[0083] As used herein, "BTK inhibitor," "BTK inhibitor compound," and "compound" refer to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, which has the following structure: It is also known as "tolebrutinib", and 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, and has the following structure: or a pharmaceutically acceptable salt thereof.

[0084] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes one and more than one such excipient.

[0085] “Treating” or “treatment” of a disease includes: (1) inhibiting the disease, for example, arresting or reducing the development of the disease or its clinical symptoms; or (2) Alleviate a disease, e.g., cause regression of the disease or its clinical symptoms.

[0086] "Optional" or "optionally" means that the subsequently described event or circumstance can occur but does not have to occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0087] "Therapeutically effective amount" means the amount of a BTK inhibitor compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0088] The "Expanded Disability Status Scale (EDSS) score" is a method of quantifying disability in multiple sclerosis and monitoring changes in disability levels over time. The EDSS scale ranges from 0 to 10, with unit increments of 0.5 indicating higher levels of disability. EDSS steps 1.0 to 4.5 involve people with MS who are able to walk without any assistance and are based on measurements of impairment in eight functional systems (FS): Pyramidal - muscle weakness or difficulty moving the limbs; Cerebellar - ataxia, loss of balance, coordination problems, or tremors; Brainstem - language disorders, swallowing disorders, and nystagmus; Sensory - numbness or loss of sensation; Bowel and bladder function; Visual function - visual impairment; Cerebral function - thinking and memory impairment. EDSS steps 5.0 to 9.5 are defined by impairment in walking. See, e.g., Figure 7 For information on this score see Kurtzke et al. Neurology 1983, 33, 1444-1452.

[0089] Before the present teachings are described in detail, it is to be understood that this disclosure is not limited to specific compositions or method steps as these may vary.

[0090] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a conjugate" includes a plurality of conjugates and reference to "a cell" includes a plurality of cells, and so forth.

[0091] Numerical ranges include the numbers that define the range. Taking into account significant figures and errors associated with measurement, measured values ​​and measurable values ​​should be understood as approximate values. In addition, the use of "comprise, comprises, comprising", "contain, contains, containing", "include, includes and including" is not intended to be limiting. It should be understood that the foregoing invention summary and specific embodiments are only exemplary and explanatory, and are not intended to limit the content of the present teaching.

[0092] Unless otherwise specified in the above description, embodiments in this specification that list "comprising" various components are also contemplated as "consisting of the listed components" or "consisting essentially of the listed components"; embodiments in this specification that list "consisting of various components" are also contemplated as "comprising the listed components" or "consisting essentially of the listed components"; and embodiments in this specification that list "consisting essentially of various components" are also contemplated as "consisting of the listed components" or "comprising the listed components" (this interchangeability does not apply to the use of these terms in the claims).

[0093] As used herein, the terms "or a combination thereof" and "or combinations thereof" refer to any and all permutations and combinations of the terms listed before the term. For example, "A, B, C, or a combination thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and if order is important in the particular context, BA, CA, CB, ACB, CBA, BCA, BAC, or CAB. Continuing with this example, specifically included are combinations containing repetitions of one or more items (item or term), such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. The skilled artisan will understand that unless otherwise apparent from the context, there is typically no limit to the number of items (items or terms) in any combination.

[0094] Unless the context requires otherwise, "or" is used in its inclusive sense, ie, is equivalent to "or".

[0095] "Ceasing" or "cessation" when used with respect to the administration of a BTK inhibitor compound means that the BTK inhibitor compound is no longer administered to a patient, either temporarily or permanently.

[0096] "Monitoring" with respect to assessing ALT levels in a patient means checking and / or detecting ALT levels in a patient at at least two time points; in some embodiments, over a period of time; in some embodiments, monthly; in some embodiments, at least monthly; in some embodiments, weekly; in some embodiments, at least weekly; in some embodiments, every 5 days; in some embodiments, every 3 days; in some embodiments, every 2 to 3 days; in some embodiments, every 2 days; in some embodiments, every day. II. Administration of BTK Inhibitor Compounds

[0097] In some embodiments, a BTK inhibitor compound, i.e., (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, is administered for the treatment of MS or MG in a patient in need thereof. In some embodiments, the BTK inhibitor compound is a pharmaceutically acceptable salt of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, a therapeutically effective amount of the BTK inhibitor compound is administered. In some embodiments, a 5 to 60 mg dose of the BTK inhibitor compound is administered. In some embodiments, a 60 mg dose of the BTK inhibitor compound is administered. In some embodiments, a 60 mg dose of the BTK inhibitor compound is administered once daily.

[0098] In some embodiments, a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is provided for use in a method for treating MS or MG in a patient in need thereof.

[0099] In some embodiments, a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is provided for use in a method for reducing the frequency of MS or MG relapses in a patient in need thereof.

[0100] The BTK inhibitor compounds can be prepared according to the methods and protocols described, for example, in U.S. Pat. No. 9,688,676 B2 (particularly at Column 62, line 8 to Column 65, line 32, and Column 67, line 28 to Column 69, which are incorporated herein by reference).

[0101] The following preparation of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one compounds is given to enable those skilled in the art to prepare the BTK inhibitor compounds. The synthetic routes should not be considered to limit the scope of the present disclosure, but are merely illustrative and representative of the present disclosure.

[0102] Exemplary Synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one:

[0103] Into a 100 mL round-bottom flask was placed (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), DCM-CH3OH (6 mL), TEA (113 mg, 1.12 mmol, 3.00 equiv). Thereafter, prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv) was added dropwise at 0°C within 5 min under stirring. The resulting solution was stirred at 0°C for 2 h. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (30:1). The crude product (100 mg) was purified by Prep-HPLC under the following conditions (column, XBridge Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase, water (containing 0.05% TFA) and ACN (25.0% ACN, reaching 45.0% in 8 min)). 54.5 mg of the product (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m / z: 465.2 (M+1). III. Treatments for Reducing the Risk of Liver Damage

[0104] Provided herein is a method for treating MS (including RMS, NRSPMS and PPMS) or MG, comprising administering to a patient in need thereof a therapeutically effective amount of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one or a pharmaceutically acceptable salt thereof. However, administration of the compound will (in certain embodiments) only be performed under certain preconditions.

[0105] In one embodiment, the level of transferrin or ferritin of the patient is measured. If it is found that the level of transferrin or ferritin of the patient is not increased, the patient will receive the BTK inhibitor compound. However, if it is found that the transferrin or ferritin of the patient is increased, the patient will not receive the compound. The increased transferrin level is determined by checking the saturation level of transferrin. In particular, the increased transferrin level is the transferrin saturation level of the patient in men>50% and in women>40%. In other words, if the transferrin saturation level of the patient is>50% in men and>40% in women, the patient will not receive the BTK compound, and if the transferrin saturation level of the patient is measured and the saturation is found to be less than or equal to 50% in men or less than or equal to 40% in women, the patient can receive the study drug. This measurement of transferrin saturation can be performed on either or both of MS and MG patients.

[0106] In some embodiments, the patient's ferritin level is measured. If the patient's ferritin level is found not to be elevated, the patient will receive a BTK inhibitor compound. Elevated ferritin levels means levels >500 μg / L. In some embodiments, for the treatment of both MS and MG, the patient's ferritin level is measured, and if it is found to be above 500 μg / L, the patient will not be administered a BTK compound. But if it is found to be less than or equal to 500 μg / L, the patient will receive a BTK compound.

[0107] In some embodiments, for the treatment of both MG and MS, the patient's iron status will be measured, including iron levels in both blood and serum, ferritin levels, and transferrin saturation. If either the ferritin level or the transferrin level is above the thresholds listed above, the patient will not receive a BTK inhibitor. However, if both the ferritin level and the transferrin level are below the thresholds listed above, the patient will receive a BTK inhibitor.

[0108] In some embodiments, there is a method of treating MS and MG, the method comprising determining a patient's alcohol consumption, and administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient in need thereof when the patient is found to have a suitable alcohol consumption. In some embodiments, suitable alcohol consumption means that the patient has no active alcohol use disorder or a history of alcohol or drug abuse within 1 year prior to the first visit. In other embodiments, suitable alcohol consumption means that the patient's current alcohol intake is >2 drinks / day for men and >1 drink / day for women (1 drink=approximately 14 grams of alcohol=350 mL beer=140 mL wine=40 mL liquor). Therefore, the patient needs to have an alcohol consumption of less than 2 drinks / day for men and 1 drink / day for women in order to administer the BTK compound.

[0109] In some embodiments, there is a method for treating MS and MG, wherein it is measured whether the patient is concomitantly taking an inducer of the CYP3A enzyme. If the patient is already taking such an inhibitor, the patient will not receive a BTK compound. Similarly, if the patient is concomitantly taking an inhibitor of CYP3C8, the patient will not be given a BTK compound.

[0110] In some embodiments, for treating both MS and MG, it will be determined whether the patient has an elevated ALT enzyme, and if so, the patient will not receive a BTK inhibitor. This refers to a patient whose alanine aminotransferase (ALT) enzyme has increased and / or has a starting value of >3× the upper limit of normal (ULN). Such a patient will not receive a BTK compound.

[0111] In one embodiment, the level of transferrin or ferritin of the patient is measured. If it is found that the level of transferrin or ferritin of the patient is not increased, the patient will continue to receive the BTK inhibitor compound. However, if it is found that the transferrin or ferritin of the patient is increased, the patient stops receiving the compound (or the compound is no longer administered to the patient). Specifically, in some embodiments, if the transferrin saturation level of the patient is>50% in males and>40% in females, the patient will stop receiving the compound. Such a therapy based on transferrin levels can be stopped for either or both of MS and MG patients.

[0112] In some embodiments, the patient's ferritin level is measured. If the patient's ferritin level is found not to be elevated, the patient will continue to receive the BTK inhibitor compound. However, if the patient's ferritin is found to be elevated, the patient discontinues receiving the compound (or the compound is no longer administered to the patient). Specifically, for the treatment of both MS and MG, the patient's ferritin level is measured, and if it is found to be above> 500 μg / L, the BTK compound is not administered to the patient and / or the patient stops receiving the compound. However, if it is found to be less than or equal to 500 μg / L, the patient will continue to receive the BTK compound.

[0113] In some embodiments, for the treatment of both MG and MS, the patient's iron status will be measured, including iron levels in both blood and serum, ferritin levels, and transferrin saturation. If either the ferritin level or the transferrin level is above the thresholds listed above, the patient will not receive a BTK inhibitor or will stop receiving the compound. If both the ferritin level or the transferrin level are above the thresholds listed above, the patient will also not receive a BTK inhibitor or will stop receiving the compound.

[0114] In some embodiments, there is a method of treating MS and MG, the method comprising determining a patient's alcohol consumption, and administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one when the patient is found to have an appropriate alcohol consumption. In some embodiments, appropriate alcohol consumption means that the patient has no active alcohol use disorder or a history of alcohol or drug abuse within 1 year prior to the first visit. In other embodiments, appropriate alcohol consumption means that the patient's current alcohol intake is >2 drinking units / day for men and >1 drinking unit / day for women (1 drinking unit=approximately 14 grams of alcohol=350 mL beer=140 mL wine=40 mL liquor). Therefore, the patient needs to have an alcohol consumption of less than 2 drinking units / day for men and 1 drinking unit / day for women in order to administer the BTK compound.

[0115] In some embodiments, there is a method for treating MS and MG, the method comprising determining the patient's alcohol consumption, and when it is found that the patient has a higher than appropriate alcohol consumption, the compound is not administered to the patient or the administration of the compound is discontinued. In some embodiments, higher than appropriate alcohol consumption means that the patient has an active alcohol use disorder or a history of alcohol or drug abuse within 1 year before the first visit. In other embodiments, higher than appropriate alcohol consumption means that the patient's current alcohol intake is>2 drinking units / day for men and>1 drinking unit / day for women (1 drinking unit=approximately 14 grams of alcohol=350mL beer=140mL wine=40mL liquor). Therefore, the patient needs to have an alcohol consumption of less than 2 drinking units / day for men and 1 drinking unit / day for women in order to administer the BTK compound or allow the patient to continue to receive the compound.

[0116] In some embodiments, there is a method for treating MS and MG, wherein it is measured whether the patient is concomitantly taking an inducer of the CYP3A enzyme. If the patient is already taking such an inhibitor, the patient will not receive a BTK compound and / or the administration of the compound will be discontinued. Similarly, if the patient is concomitantly taking an inhibitor of CYP3C8, the patient will not be given a BTK compound (or the administration of the compound will be discontinued).

[0117] In some embodiments, for treating both MS and MG, it will be determined whether the patient has an elevated ALT enzyme, and if so, the patient will not receive a BTK inhibitor or will cease receiving the compound. This refers to a starting value of the alanine aminotransferase (ALT) enzyme that has increased and / or has >3× the upper limit of normal (ULN). Such patients will not receive a BTK compound or administration of the compound will be stopped.

[0118] In one embodiment, for MG or MS patients, the patient will be classified as having mild, moderate or severe liver damage, as measured by the Child-Pugh grading scale. In some embodiments, if the patient is determined to have severe liver damage, the patient will not receive the compound or the administration of the compound to the patient will be stopped. In some embodiments, if the patient is determined to have moderate liver damage, the patient will not receive the compound or the administration of the compound to the patient will be stopped. In some embodiments, if the patient is determined to have mild liver damage, the patient will not receive the compound or the administration of the compound to the patient will be stopped.

[0119] In some embodiments, for both MS and MG treatment, patients will be screened to determine if ALT>1.5×ULN or AST>1.5×ULN or alkaline phosphatase>2×ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder) or total bilirubin>1.5×ULN (unless due to Gilbert's syndrome or a non-liver related disorder). Such patients with enzymes above these levels will not be administered the compound, or if they are already receiving the compound, will discontinue receiving the compound.

[0120] In some embodiments, the dosage is once daily. In some embodiments, the dosage is administered once daily with food. In some embodiments, the dosage is 60 mg and is administered once daily with food. In some embodiments, the BTK inhibitor compound is administered as a monotherapy.

[0121] In some embodiments, the patient is a mammal. In some embodiments, the mammal is a human. In some embodiments, the patient is a human subject ranging in age from 12 to 55 years old.

[0122] In some embodiments, the therapeutically effective amount is about 5 to about 60 mg. In some embodiments, the patient is a mammal. In some embodiments, the mammal is a human. In some embodiments, the patient is a human patient ranging in age from 12 to 55 years old.

[0123] In some embodiments, the therapeutically effective amount is about 5 to about 60 mg. In some embodiments, the patient is a mammal. In some embodiments, the mammal is a human. In some embodiments, the patient is a human patient ranging in age from 12 to 55 years old.

[0124] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as a monotherapy. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as a monotherapy at a dose of 60 mg. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered once daily as a monotherapy at a dose of 60 mg. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered once daily as monotherapy at a dose of 60 mg with food.

[0125] In some embodiments, a dose of about 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, or 55-60 mg is administered. In some embodiments, the dose is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg. In some embodiments, the dose is 5 mg. In some embodiments, the dose is 15 mg. In some embodiments, the dose is 30 mg. In some embodiments, the dose is 60 mg.

[0126] In some embodiments, the dosage is applied every day. The daily dosage can be delivered as a single dose or divided into multiple parts. For example, in some embodiments, the dosage is applied once a day (e.g., approximately every 24 hours). In some embodiments, the dosage is applied twice a day. In some embodiments, the dosage is subdivided into two parts to be applied twice a day (e.g., approximately every 12 hours). In some embodiments, the dosage is subdivided into three parts to be applied three times a day (e.g., approximately every 8 hours). In some embodiments, the dosage is subdivided into four parts to be applied four times a day (e.g., approximately every 6 hours).

[0127] In some embodiments, the dosage is administered orally. In some embodiments, the dosage is administered in the form of a tablet. In some embodiments, the dosage is administered in the form of a pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0128] In some embodiments, the BTK inhibitor compound is administered to the patient for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or for a lifetime. In some embodiments, the BTK inhibitor compound is administered to the patient for a period of about 12 months. In some embodiments, the dosage is once a day. In one embodiment, a method for treating MS or MG is provided, the method comprising administering 60 mg of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one to a patient in need.

[0129] In some embodiments, the BTK inhibitor compound is administered as a monotherapy. In some embodiments, the method comprises administering a BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent can be administered concurrently or sequentially with the BTK inhibitor compound.

[0130] The determination of the frequency of administration can be made by a person skilled in the art (e.g., an attending physician) based on consideration of the following factors: the condition being treated, the age of the subject being treated, the severity of the condition being treated, the general health status of the subject being treated, etc. In some embodiments, the BTK inhibitor compound is administered in a therapeutically effective amount for the treatment of RMS. The therapeutically effective amount generally depends on the weight of the subject being treated, his or her physical or health condition, the extensiveness of the condition to be treated, or the age of the subject being treated, the drug formulation method, or the method of administration (e.g., administration time and administration route).

[0131] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the following steps: performing an iron status test using the patient's blood or serum, and if the patient has suitable iron status, administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the iron status test measures any one or more of the iron level, ferritin level, transferrin saturation level and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, suitable iron status includes one or more of the following: (i) iron levels of 60 to 170 μg / dL, (ii) ferritin levels of ≤500 μg / L, (iii) transferrin saturation levels of ≤50% in male patients or ≤40% in female patients, and (iv) TIBC of 240 to 450 μg / dL.

[0132] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the following steps: performing an iron status test in the patient's blood or serum, detecting a level of the iron status test within the normal range, and administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the iron status test measures any one or more of the iron level, ferritin level, transferrin saturation level and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range for the iron status test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of ≤500 μg / L, (iii) a transferrin saturation level of ≤50% in male patients or ≤40% in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0133] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method for treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the steps of performing an iron status test in the patient's blood or serum, detecting a level of the iron status test within a normal range, and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the iron status test measures any one or more of the iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range for the iron status test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of ≤500 μg / L, (iii) a transferrin saturation level of ≤50% in male patients or ≤40% in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0134] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the following steps: determining the transferrin saturation level in the patient's blood or serum, and if the transferrin saturation level is appropriate, administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the appropriate transferrin saturation level in the blood or serum of a male patient is ≤50% transferrin saturation. In some embodiments, the appropriate transferrin saturation level in the blood or serum of a female patient is ≤40% transferrin saturation.

[0135] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the following steps: detecting a transferrin saturation level within a normal range in the patient's blood or serum, and administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a male patient is ≤50% of transferrin saturation. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a female patient is ≤40% of transferrin saturation.

[0136] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the steps of detecting a transferrin saturation level within a normal range in the patient's blood or serum, and administering a therapeutically effective amount of the compound to the patient. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a male patient is ≤50% transferrin saturation. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a female patient is ≤40% transferrin saturation.

[0137] In some embodiments, a method of treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the steps of determining the ferritin level in the patient's blood or serum, and if the ferritin level is appropriate, administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the appropriate ferritin level in the patient's blood or serum is ≤500 μg / L.

[0138] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the following steps: detecting a ferritin level within a normal range in the patient's blood or serum, and administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the ferritin level within a normal range in the patient's blood or serum is ≤500 μg / L.

[0139] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the steps of detecting a ferritin level within a normal range in the patient's blood or serum, and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the ferritin level within a normal range in the patient's blood or serum is ≤500 μg / L.

[0140] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the following steps: performing a liver function test in a patient, and if the patient has suitable liver function, administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the liver function test measures one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein. In some embodiments, patients with adequate liver function have one or more of: ALT levels ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, and alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

[0141] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the steps of performing a liver function test in a patient, detecting appropriate liver function, and administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the liver function test measures one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein. In some embodiments, patients with adequate liver function have one or more of: ALT levels ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, and alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

[0142] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the steps of performing a liver function test in a patient, detecting appropriate liver function, and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the liver function test measures one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein. In some embodiments, patients with adequate liver function have one or more of: ALT levels ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, and alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

[0143] In some embodiments, the liver function test is performed at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about every month. In some embodiments, the liver function test is performed at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about every week.

[0144] In some embodiments, a method of treating MS (including RMS, NRSPMS, and PPMS) or MG is provided, the method comprising the steps of: a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT level >8x upper limit of normal (ULN) detected; d) ceasing administration of the compound to the patient; and optionally e) monitoring ALT levels in said patient; and f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0145] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT level >8x upper limit of normal (ULN) detected; d) ceasing administration of the compound to the patient; and optionally e) monitoring ALT levels in said patient; and f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0146] In some embodiments, a method of treating MS (including RMS, NRSPMS, and PPMS) or MG is provided, the method comprising the steps of: a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT levels >5x upper limit of normal (ULN) detected during a period of at least two weeks; d) ceasing administration of the compound to the patient; and optionally e) monitoring ALT levels in said patient; and f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0147] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT levels >5x upper limit of normal (ULN) detected during a period of at least two weeks; d) ceasing administration of the compound to the patient; and optionally e) monitoring ALT levels in said patient; and f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0148] In some embodiments, a method of treating MS (including RMS, NRSPMS, and PPMS) or MG is provided, the method comprising the steps of: a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT level >3x upper limit of normal (ULN) detected; d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; e) One or more of total bilirubin >2 x ULN and INR >1.5 was detected; f) ceasing administration of the compound to the patient; and optionally g) monitoring ALT levels in said patient; and h) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0149] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT level >3x upper limit of normal (ULN) detected; d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; e) One or more of total bilirubin >2 x ULN and INR >1.5 was detected; f) ceasing administration of the compound to the patient; and optionally g) monitoring ALT levels in said patient; and h) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0150] In some embodiments, a method of treating MS (including RMS, NRSPMS, and PPMS) or MG is provided, the method comprising the steps of: a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT level >3x upper limit of normal (ULN) detected; d) if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia>5%, discontinuing administration of the compound to the patient; and optionally e) monitoring ALT levels in said patient; and f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0151] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring alanine aminotransferase (ALT) levels in said patient; c) ALT level >3x upper limit of normal (ULN) detected; d) if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia>5%, discontinuing administration of the compound to the patient; and optionally e) monitoring ALT levels in said patient; and f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0152] In some embodiments, the ALT level in the patient is measured at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about every month. In some embodiments, the ALT level in the patient is measured at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about every week.

[0153] In some embodiments, ALT levels are monitored in the patient about every 2 to 3 days, about every 3 days, about every 2 days, or about every day after cessation of administration of the compound.

[0154] In some embodiments, a method of treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient, wherein the patient is not receiving a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 liver enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampicin, carbamazepine, phenobarbital, St. John's wort extract, avasimib, lumacato, rifapentine, rifabutin and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semacid, anaprevir, belabuvir, daclatasvir, phenbarate, nafcillin, lesinade, modafinil, bosentan, terostat ethyl, thioridazine, elagolix and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0155] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising administering a therapeutically acceptable amount of the compound to a patient, wherein the patient is not receiving a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 liver enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampicin, carbamazepine, phenobarbital, St. John's wort extract, avasimib, lumacato, rifapentine, rifabutin and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semacid, anaprevir, belabuvir, daclatasvir, phenbarate, nafcillin, lesinade, modafinil, bosentan, terostat ethyl, thioridazine, elagolix and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0156] In some embodiments, a method for treating MS (including RMS, NRSPMS and PPMS) or MG is provided, the method comprising the steps of: advising the patient to limit alcohol consumption during treatment, and administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the patient is female and is advised to limit alcohol consumption to 1 drinking unit / day or less. In some embodiments, 1 drinking unit is approximately 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of liquor). In some embodiments, the patient is male and is advised to limit alcohol consumption to 2 drinking units / day or less. In some embodiments, 2 drinking units are approximately 28 grams of alcohol.

[0157] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating MS (including RMS, NRSPMS and PPMS) or MG, the method comprising the steps of: advising the patient to limit alcohol consumption during treatment, and administering a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to the patient. In some embodiments, the patient is female and is advised to limit alcohol consumption to 1 drink per day or less. In some embodiments, 1 drinking unit is about 14 grams of alcohol (e.g., 350 mL beer, 140 mL wine, or 40 mL liquor). In some embodiments, the patient is male and is advised to limit alcohol consumption to 2 drinking units / day or lower. In some embodiments, 2 drinking units are about 28 grams of alcohol.

[0158] The selection of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, a formulation in the form of tablets, pills or capsules is preferred) and the bioavailability of the drug substance. Recently, based on the principle that bioavailability can be increased by increasing surface area (i.e., reducing particle size), a pharmaceutical formulation specifically for drugs showing poor bioavailability has been developed. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation, the size of which is within the range of 10 to 1,000 nm, wherein the active material is loaded on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation, wherein in the presence of a surface modifier, the drug substance is crushed into nanoparticles (average particle size of 400 nm), which are then dispersed in a liquid medium to obtain a pharmaceutical formulation showing very high bioavailability. The bioavailability of a drug decomposed at gastric pH can be increased by administering such a drug with a formulation that releases the drug in the duodenum.

[0159] The composition is generally composed of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient (e.g., a binder, a surfactant, a diluent, a buffer, an anti-adhesive agent, a glidant, a hydrophilic or hydrophobic polymer, a retardant, a stabilizing agent or stabilizer, a disintegrant or super disintegrant, an antioxidant, an antifoaming agent, a filler, a flavoring agent, a pigment, a lubricant, an adsorbent, a preservative, a plasticizer or a sweetener or a mixture thereof) in combination, wherein the excipient facilitates processing of the BTK inhibitor compound or a pharmaceutically acceptable salt thereof into a preparation that can be used pharmaceutically. Any well-known techniques and excipients may be used as appropriate and as understood in the art, see, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., (Pharmaceutical Press, 2005); Liberman, HA, Lachman, L. and Schwartz, JB, eds., Pharmaceutical Dosage Forms, Vol. 1-2 Taylor & Francis 1990; and RI Mahato, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 2nd ed. (Taylor & Francis, 2012).

[0160] In certain embodiments, the formulation may include one or more pH adjusters or buffers, for example, acids such as acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris; and buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride, and the like. Such buffers used as bases may have other counterions in addition to sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0161] In certain embodiments, the formulation may also include one or more salts in an amount required to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0162] In certain embodiments, the formulation may also include one or more defoamers to reduce foaming during processing which may cause coagulation of the aqueous dispersion, the appearance of bubbles in the finished film, or generally impair processing. Exemplary defoamers include silicone emulsions or sorbitan sesquioleate.

[0163] In certain embodiments, the formulation may also include one or more antioxidants, such as non-thiol antioxidants, for example butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivatives and tocopherol or its derivatives. In certain embodiments, antioxidants enhance chemical stability when necessary. Other agents such as citric acid or citrate or EDTA may also be added to slow down oxidation.

[0164] In certain embodiments, the formulation may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0165] In certain embodiments, the formulation may also include one or more binders. Binders impart viscosity and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ) and microcrystalline cellulose (e.g., ); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acid; bentonite; gelatin; polyvinyl pyrrolidone / vinyl acetate copolymer; cross-linked polyvinylpyrrolidone; povidone; starch; pregelatinized starch; tragacanth; dextrin; sugars, such as sucrose (e.g., ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ) and lactose; natural or synthetic gums, such as gum arabic, gum tragacanth, gum mucilage from the bark of the isapol tree; polyvinylpyrrolidone (e.g., CL, CL, XL-10); larch arabinogalactan; Polyethylene glycol; polyethylene oxide; wax; sodium alginate, etc.

[0166] In certain embodiments, the formulation may also include a dispersant or viscosity modifier. Dispersants or viscosity modifiers include materials that control the diffusion and uniformity of the drug through the liquid medium or granulation process or blending process. In some embodiments, these agents also contribute to the effectiveness of the coating or erosion matrix. Exemplary diffusion enhancers / dispersants include, for example, hydrophilic polymers, electrolytes, 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as ), and carbohydrate-based dispersants (such as, for example, hydroxypropyl cellulose (e.g., HPC, H--PC-SL and HPC-L), hydroxypropyl methylcellulose (e.g., HPMC K100, RPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate stearate (HPMCAS), non-crystalline cellulose), polyethylene oxide, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronic and which is a block copolymer of ethylene oxide and propylene oxide), and poloxamines (e.g., Tetronic Also known as Poloxamine which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ), polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30, polyvinyl pyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to 5400), sodium carboxymethyl cellulose, methyl cellulose, polysorbate 80, sodium alginate, gums (such as, for example, gum tragacanth and gum arabic), guar gum, xanthan (including xanthan gum gum), sugars, cellulose (such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan, and combinations thereof. Plasticizers such as cellulose or triethylcellulose may also be used as dispersants. Dispersants particularly useful for liposomal dispersions and self-emulsifying dispersions are dimyristoylphosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol, and isopropyl myristate. Typically, binder levels of about 10% to about 70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary, whether direct compression, wet granulation, roller compaction, or use of other excipients (such as fillers, which themselves can act as moderate binders). The formulator skilled in the art can determine the binder level for a formulation, but binder usage levels of up to 90%, more typically up to 70%, are common in tablet formulations.

[0167] In certain embodiments, the formulation may also include one or more diluents, which refers to chemical compounds used to dilute the compound of interest prior to delivery.

[0168] Diluents can also be used to stabilize the compound because they can provide a more stable environment. Salts dissolved in buffered solutions (which can also provide pH control or maintenance) are used as diluents in the art, including but not limited to phosphate buffered saline solutions. In certain embodiments, the diluent increases the volume of the composition to aid compression or to create enough homogenous blend volume for capsule filling. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose, such as Dicalcium phosphate; Dicalcium phosphate dihydrate; Tricalcium phosphate; Calcium phosphate; Anhydrous lactose; Spray-dried lactose; Pregelatinized starch; Compressible sugars, such as (Amstar); hydroxypropyl methylcellulose; hydroxypropyl methylcellulose acetate stearate; sucrose-based diluents; confectioners sugar; calcium dihydrogen sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite, etc.

[0169] In certain embodiments, the formulation may also include one or more disintegrants, which both dissolve and disperse the dosage form when it comes into contact with gastrointestinal fluids. Disintegration agents or disintegrants aid in the decomposition or disintegration of a substance. Examples of disintegrants include starches, for example, natural starches (such as corn starch or potato starch), pregelatinized starches (such as National 1551), or sodium starch glycolate (such as or ); cellulose, such as wood products, methyl crystalline cellulose (e.g., PH101, PH102, PH105, P100, and ), methylcellulose, cross-linked carboxymethylcellulose or cross-linked cellulose (such as cross-linked carboxymethylcellulose sodium cross-linked carboxymethyl cellulose or cross-linked cross-linked carboxymethyl cellulose); cross-linked starch (such as sodium starch glycolate); cross-linked polymers, such as cross-linked povidone, cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or salts of alginic acid such as sodium alginate; clays, such as HV (magnesium aluminum silicate); gums such as agar, guar gum, locust bean gum, karaya gum, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponge; surfactant; resin, such as cation exchange resin; citrus pulp; sodium lauryl sulfate; a combination of sodium lauryl sulfate and starch, etc.

[0170] In certain embodiments, the formulation may also include an erosion promoter. Erosion promoters include materials that control the erosion of specific materials in gastrointestinal fluids. Erosion promoters are generally known to those of ordinary skill in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0171] In certain embodiments, the formulation may also include one or more fillers, including compounds such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0172] In certain embodiments, the formulations may also include one or more flavoring agents or sweeteners, such as acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, sodium cyclamate, sodium cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizate, glycyrrhiza / licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, cream), mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti The flavoring ingredients include anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0173] In certain embodiments, the formulations may also include one or more lubricants and glidants, which are compounds that prevent, reduce or inhibit the sticking or friction of materials.

[0174] Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons (e.g., mineral oil), or hydrogenated vegetable oils (e.g., hydrogenated soybean oil), higher fatty acids and their alkali metal and alkaline earth metal salts (e.g., aluminum, calcium, magnesium, zinc), stearic acid, sodium stearate, glycerol, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG4000) or methoxy polyethylene glycol (e.g., ), sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silicon dioxide (such as ), starch (such as corn starch), silicone oil, surfactants, etc.

[0175] In certain embodiments, formulations can also include one or more plasticizers, which are compounds used to soften enteric or delayed release coatings to make them less fragile. Suitable plasticizers include, for example, polyethylene glycol (such as PEG300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800), stearic acid, propylene glycol, oleic acid, triethyl citrate, dibutyl sebacate, triethylcellulose and triacetin. In some embodiments, plasticizers can also act as dispersants or wetting agents.

[0176] In certain embodiments, the formulation may also include one or more solubilizing agents, such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, docusate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin (e.g. ), ethanol, n-butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-600, tetrahydrofuran glycol ether, diethylene glycol monoethyl ether, propylene glycol and isosorbide dimethyl ether and the like. In one embodiment, the solubilizer is vitamin E TPGS or or β-hydroxypropyl cyclodextrin.

[0177] In certain embodiments, the formulation may also include one or more suspending agents, including polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone K112, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30), vinyl pyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (e.g., the polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose acetate stearate, polysorbate 80, hydroxyethyl cellulose, sodium alginate, gums (such as, for example, gum tragacanth and gum arabic), guar gum, xanthan gum (including xanthan gum (xanthan gum) gum)), sugars, cellulose (such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, povidone and the like compounds.

[0178] In certain embodiments, the formulation may also include one or more surfactants, including surfactants such as sodium lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., (BASF) and other compounds. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil) and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., octylphenol polyether 10, octylphenol polyether 40). In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0179] In certain embodiments, the formulation may also include one or more viscosity enhancers including, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol alginate, gum arabic, chitosan, and combinations thereof.

[0180] In certain embodiments, the formulation may also include one or more wetting agents, including compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and the like.

[0181] The pharmaceutical preparations disclosed herein can be obtained by mixing one or more solid excipients (such as carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof) with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granule mixture after adding suitable excipients (if necessary) to obtain tablets.

[0182] Pharmaceutical preparations disclosed herein also include capsules made of gelatin and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Capsules can also be made of polymers (such as hypromellose). Capsules can contain a mixture of active ingredients and fillers (such as lactose), adhesives (such as starch) or lubricants (such as talc or magnesium stearate) and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, lipid, solubilizer or liquid polyethylene glycol). In addition, stabilizers can be added. The dosage of all formulations for oral administration should be suitable for such administration.

[0183] These formulations can be made by conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, (6) melting, or (7) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd edition (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, extrusion / spheronization, etc.

[0184] It should be understood that there is considerable overlap between the excipients used in the solid dosage forms described herein. Therefore, the additives listed above should be considered as merely exemplary and non-limiting types of excipients that can be included in the solid dosage forms described herein. The type and amount of such excipients can be easily determined by those skilled in the art based on the specific properties desired.

[0185] In some embodiments, the solid dosage form described herein is an enteric coated oral dosage form, i.e., an oral dosage form as a pharmaceutical composition as described herein, which utilizes an enteric coating to affect the release of a compound in the intestine of the gastrointestinal tract. An "enteric coated" drug or tablet refers to a drug or tablet coated with a material that remains intact in the stomach but dissolves and releases the drug once it reaches the intestine (in one embodiment, the small intestine). As used herein, an "enteric coating" is a material, such as one or more polymeric materials, that is used as a dosage form or as a particle to encapsulate a core of a therapeutically active agent. Typically, a large amount or all of the enteric coating material is dissolved before the therapeutically active agent is released from the dosage form, thereby achieving delayed dissolution of the core or particles of the therapeutically active agent in the small intestine or large intestine. Enteric coatings are discussed, for example Loyd, V.Allen, Remington: The Science and Practice of Pharmacy, 21st edition, Pharmaceutical Press, 2005; and PJ Tarcha, Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991. Methods for applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, US Patent Publication No. 2006 / 0045822.

[0186] Enteric coated dosage forms can be compressed or molded or extruded tablets (coated or uncoated) containing granules, powders, pellets, beads or granules of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof or other excipients, which are themselves coated or uncoated, provided that at least the tablet or BTK inhibitor compound is coated. Enteric coated oral dosage forms can also be capsules (coated or uncoated) containing pellets, beads or granules of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof or other excipients, which are themselves coated or uncoated, provided that at least one of them is coated. Some examples of coatings originally used as enteric coatings are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, frankincense and shellac and shellac and stearic acid (U.S. Pat. No. 2,809,918); polyvinyl acetate and ethylcellulose (U.S. Pat. No. 3,835,221). More recently, coatings used have been neutral copolymers of polymethacrylates (Eudragit L30D). (FW Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymers of methacrylic acid and methyl methacrylate (Eudragit S), or neutral copolymers of polymethacrylates containing metal stearates (U.S. Pat. Nos. 4,728,512 and 4,794,001 to Mehta et al.); cellulose acetate succinate and hypromellose phthalate.

[0187] In the methods and compositions described herein, any anionic polymer that exhibits a pH-dependent solubility curve can be used as an enteric coating to achieve delivery to the intestine. In one embodiment, delivery can be to the small intestine. In another embodiment, delivery can be to the duodenum. In some embodiments, the polymer described herein is an anionic carboxylic acid polymer. In other embodiments, polymers and compatible mixtures thereof and some of their characteristics include, but are not limited to, the following.

[0188] Shellac: Also known as purified lac, it is a refined product obtained from the resinous secretions of insects. This coating dissolves in a medium with a pH > 7.

[0189] Acrylic polymers: The properties of acrylic polymers (primarily their solubility in biological fluids) can vary depending on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series L, S and RS (manufactured by Rohm Pharma and known as ) are soluble in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract, but permeable and are primarily used for colon targeting. Eudragit series L, L-30D and S are insoluble in the stomach and soluble in the intestine and can be selected and formulated to dissolve at pH values ​​greater than 5.5 or as low as greater than 5 or as high as greater than 7.

[0190] Cellulose derivatives: Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of cellulose acetate esters with phthalic anhydride. The properties may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water-based system and is a spray-dried CAP pseudolatex with particles <1 μm. Other components in Aquateric may include Pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (HPMCAS, such as AQOAT (Shin Etsu)). The properties may vary depending on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, and HP-55F are suitable. The properties may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF) which dissolves at pH 5, AS-MG (MF) which dissolves at pH 5.5, and AS-HG (HF) which dissolves at higher pH. These polymers are provided as granules or as fine powders for aqueous dispersions.

[0191] Polyvinyl acetate phthalate (PVAP): PVAP dissolves at pH>5 and is much less permeable to water vapor and gastric fluid. A detailed description of the above polymers and their pH-dependent solubility can be found in the article entitled "Enteric coated hard gelatin capsules" by Professors Karl Thoma and Karoline Bechtold at http: / / pop.www.capsugel.com / media / library / enteric-coated-hard-gelatin-capsules.pdf. In some embodiments, the coating can and usually does contain a plasticizer and possibly other coating excipients, such as colorants, talc or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (triacetin), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers typically contain 10%-25% by weight of plasticizers, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques (such as fluidized bed or Wurster coaters, or spray coating or pan coating). The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired local delivery site in the intestinal tract.

[0192] In addition to plasticizers, colorants, surfactants, anti-adherents, defoamers, lubricants (eg, carnauba wax or PEG) and other additives may be added to the coating to dissolve or disperse the coating material and to improve coating properties and the coated product.

[0193] To accelerate the dissolution of the enteric coating, a half-thick double layer of enteric polymer can be applied (e.g., Eudragit L30 D-55), and the inner enteric coating can have a buffer up to pH 6.0 in the presence of 10% citric acid, followed by a final layer of standard Eudragit L 30 D-55. Liu and Basit applied two layers of enteric coating (each layer half the thickness of a typical enteric coating), which was able to accelerate the dissolution of the enteric coating compared to a similar coating system applied as a single layer without buffer (Liu, F. and Basit, A. Journal of Controlled Release. 147 (2010) 242-245).

[0194] The integrity of the enteric coating can be measured, for example, by the degradation of the drug within the pellets. As described in the USP, enteric coated dosage forms or pellets can be tested in dissolution tests first in gastric fluid and separately in intestinal fluid to determine their functionality.

[0195] Enteric coated tablets and capsule formulations containing the disclosed compounds can be prepared by methods well known in the art. For example, tablets containing the compounds disclosed herein can be coated using a Freund Hi-Coater with a coating containing Enteric coating is performed with a coating solution of diethyl phthalate, isopropyl alcohol, talc and water.

[0196] Alternatively, multiple unit dosage forms comprising enteric coated pellets which may be incorporated into tablets or capsules may be prepared as follows.

[0197] Core material: The core material of the enteric coated layered pellets can be composed according to different principles. Seeds layered with active agents (i.e., BTK inhibitor compounds or pharmaceutically acceptable salts thereof), optionally mixed with alkaline substances or buffers, can be used as core materials for further processing. The seeds to be layered with active agents can be water-insoluble seeds containing different oxides, cellulose, organic polymers and other materials, either alone or in a mixture, or water-soluble seeds containing different inorganic salts, sugars, sucrose pellets (non-pareil) and other materials, either alone or in a mixture.

[0198] In addition, the seed may contain an activating agent in the form of crystals, agglomerates, briquettes, etc. The size of the seed is insignificant for the present disclosure, but the size range may be approximately 0.1 to 2 mm. The seed layered with the activating agent is produced by powder or solution / suspension layering using, for example, granulation or spraying layering equipment. Before the seed is layered, the activating agent may be mixed with other components.

[0199] Such components can be binders, surfactants, fillers, disintegrants, alkaline additives or other components or pharmaceutically acceptable ingredients, either alone or in the form of a mixture. Binders are, for example, polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, polyvinyl pyrrolidone (PVP), or sugars, starches or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants can be found in the following group: pharmaceutically acceptable nonionic or ionic surfactants, such as, for example, sodium lauryl sulfate.

[0200] Alternatively, the activating agent optionally mixed with the appropriate ingredients can be formulated into a core material. The core material can utilize conventional processing equipment to produce by extrusion / spheronization, spheronization or compression. The size of the prepared core material is approximately 0.1 to 4mm, and for example 0.1 to 2mm. The manufactured core material can be further layered with the other composition comprising the activating agent, or can be used for further processing.

[0201] The active agent is mixed with the pharmaceutical ingredients to obtain the preferred handling and processing characteristics and the appropriate concentration of the active agent in the final formulation. Pharmaceutical ingredients such as fillers, binders, lubricants, disintegrants, surfactants and other pharmaceutically acceptable additives may be used.

[0202] Alternatively, the aforementioned core material may be prepared by using spray drying or spray congealing techniques.

[0203] One or more enteric coating layers: Before the one or more enteric coating layers are applied to the core material in the form of individual pellets, the pellets may optionally be covered with one or more separating layers comprising pharmaceutical excipients, which optionally include alkaline compounds, such as pH buffering compounds. This / these separating layers separate the core material from the outer layer which is one or more enteric coating layers. This / these separating layers protecting the active agent core material should be water soluble or rapidly disintegrate in water.

[0204] One or more separating layers can be applied to the core material in suitable equipment (such as coating pan, coating granulator) or in a fluidized bed apparatus using water or organic solvent for coating process, optionally by coating or layering procedure. As an alternative, the one or more separating layers can be applied to the core material by using powder coating technology. The material used for the separating layer is a pharmaceutically acceptable compound used alone or in a mixture form, such as water-soluble salts of sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, enteric coating polymers, etc. Additives (such as plasticizers, colorants, colorants, fillers, anti-adhesives and antistatic agents, such as magnesium stearate, titanium dioxide, talcum and other additives) can also be included in the one or more separating layers.

[0205] When an optional separating layer is applied to the core material, it can constitute a variable thickness. The maximum thickness of the one or more separating layers is usually limited only by processing conditions. The separating layer can be used as a diffusion barrier and can be used as a pH buffer. The one or more separating layers optionally applied are not critical for the embodiments of the present disclosure. However, the one or more separating layers can improve the chemical stability of the active substance or the physical properties of the novel multiple unit tablet dosage form.

[0206] Alternatively, the separating layer can be formed in situ by a reaction between an enteric coating polymer layer applied on the core material and an alkaline reacting compound in the core material. Thus, the separating layer formed comprises a water-soluble salt formed between the one or more enteric coating layer polymers and an alkaline reacting compound in a position to form a salt.

[0207] By using suitable coating technology, one or more enteric coating layers are applied on the core material or are covered with one or more separating layers on the core material. The enteric coating layer material can be dispersed or dissolved in water or in a suitable organic solvent. As the enteric coating layer polymer, one or more of the following can be used alone or in combination, for example, a solution or dispersion of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, shellac or one or more other suitable enteric coating polymers.

[0208] The enteric coating layer contains a pharmaceutically acceptable plasticizer to obtain desired mechanical properties, such as flexibility and hardness of the enteric coating layer. Such plasticizers are, for example, but not limited to, triacetin, citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate or other plasticizers.

[0209] About the one or more enteric coating layer polymers selected, the one or more plasticizers selected and the applied amount of the one or more polymers, the amount of plasticizer is optimized for each enteric coating layer formulation, and the mechanical properties are adjusted in such a way that the flexibility and hardness of the one or more enteric coating layers are adjusted, for example, with Vickers hardness as an example, so that if tablets are needed, the acid resistance of the pellets covered with one or more enteric coating layers will not be significantly reduced during the process of compressing the pellets into tablets. According to the weight of the one or more enteric coating layer polymers, the amount of plasticizer is usually higher than 5%, such as 15%-50%, further such as 20%-50%. Additives (such as dispersants, colorants, colorant polymers such as poly (ethyl acrylate, methyl methacrylate), anti-adhesive agents and defoamers) can also be included in the one or more enteric coating layers. Other compounds can be added to increase film thickness and reduce the diffusion of acidic gastric juice into acid-sensitive materials. The maximum thickness of the enteric coating applied is usually only limited by processing conditions and desired dissolution curves.

[0210] Outer coating layer: The pellets covered with one or more enteric coating layers may be optionally further covered with one or more outer coating layers. The one or more outer coating layers should be water-soluble or rapidly disintegrate in water. The one or more outer coating layers may be applied to the enteric coated layered pellets by coating or layering procedures in suitable equipment (such as coating pans, coating granulators) or in fluidized bed apparatus using water or organic solvents for coating or layering processes. The materials used for the outer coating layer are selected from pharmaceutically acceptable compounds used alone or in the form of a mixture, such as, for example, sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. Additives (such as plasticizers, colorants, colorants, fillers, anti-adhesives and antistatic agents, such as, for example, magnesium stearate, titanium dioxide, talc and other additives) may also be included in the one or more outer coating layers. The outer coating layer can further prevent the potential agglomeration of the enteric coated layered pellets, it can also protect the enteric coating layer from rupture during the compression process, and enhance the tableting process. The maximum thickness of the applied one or more outer coating layers is usually limited only by processing conditions and the desired dissolution profile. The outer coating layer can also be used as a tablet film coating layer.

[0211] Enteric coatings for soft gelatin capsules can contain emulsions, oils, microemulsions, self-emulsifying systems, lipids, triglycerides, polyethylene glycols, surfactants, other solubilizing agents, etc. and combinations thereof, to dissolve active agents. The flexibility of soft gelatin capsules is maintained by residual water and plasticizers. In addition, for gelatin capsules, gelatin can be dissolved in water so that spraying must be completed at a rate with relatively low relative humidity, such as can be completed in a fluidized bed or Wurster. In addition, drying should be completed without removing residual water or plasticizers to cause capsule shell rupture. Commercially available blends optimized for enteric coatings for soft gelatin capsules, such as Instamodel EPD (enteric polymer dispersions), can be purchased from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a laboratory scale, enteric coated capsules can be prepared by a) swirling the capsules in a flask of mildly heated enteric coating material and plasticizer at the lowest possible temperature or dipping the capsules into a solution of mildly heated enteric coating material and plasticizer, or b) in a laboratory scale sprayer / fluidized bed followed by drying.

[0212] For aqueous active agents, it may be particularly desirable to incorporate the drug into the aqueous phase of the emulsion. Such "water-in-oil" emulsions provide a suitable biophysical environment for the drug and can provide an oil-water interface that can protect the drug from the adverse effects of pH or enzymes that may degrade the drug. In addition, such water-in-oil formulations can provide a lipid layer that can advantageously interact with lipids in body cells and can increase the distribution of the formulation on the cell membrane. This distribution can increase the absorption of the drug in such formulations in the circulation, and thus can increase the bioavailability of the drug.

[0213] In some embodiments, the water-in-oil emulsion contains an oil phase composed of a medium-chain or long-chain carboxylic acid or its ester or alcohol, a surfactant (surfactant or surface-active agent), and an aqueous phase mainly containing water and an active agent.

[0214] Medium-chain and long-chain carboxylic acids are those ranging from C8 to C22, with up to three unsaturated bonds (also branched). Examples of saturated straight-chain acids are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Unsaturated monoolefin straight-chain monocarboxylic acids are also useful.

[0215] Examples of these carboxylic acids are oleic acid, gadoleic acid and erucic acid. Unsaturated (polyene) straight chain monocarboxylic acids are also useful. Examples of these carboxylic acids are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid and behenic acid. Useful branched chain acids include, for example, diacetyltartaric acid. The unsaturated olefin chains may also be hydroxylated or ethoxylated to prevent oxidation or to alter surface properties.

[0216] Examples of long chain carboxylic acid esters include, but are not limited to, those from the group consisting of glyceryl monostearate; glyceryl monopalmitate; a mixture of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoleate; glyceryl monooleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, and glyceryl monolinoleate; glyceryl monolinolenate; glyceryl monocodoleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monocodoleate, and glyceryl monocodoleate; acetylated glycerides, such as distilled acetylated monoglycerides; propylene glycol monoesters, distilled monoglycerides, sodium steroyl lactylate, lactylate) and silica; d-alpha tocopheryl polyethylene glycol 1000 succinate; mixtures of mono- and diglycerides such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and diglycerides; lactic acid mono- and diglycerides; lactylic acid carboxylic acid esters of glycerol and propylene glycol; lactylic acid esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids; propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearoyl monocitrate; stearoyl heptanoate; cetyl esters of waxes; stearoyl caprylate; C8-C30 cholesterol / lanosterol esters; and sucrose long chain carboxylic acid esters.

[0217] The example of self-emulsifying long chain carboxylates includes those from the group of stearate, palmitate, ricinoleate, oleate, behenate, ricinolenate, myristate, laurate, caprylate and caproate. In some embodiments, the oil phase can include a combination of 2 or more long chain carboxylic acids or their esters or alcohols. In some embodiments, a medium chain surfactant can be used, and the oil phase can include a mixture of caprylic / capric triglyceride and caprylic C8 / C10 monoglyceride / diglyceride, caprylic glyceride or propylene glycol monocaprylate or a mixture thereof.

[0218] Alcohols that can be used are exemplified by the hydroxyl forms of the above-exemplified carboxylic acids and stearyl alcohol.

[0219] Surfactants are long chain molecules that can accumulate at hydrophilic / hydrophobic (water / oil) interfaces and reduce the surface tension at the interface. Thus, they can stabilize emulsions. In some embodiments, surfactants may include: (polyoxyethylene sorbate) family of surfactants, (Sorbitan long-chain carboxylate) family of surfactants, (ethylene oxide or propylene oxide block copolymer) family of surfactants, and (each a polyglycolyzed glyceride) family surfactants, sorbitan esters of oleic acid, stearic acid, lauric acid or other long-chain carboxylic acids, poloxamers (polyethylene glycol-polypropylene glycol block copolymers or ), other sorbitan or sucrose long chain carboxylates, mono- and di-glycerides, PEG derivatives of caprylic / capric triglycerides, and mixtures thereof, or mixtures of two or more of the foregoing. In some embodiments, the surfactant phase may include polyoxyethylene (20) sorbitan monooleate (Tween ) and sorbitan monooleate mixture.

[0220] The aqueous phase may optionally contain the active agent and a buffering agent suspended in water.

[0221] In some embodiments, such emulsions are macroemulsions, microemulsions, and liquid crystal emulsions. In other embodiments, such emulsions may optionally contain a penetration enhancer. In other embodiments, spray-dried dispersions or microparticles or nanoparticles containing encapsulated microemulsions, macroemulsions, or liquid crystals may be used.

[0222] In some embodiments, the solid dosage form described herein is a non-enteric delayed release dosage form. As used herein, the term "non-enteric delayed release" refers to a delivery that allows the release of the drug to be completed at a generally predictable location in the intestine, which is farther away than where it would be completed without the delayed release change. In some embodiments, the method for delayed release is a coating that becomes permeable, dissolved, ruptured or no longer intact after a designed duration. The coating in the delayed release dosage form can have a fixed dissolution time, after which the drug is released (suitable coatings include polymer coatings such as HPMC, PEO, etc.), or have a core composed of one or more super disintegrants or one or more osmotic agents or water attractants (such as salts, hydrophilic polymers (typically polyethylene oxide or alkyl cellulose), salts (such as sodium chloride, magnesium chloride, sodium acetate, sodium citrate), sugars (such as glucose, lactose or sucrose), etc., the water attractant passes through a semipermeable membrane or a gas generator (such as citric acid and sodium bicarbonate), with or without In the presence of an acid (such as citric acid or any of the foregoing acids incorporated into the dosage form), water is drawn out. The semipermeable membrane, while mostly impermeable to the drug and osmotic agent, is permeable to water, which penetrates into the dosage form at a near constant rate to increase the pressure, and ruptures after the swelling pressure exceeds a certain threshold for a desired delay time. The permeability of the drug through this membrane should be less than 1 / 10 of that of water, and in one embodiment, less than 1 / 100 of the permeability of water. Alternatively, the membrane can be made porous by leaching an extractable aqueous solution for a desired delay time.

[0223] Osmotic dosage forms have been described in U.S. Pat. No. 3,760,984 of Theeuwes, and osmotic burst dosage forms are described in U.S. Pat. No. 3,952,741 of Baker. If different devices with different timings are used, this osmotic burst dosage form can provide a single release pulse or multiple pulses. The timing of osmotic bursting can be controlled by selecting the thickness or area of ​​the semipermeable membrane around the core containing both the polymer and the drug and the osmotic agent or the attractant. As the pressure in the dosage form increases with additional osmotic water, the membrane stretches until its breaking point, and then the drug is released. Alternatively, by having a thinner, weaker area in the membrane, or by adding a weaker material to the area of ​​the coating membrane, a specific rupture area can be produced in the membrane. Some preferred polymers with high water permeability that can be used as semipermeable membranes are cellulose acetate, cellulose acetate butyrate, nitrocellulose, cross-linked polyvinyl alcohol, polyurethane, nylon 6, nylon 6.6 and aromatic nylon. Cellulose acetate is a particularly preferred polymer.

[0224] In another embodiment, the delayed release coating that begins to delay the release of the drug after the enteric coating is at least partially dissolved is composed of a hydrophilic, erodible polymer that begins to gradually dissolve over time when in contact with water. Examples of such polymers include cellulosic polymers and derivatives thereof, including but not limited to hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose; polysaccharides and derivatives thereof; polyalkylene oxides, such as polyethylene oxide or polyethylene glycol, particularly high molecular weight polyethylene glycol; chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly(vinyl pyrrolidone); starch and starch-based polymers; maltodextrin; poly(2-ethyl-2-oxazoline); poly(ethyleneimine); polyurethanes; hydrogels; cross-linked polyacrylic acid; and combinations or blends of any of the foregoing.

[0225] Some preferred erodible hydrophilic polymers suitable for forming the erodible coating are poly(ethylene oxide), hydroxypropyl methylcellulose, and combinations of poly(ethylene oxide) and hydroxypropyl methylcellulose. Poly(ethylene oxide) is used herein to refer to linear polymers of unsubstituted ethylene oxide. The molecular weight of the poly(ethylene oxide) polymer can be about 10 5 Dalton to about 10 7 The preferred molecular weight range of the poly(ethylene oxide) polymer is about 2x10 5 Up to 2x10 6 Daltons and is commercially available from Dow Chemical Company (Midland, Michigan) as SENTRYR POLYOX TM Water-soluble resin, NF (National Pharmacopoeia) grade. When a higher molecular weight polyethylene oxide is used, other hydrophilic agents such as salts or sugars (such as glucose, sucrose or lactose) that promote erosion or disintegration of the coating are also included.

[0226] Delayed dosage forms can be mechanical boluses (such as capsules or pH-sensitive capsules) that can release the drug after a pre-programmed time or when it receives a signal that can be transmitted or once it leaves the stomach.

[0227] The amount of the compound of the present disclosure in the formulation can vary within the full range used by those skilled in the art. Typically, based on the weight percentage (wt%) of the total formulation, the formulation will contain about 0.01-99.99wt% of the BTK inhibitor compound, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80wt%.

[0228] For the purpose of clarity and understanding, the aforementioned disclosure has been described in some detail by way of illustration and example. Therefore, it should be understood that the above description is intended to be illustrative and not restrictive. Therefore, the scope of the present disclosure should not be determined with reference to the above description, but should be determined with reference to the full scope of the equivalents described in the following claims and these claims. In addition, the attached examples provide exemplary research schemes, showing how clinical research can be implemented. Example

[0229] The following examples are provided to illustrate certain disclosed embodiments, and should not be construed as limiting the scope of the present disclosure in any way.In the examples discussed below, BTK inhibitors as defined above may also be referred to interchangeably as "compounds" or "drugs." Example 1 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Tolebrutinib (SAR442168) in Adults with Generalized Myasthenia Gravis

[0230] The objectives of this study were to evaluate the efficacy and safety of tolebrutinib 60 mg daily compared with placebo in adult participants with moderate to severe generalized myasthenia gravis (gMG) receiving SoC.

[0231] A graphical scheme of the study design is shown in Figure 1A middle. Figure 1A Abbreviations used in: DB: double-blind; EOT: end of treatment; MMS: minimally manifested state; OLE: open-label extension; R: randomization; SoC: standard of care; W: week. Tables 1A1 and 1A2 shown below describe the timeline of activities during the course of the study. Table 1B that follows describes the objectives and endpoints of the overall study. Table 1A1: Schedule of Activities (SOA) - Screening and DB Period Table 1A2: Timeline of Activities (SOA) - OLE to Follow-up AChR: acetylcholine receptor; AE: adverse event; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BUN: blood urea nitrogen; AChEI: acetylcholinesterase inhibitor; C-SSRS: Columbia-Suicide Severity Rating Scale; D: day; eCRF: electronic case report form; DB: double-blind; EOS: end of study; EQ-5D-5L: EuroQoL 5 dimensions and 5 levels; EU: European Union; ECG: electrocardiogram; EOT: end of treatment; FU: follow-up; FSH: follicle-stimulating hormone; h: hour; HCRU-MG: healthcare resource utilization-myasthenia gravis; HIV: human immunodeficiency virus; ICF: informed consent; IgG: immunoglobulin G; IgM: immunoglobulin M; IMP: investigational product; INR: international normalized ratio; IRT: interactive response technique; MG: myasthenia gravis; MG-ADL: myasthenia gravis-activities of daily living; MGFA-PIS: Myasthenia Gravis Foundation of America- Postintervention status; MGII: myasthenia gravis impairment index; MG-QoL15: myasthenia gravis-quality of life 15-item scale; MuSK: muscle-specific kinase; OLE: open-label extension; pEOT: premature end of treatment; PGIS: patient global impression-severity; PK: pharmacokinetics; PT: prothrombin time; QMG: quantitative myasthenia gravis; SAE: serious adverse event; TB: tuberculosis; TIBC: total iron-binding capacity; V: visit; W: week; WOCBP: women of childbearing potential; β-HCG: β-human chorionic gonadotropin. aThe Screening Period may range from D-28 to D-1. The Randomization Visit may be performed only once. The IMP may be obtained on-site. The interval between the Screening and Randomization Visits may range from 11 days (minimum) to 28 days (maximum). However, if desired, the Randomization Visit may be performed earlier than 11 days after receipt of the IMP on-site, assuming the participant is eligible for randomization. b From D1 to EOT, the investigator may conduct unscheduled visits at any time (e.g., for suspected MG crisis or to evaluate AEs). Assessments may be performed as needed to evaluate the participant based on the investigator's best judgment and according to the study protocol. At a minimum, a physical examination should be performed, and temperature and vital signs should be measured. In the event of suspected MG crisis, at least an MG-ADL assessment should be performed (see Rescue Therapy). cThe Week 26 visit will also be Day 1 of the OLE. Participants will start OLE treatment (open-label tolebrutinib 60 mg once daily) on Day 2. dThe EOS visit will be the FU visit, 4 to 8 weeks after the last dose of study intervention. eDuring the DB phase, if a participant prematurely and permanently discontinues treatment with IMP, they will undergo a pEOT visit as soon as possible. The participant will then be asked to continue in the study for all study procedures / visits, except those related to IMP administration. In the OLE phase, participants with pEOT will be encouraged to attend a safety FU visit (4 to 8 weeks after pEOT), which will be considered an EOS. fFor participants who prematurely discontinue DB IMP and do not wish to continue the study, the safety FU visit needs to be performed 4 to 8 weeks after pEOT, or 4 to 8 weeks after EOT. This visit will be considered an EOS. In cases where the FU visit is performed as a home visit and some assessments (e.g., the neurological examination portion of the physical examination) are not possible during the visit, these portions of the assessment may be skipped. gHome visits may be replaced by on-site visits with identical assessments and procedures, based on the investigator’s assessment and / or local regulatory requirements. hAny MG medication taken at any time prior to signing the informed consent needs to be reported in the eCRF; other past medications taken in the 6-month period prior to signing the ICF will be reported. iTrial drug allocation for participants who will continue into the OLE period. jDiaries will be collected at EOS for participants who complete their study and at pEOT for participants who discontinue the study prematurely. kA complete physical examination should be performed at Screening, D1, Visit 7 (Week 26), Visit 11 (Week 78), and EOT. A simple physical examination is sufficient for the remaining visits (complete and simple physical examinations will include a neurological examination). l Vital signs will be measured, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), and temperature (°C). mSerum beta-HCG performed at the central laboratory at Screening, and urine pregnancy test performed within 24 hours before the first dose of IMP and at scheduled times during the study. In addition to scheduled visits, monthly pregnancy tests will be performed for all participants who are WOCBP. Additional serum or urine pregnancy tests may be performed as deemed necessary by the Investigator or required by local regulations to establish that the participant is not pregnant at any time during the participant's participation in the study. nAmong female participants only, if necessary to establish menopausal status. o To be performed for all participants at screening. To be repeated based on clinical judgement, borderline results, or clinical suspicion of TB infection. Refer to exclusion criteria (Table 1D). pClinical chemistry (blood urea nitrogen [BUN], creatinine, glucose, potassium, sodium, chloride, bicarbonate, calcium), liver function tests [AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein; creatine phosphokinase], hematology (platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin content, reticulocytes, white blood cell differential count: neutrophils, lymphocytes, monocytes, eosinophils, basophils). Lipase will be tested only at the Screening Visit. Week 19 will include only hematology and a full liver profile (see Table 1G). qAt the intermediate time points W6, W10, W30, W32, W34, and W36, only liver function tests will be collected (AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein, and creatine phosphokinase); these can be performed centrally or in local laboratories. rDuring the OLE, urinalysis will be performed at Visits 9, 11, and 13. s During the OLE, ECGs will be performed at Visits 8, 9, and 13. For all visits with QMG or MGII assessments: In order to reduce the fluctuation of functional test performance due to the temporary symptom effect associated with AChEI use, AChEI should be disabled for at least 12 hours before the efficacy endpoint test of each visit. It is important that participants complete the outcome assessment after signing the ICF and before any treatment-related activities or research-related activities (including the administration of the study intervention, laboratory work, radiological assessment, discussion of their treatment or health status with the participant, and similar activities). This ensures the objectivity of the data. Detailed on-site training on clinical outcome assessments will be provided. These clinical outcome assessments will be managed and recorded electronically by both the investigator and the participant. u Pharmacokinetic analysis will be performed in a subset of participants aged ≥50 years (approximately 40 participants). On the day of PK sampling, the IMP will need to be taken with a meal at the study site. v Two plasma samples were taken at Visit 2 between 0.5 to 1.5 hours and 3 to 4 hours post-dose. w A plasma sample was obtained at Visit 5 and Visit 7 0.5 to 1.5 hours after dose. x If applicable locally, DNA sampling may be performed at any time after signing the consent form (in the event that it is not performed for some reason, at screening). For participants in China, this DNA sample will not be collected. yAt Screening, an archival blood sample will be collected and stored for use in the event of any unexpected safety issues, to ensure pre-dose baseline values ​​are available for parameters not previously assessed (e.g., serology), and for biomarker studies (if consent is given). This archival sample will not be collected for participants in China. If the results of the pilot assessment confirm feasibility, non-invasive digital tools for monitoring participant activity or function may optionally be implemented by the Sponsor in a subset of participants during the study. A Baseline Assessment will be performed at Screening.

[0233] The goals and endpoints of treatment are shown in Table 1B. Table 1B - Objectives and End Points Abbreviations: AChR: acetylcholine receptor; AE: adverse event; AESI: adverse event of special interest; DB: double-blind; ECG: electrocardiogram; EOS: end of study; EOT: end of treatment; gMG: generalized MG; HCRU-MG: healthcare resource utilization-MG; IgG: immunoglobulin G; IgM: immunoglobulin M; MG-ADL: myasthenia gravis-activities of daily living; MGFA-PIS: Myasthenia Gravis Foundation of America-postintervention status; MG-QoL15: myasthenia gravis-quality of life 15-item scale; MGII: myasthenia gravis impairment index; MuSK: muscle-specific kinase; OCS: oral corticosteroids; OLE: open-label extension; PD: pharmacodynamics; PK: pharmacokinetics; QMG: quantitative myasthenia gravis; QoL: quality of life; SoC: standard of care. Brief Overview

[0234] This is a multicenter, randomized, DB, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of tolebrutinib 60 mg daily compared with placebo in adult participants aged 18 to 85 years with moderate to severe gMG who are receiving SoC. The 26-week DB treatment period will include 7 site visits, followed by a 2-year OLE period with quarterly visits.

[0235] The efficacy of tolebrutinib compared to placebo during the DB phase will be assessed by clinical evaluations that include scales based on physician examination or direct participant feedback, i.e., clinical outcome assessments. These evaluations will continue during the OLE to measure long-term efficacy and safety. Number of participants

[0236] Approximately 192 people will be screened to achieve randomization of 154 participants to the study intervention in a 1:1 randomization ratio (assuming a 20% screening failure rate). Intervention groups and duration

[0237] The DB phase will include a screening period (up to 28 days), after which eligible participants will be randomized to a treatment group, either tolebrutinib 60 mg orally daily or matching placebo.

[0238] The duration of the treatment period will be 26 weeks.

[0239] The OLE will include all eligible participants who have completed the DB period after treatment. Participants will receive 60 mg of tolebrutinib orally daily for a duration of up to 2 years.

[0240] Post-trial visits may be considered if necessary and approved by local regulations.

[0241] Study Intervention

[0242] Experimental drugs -Preparation: Tolebutinib film-coated tablets -Route of administration: Oral -Dosage regimen: 60 mg once daily with food

[0243] Experimental drugs - Formulation: Placebo to match tolerabine film-coated tablets -Route of administration: Oral -Dosage regimen: Once daily with food

[0244] The modified intention-to-treat (mITT) population will include all randomized and treated participants with a baseline value and at least 1 post-baseline value for any efficacy assessment. Participants will be analyzed according to randomization. This will be the primary efficacy population.

[0245] Study Group

[0246] Inclusion criteria Participants were eligible for inclusion in the study only if all of the following criteria as shown in Table 1C applied. Table 1C - Inclusion criteria

[0247] Exclusion criteria

[0248] Participants were excluded from the study if any of the following criteria as shown in Table ID applied. Table 1D - Exclusion criteria

[0249] Lifestyle considerations

[0250] Meals and Dietary Restrictions

[0251] Tolebrutinib should be taken with regular meals. When possible, meals taken with tolebrutinib (e.g., breakfast, lunch, or dinner) should be consistent throughout the study. Typical meals taken with the study intervention will be recorded at each visit. In the event that the meal times for study intervention administration need to be changed, a minimum interval of 12 hours should be maintained between 2 doses.

[0252] Caffeine, alcohol, and tobacco

[0253] For each visit with PK / PD assessments, participants will abstain from caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 2 hours prior to starting treatment until the final PK and / or PD sample is collected later that day.

[0254] For each visit with PK / PD assessments, participants will abstain from alcohol for 24 hours prior to starting treatment until the final PK and / or PD samples are collected later that day.

[0255] Participants should be advised not to consume heavy alcohol, defined as >14 g (1 standard drink) per day in female participants or >28 g (2 standard drinks) per day in male participants, on a regular basis throughout the study.

[0256] Individuals who do not meet the study participation criteria may be rescreened up to 2 times. Rescreened participants should be assigned a new participant number. No waiting period is required between the screening failure date and rescreening.

[0257] If a participant does not meet inclusion criteria for certain dynamic laboratory tests at Screening (Visit 1), these laboratory assessments may be repeated at the discretion of the Investigator if the parameter results are judged to be likely to return to an acceptable range for study inclusion during the Screening Period prior to Baseline / Randomization (Visit 2). Such a participant need not be failed Screening if the tests ultimately meet inclusion criteria.

[0258] Study interventions and concomitant therapies

[0259] A study intervention is defined as any experimental intervention(s), commercially available product(s), placebo, or medical device(s) intended to be administered to study participants according to the study protocol.

[0260] Table 1E - Summary of Study Interventions Administered

[0261] Table 1F - Groups and relevant interventions

[0262] Dose Modifications

[0263] Dose reductions are not foreseen in this study. Interruption or permanent discontinuation of treatment may be necessary if deemed necessary due to AEs.

[0264] Concomitant therapy

[0265] Prohibited medication

[0266] Any medications (including over-the-counter or prescription medications, recreational drugs, vitamins and / or herbal supplements), vaccines, or medical procedures that the participant is taking at the time of enrollment or receives during the study must be recorded along with the following: - Reason for use - Date of application, including start and end dates - Dosage information, including dosage and frequency If any questions exist regarding concomitant or prior therapy, the sponsor should be contacted.

[0267] Participants were required to abstain from taking prescription or over-the-counter herbal medicines containing St. John's wort extract from 14 days before starting the study intervention until the last visit.

[0268] Live (attenuated) vaccines should not be administered during the study.

[0269] For some contraindicated concomitant medications (eg, aspirin for headache), if use is not chronic, temporary discontinuation of the IMP may be considered before a decision is made to permanently discontinue the IMP.

[0270] Treatments prohibited during the study will also include: -IV CS and OCS > 20 mg / day, except as rescue therapy -Cyclosporin and cyclophosphamide. - Rituximab and other B cell depleting therapies (anti-CD20 or anti-CD19), eculizumab and other complement pathway-targeted agents, anti-FcRn, or any monoclonal antibodies.

[0271] Anticoagulant / antiplatelet therapy is not permitted concomitantly with IMP, including: - Acetylsalicylic acid (aspirin) > 81 mg / day -Antiplatelet drugs (eg, clopidogrel) -Warfarin (vitamin K antagonist) -Heparin, including low molecular weight heparin (antithrombin agent) -Dabigatran (direct thrombin inhibitor) -Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors) -CYP Inhibitors / Inducers: Strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes were not permitted during the entire study period.

[0272] Tolebrutinib is a substrate for both CYP3A4 and CYP2C8 isozymes. In healthy participants, a strong CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased tolebrutinib (area under the curve [AUC]) exposure by 1.8-fold, and a strong CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased tolebrutinib (AUC) exposure by 8.4-fold. Based on a satisfactory safety and tolerability profile and based on exposures observed in healthy participants who received tolebrutinib once daily for 14 days under fed conditions at doses up to 240 mg, drugs that strongly inhibit CYP3A4 were allowed and drugs that strongly inhibit CYP2C8 were not allowed. In healthy participants, strong CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) reduced tolebrutinib exposure by 6-fold. Therefore, strong and moderate (based on prediction) CYP3A inducers are not permitted due to their potential to decrease tolebrutinib exposure and efficacy.

[0273] Other drugs allowed with some restrictions:

[0274] Anticoagulants / antiplatelet drugs - Acetylsalicylic acid (aspirin) ≤ 81 mg / day - Paracetamol / acetaminophen at a dose of ≤3 g / day is allowed at any time during the study. A short course (up to 5 days) of recommended doses of nonsteroidal anti-inflammatory drugs (NSAIDs) (except acetylsalicylic acid) may be given during the study if clinically indicated for treatment of an existing medical condition or new event. The investigator must record the use of NSAIDs (and any other concomitant medications) in the eCRF. The investigator should assess participants taking NSAIDs and IMPs for signs of bleeding events. NSAIDs should be discontinued for Grade 2 and higher bleeding events. Rescue therapy

[0275] In the case of an increase of at least 2 points in the individual non-ocular MG-ADL items compared to the MG-ADL value on Day 1 or new respiratory / bulbar symptoms or worsening of respiratory / bulbar symptoms, rescue therapy for gMG exacerbation will be allowed at any time during both the DB and OLE parts of the study at the discretion of the Investigator. Rescue therapy may include any use of IVIg, plasma exchange, SoCOCS dose change, or new CS. If rescue therapy is required, the Sponsor should be informed, preferably before the administration of treatment, if possible, without compromising the safety of the participant. The date and time of rescue therapy administration as well as the name and dosage regimen must be recorded. In the case of rescue therapy used during the DB period, the study intervention should be permanently discontinued.

[0276] The provision of rescue therapy will be regulated at the national level. The use of rescue therapy must be documented in the eCRF. Liver Chemistry Stop Criteria

[0277] After participants met the criteria outlined in the algorithm (see Figure 4A and Figure 4B Discontinuation of the study intervention due to abnormal liver function tests may be necessary if one of the following conditions occurs: 1. Discontinuation of the study intervention in the presence of abnormal liver chemistries that do not meet the protocol-specified stopping rules may be necessary if the investigator believes that it is in the best interest of the participant. QTc stopping criteria

[0278] If clinically significant findings are identified in the ECG after enrollment (including but not limited to changes from baseline in the QT interval [QTcF] corrected using the Fridericia formula), the investigator or qualified designee will determine whether the participant can continue to receive the study intervention and whether any changes are required in the management of the participant. Review of the ECG findings by a cardiologist may be considered to decide to definitively discontinue the study intervention due to ECG changes. This review of the printed ECG at the time of collection must be documented. Any new clinically relevant findings should be reported as AEs. Temporary suspension

[0279] The investigator may consider a temporary interventional suspension for suspected AEs or for interruption of clinical studies due to a regional or national emergency declared by a government agency. For all temporary interventional suspensions, the investigator should record the duration on the appropriate page of the eCRF.

[0280] If surgery is required during the study, the benefits and risks of withholding IMP for at least 3 to 7 days before and after surgery should be considered, as well as the risk of bleeding.

[0281] The following should lead to temporary discontinuation of treatment: · Cytopenia: should follow Figure 2 and Figure 3The sponsor of the algorithm targets neutropenia and thrombocytopenia. Increased serum creatinine, creatine phosphokinase (CPK), and liver enzymes: Follow the Figure 5 The corresponding algorithm. Arrhythmia (atrial fibrillation): Any Grade 3 event (symptomatic, indicating urgent intervention, device [e.g., pacemaker], ablation, new onset). Suicide risk according to the C-SSRS: if the participant rated “yes” to item 4 or 5 of the suicidal ideation section or “yes” to any item of the suicidal behavior section.

[0282] If necessary, the Investigator or Participant may consider a temporary treatment suspension for any other reason, including any safety concerns arising from interrupting the study due to a regional or national emergency declared by a government agency (such as COVID-19), or another illness, or if there is a need for prohibited concomitant medication. Treatment may then be resumed when deemed safe and appropriate.

[0283] If participants no longer wish to take the IMP, they will be encouraged to remain in the study.

[0284] The investigator should discuss with the participant the key visits to be attended. The value of all study data collected from participants during their continued participation will be emphasized as being important to the public health value of the study.

[0285] Participants withdrawing from a research intervention should be explicitly asked about the impact of possible AEs on their decision, and any AE information elicited must be recorded.

[0286] The investigator should record all study withdrawals in the appropriate screen of the CRF or eCRF and in the participant's medical record. In the medical record, at a minimum, the date and reason for withdrawal should be recorded.

[0287] In addition, participants may withdraw their consent to stop participating in the study. Withdrawal of consent for an intervention should be distinguished from withdrawal of consent for FU visits and withdrawal of consent for contact with non-participants FU (e.g., medical record review). The site should record any circumstances in which consent is withdrawn.

[0288] Participants who have withdrawn from the study cannot be re-randomized / reassigned (to treatment) in the study. Their inclusion and intervention numbers must not be used again. Table 1G - Laboratory Assessments Required by the Protocol AChR: acetylcholine receptor; AESI: adverse event of special interest; aPTT: activated thromboplastin time; DNA: deoxyribonucleic acid; HBV: hepatitis B virus; HIV: human immunodeficiency virus; IEC: institutional ethics committee; IgM: immunoglobulin M; INR: international normalized ratio; IRB: institutional review board; MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin content; MuSK: muscle-specific kinase, PT: prothrombin time, RNA: ribonucleic acid; SAE: serious adverse event; TIBC: total iron-binding capacity; ULN: upper limit of normal. Notice: aDetails of liver chemistry stopping criteria and required activities and follow-up after ALT>3×ULN is observed are given under the headings Liver Chemistry Stopping Criteria and Hepatic and Other Safety. All events of ALT>3 x ULN that may indicate liver impairment must be reported to the Sponsor on an expedited basis. Clinical laboratory findings of ALT>3ULN and bilirubin ≥2×ULN (>35% direct bilirubin) or ALT>3×ULN and INR>1.5 (if INR is measured) that may suggest severe liver impairment (possible Hy's Law) must be reported as a SAE. bOther renal function parameters, creatinine clearance (CrCl), will be calculated. cWith the noted exception of the screening visit when serum testing is required, local monthly urine testing will be the protocol standard unless serum testing is required by local regulations or the IRB / IEC. dSee E 03 for further details. Hepatic and other safety: activity and follow-up assessments

[0289] Table 1H and Figure 2-Figure 8 These activities described in the study were only required for the events of ALT increase and thrombocytopenia. For all other safety events described, these activities were recommended based on the medical judgment of the investigator.

[0290] Neutropenia was to be recorded as an AE only if at least 1 of the criteria listed in the general guidance for reporting AEs was met.

[0291] Thrombocytopenia should be recorded as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0292] Figure 4AAbbreviations: ALT: alanine aminotransferase; ANCA: anti-neutrophil cytoplasmic antibody; AST: aspartate aminotransferase; CMV: cytomegalovirus; CRF: case report form; DNA: deoxyribonucleic acid; dsDNA: double-stranded DNA; EBV: Epstein-Barr virus; GGT: gamma glutamyltransferase; HAV: hepatitis A virus; HBc: hepatitis B core; HBV: hepatitis B virus; HCV: hepatitis C virus; HEV: hepatitis E virus; IgM: immunoglobulin M; IMP: investigational medicinal product; INR: international normalized ratio; lab: laboratory; LFT: liver function test; PT: prothrombin time; RNA: ribonucleic acid; LKM: liver kidney microsome; ULN: upper limit of normal.

[0293] NOTE: "Baseline" refers to the ALT sampled at the Baseline Visit; or if a baseline value is not available, the most recent ALT sampled at the Baseline Visit. The algorithm is not applicable in the event of an increase in ALT during the Screening period. Table 1H Activities to confirm ALT elevation

[0294] Increased serum creatinine should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting Adverse Events in Appendix 3 (Section 10.3) is met.

[0295] CPK increase should be reported as an AE only if at least 1 of the criteria in the General Guidelines for Reporting Adverse Events is met.

[0296] Examples of drugs with the potential to alter the metabolism of tolebrutinib

[0297] The following drugs have the potential to alter the kinetics of tolebrutinib due to their interactions with P450-mediated metabolism, being strong / moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes (listed according to the University of Washington Drug Interaction Database Program) and should be discontinued concomitantly with IMP during the study.

[0298] Please note that the list provided is not complete and the product information for drugs intended for concomitant use should be consulted. Table 1J - CYP3A inducers and CYP2C8 inhibitors abbreviation AChEI: acetylcholinesterase inhibitor AChR: acetylcholine receptor ADL: Activities of Daily Living AE: Adverse event AESI: Adverse events of special interest ALT: Alanine aminotransferase ANCOVA: Analysis of Covariance AUC: Area Under the Curve BCR: B cell receptor BTK: Bruton's tyrosine kinase BUN: blood urea nitrogen CFR: Code of Federal Regulations CI: Confidence Interval CIOMS: Council for International Organizations of Medical Sciences COVID-19: Coronavirus Disease 2019 CPK: Creatine phosphokinase CRF: Case Report Form CS: Corticosteroids CSICF: Core Research Informed Consent Form C-SSRS: Columbia-Suicide Severity Rating Scale CTCAE: Common Terminology Criteria for Adverse Events CYP: Cytochrome DB: Double Blind DILI: Drug-induced liver injury DTP: Direct to Patient ECG: Electrocardiogram eCRF: Electronic Case Report Form EOS: Research completed EOT: End of Treatment EQ: EuroQoL EQ-5D: EuroQoL 5 dimensions EQ-5D-5L: EuroQoL 5 dimensions 5 levels EQ-VAS: EuroQoL-Visual Analogue Scale EU: European Union FcRn: neonatal Fc receptor FcγR: Fc-gamma receptor FcεR: Fc-ε receptor FSH: Follicle stimulating hormone FU: Follow-up GCP: Good Clinical Practice Guidelines GDPR: General Data Protection Regulation gMG: generalized myasthenia gravis HCRU-MG: Healthcare Resource Utilization - Myasthenia Gravis HIV: Human Immunodeficiency Virus HRT: Hormone Replacement Therapy IA: Interim analysis IB: Investigator's Handbook ICE: Intercurrent Events ICF: Informed Consent ICH: International Council for Harmonization IDMC: Independent Data Monitoring Committee IEC: Independent Ethics Committee Ig: immunoglobulin IgG: Immunoglobulin G IgM: Immunoglobulin M IMP: Investigational Medicinal Product IMP: Investigational Medicinal Product IRB: Institutional Review Board IST: Immunosuppressive therapy ITT: intention to treat IUD: intrauterine device IUS: intrauterine hormone-releasing system IVIg: intravenous immunoglobulin MG: Myasthenia Gravis MG-ADL: Myasthenia gravis - Activities of daily living MGFA: Myasthenia Gravis Foundation of America MGFA-PIS: Myasthenia Gravis Foundation of America-Post-Intervention State MGII: Myasthenia Gravis Impairment Index MG-QoL15: Myasthenia gravis quality of life 15-item scale mITT: modified intention to treat MMRM: Repeated measures mixed effects model MS: Multiple Sclerosis MuSK: muscle-specific kinase NCI: National Cancer Institute NSAID: Nonsteroidal anti-inflammatory drug OCS: oral corticosteroids OLE: Open Label Extension PCSA: Potentially Clinically Significant Abnormality PD: Pharmacodynamics pEOT: premature end of treatment PGIS: Patient Global Impression-Severity PK: Pharmacokinetics QMG: Quantitative Myasthenia Gravis QoL: Quality of life QTcF: QT interval corrected using Fridericia's formula RMS: Relapsing multiple sclerosis SAE: Serious Adverse Event SAP: Statistical Analysis Program SD : Standard deviation SoA: Schedule of Activities SoC: Standard of Care SUSAR: Suspected unexpected serious adverse reaction TE: Emerging during treatment TEAE: Treatment-emergent adverse event TLR: Toll-like receptor ULN: Upper limit of normal US:United States VAS: Visual Analogue Scale WOCBP: Women of childbearing potential Example 2 - A Phase 3, Randomized, Double-Blind Efficacy and Safety Study Comparing SAR442168 with Teriflunomide in Participants with Relapsing Forms of Multiple Sclerosis (GEMINI 2)

[0299] The goal of this Phase 3 study is to evaluate SAR442168 in the RMS population. Efficacy will be assessed by adjudicating relapse rate, disability progression, and MRI findings of disease activity (Gd-enhanced lesions and new / enlarged T2 high-signal lesions). Together with the evaluation of other secondary and exploratory endpoints, this study will provide a comprehensive evaluation of the efficacy and safety of SAR442168 in the RMS population.

[0300] A graphical scheme of the study design is shown in Figure 1B middle. Figure 1B Abbreviations used in: EOS, end of study; MRI, magnetic resonance imaging; R, randomization. "Month 1 (D-28-D-1)" refers to the screening period as "Day -28 to Day -1"; "Month 0 (D1)" refers to randomization on Day 1.

[0301] Tables 2A1 and 2A2 shown below describe the timeline of activities during the course of the study. Table 2B that follows describes the overall study objectives and endpoints. Table 2A1: Schedule of Activities (SOA) - Screening and Year 1 Table 2A2: Schedule of Activities (SOA) - from M15 to follow-up visit aPTT: activated partial thromboplastin time; β-HCG: β-human chorionic gonadotropin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; Chi3L1: chitinase 3-like protein 1; CRF: case report form; C-SSRS: Columbia-Suicide Severity Rating Scale; D: day; DNA: deoxyribonucleic acid; ECG: electrocardiogram; EDSS: expanded disability status scale; EOS: end of study; EOT: end of treatment; EQ-5D-5L: EuroQol 5-dimension 5-level questionnaire; FSH: follicle-stimulating hormone; FU: follow-up; Ig: immunoglobulin; HIV: human immunodeficiency virus; ICF: informed consent; IMP: investigational medicinal product; INR: international normalized ratio; IRT: interactive response technology; LTS: long-term safety study; M: month (28 days); MRI: magnetic resonance imaging; MS: multiple sclerosis; MSQoL-54: multiple sclerosis quality of life-54; NfL: neurofilament light chain; pEOT: premature end of treatment; PT: prothrombin time; SDMT: symbol digital modality test; SWI: susceptibility-weighted imaging; TB: tuberculosis; TIBC: total iron-binding capacity; V: visit; WBC: white blood cell. NOTE: All assessments should be performed as specified in this SoA unless not permitted under local regulations. All visit assessments should be performed during the visit window unless otherwise specified in this protocol. aThe Screening Period may range from D-28 to D-1; the Randomization Visit may be performed only once. The IMP may be available on site. The interval between the Screening and Randomization Visits may range from 11 days (minimum) to 28 days (maximum). However, if necessary, the Randomization Visit may be performed earlier than 11 days after receipt of the IMP on site, assuming the participant is eligible for randomization. In the event that the Screening MRI must be rescheduled (e.g., technical problems) or repeated, an additional 1 week (7 days) is allowed. b From D1 to EOS, the investigator may conduct unscheduled visits (e.g., for evaluation of adverse events) at any time. Assessments may be performed as needed to evaluate the participant based on the investigator's best judgment and in accordance with the study protocol. At a minimum, a physical examination should be performed, and temperature and vital signs should be measured. cAt EOS, participants who have completed the study and remain on IMP will be invited to participate in the long-term safety study. Only those participants who do not wish to participate in the long-term safety study will be evaluated at the follow-up visit. dThese visits may be conducted as home health visits (where applicable) or on-site visits (preferably with testing performed in a central laboratory). In any case where this is not possible (to be documented in the source documents), the testing for these visits may be performed in a local laboratory. eIf a participant prematurely permanently discontinues treatment with IMP, the participant will undergo a premature EOT visit as soon as possible. The participant will then be asked to continue with the planned study visits until a comprehensive EOS visit is reached. During these visits, all study procedures / assessments will be performed, except for IMP administration and blood sampling for biomarkers (NfL, Chi3L1 and Ig levels). MRI scans for these participants will only be performed annually (using the next annual visit as a starting point). fA common EOS visit will be conducted in anticipation of reaching the pre-specified number of events at 6-month CDW. The timing and window of this visit will be communicated to the site. gAny disease-modifying therapy for MS taken at any time prior to signing the informed consent needs to be reported on the CRF; other prior medications taken within the 6-month period prior to signing the ICF will be reported. h Additional safety assessments may be performed if required by local regulations; such testing may be performed locally. Additional visits may be added if required by local regulations. iA complete physical examination should be performed at Screening, Baseline, Annually, and EOS. A simple physical examination is sufficient for the remainder of the visits (a complete and simple physical examination will include a neurological examination and collection of the following vital signs: arterial blood pressure, heart rate, and temperature). jTo be performed for all participants at Screening. To be repeated based on clinical judgment, borderline results, or clinical suspicion for TB infection. Screening tests for TB are described in Table 2F. kHematology (platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin content, reticulocytes, differential white blood cell count: neutrophils, lymphocytes, monocytes, eosinophils, basophils). Biochemistry (blood urea nitrogen [BUN], creatinine, glucose, potassium, sodium, chloride, bicarbonate, calcium; liver function tests [AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein; creatine phosphokinase], lipase, at the screening visit and then quarterly). Monthly visits (M1, M2, M4, M5) will include only hematology and a full liver profile. Additional safety assessments may be performed if required by local regulations. Such testing should be performed in a local laboratory. NOTE: If abnormal laboratory test values ​​are considered transient, a one-time retest may be performed at screening. Additional visits may be added if required by local regulations. At the intermediate time points M1.5 and M.2.5, only liver function tests will be collected (AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein, and creatine phosphokinase); these can be performed centrally or in a local laboratory. mSerum beta-HCG pregnancy test performed at the central laboratory at Screening, and urine pregnancy test performed within 24 hours before the first dose of IMP and at scheduled times during the study. Additional serum or urine pregnancy tests may be performed as determined necessary by the Investigator or required by local regulations to establish the absence of pregnancy at any time during the participant's participation in the study. Telephone communication with the site regarding the results of pregnancy tests performed at home is permitted. nIn all relevant EU countries, pregnancy tests will be performed monthly. oIn female participants only, if needed to establish menopausal status. p Both the SDMT and the CVLT-II will be administered in all participants. If for some reason the CVLT-II is not available at a given site due to reasons such as lack of translation, local certification, etc., only the SDMT will be assessed for that participant. q A subset of sites with 3T MRI capabilities will perform additional sequences (e.g., SWI). Further details will be defined in a separate center MRI manual. For systemic corticosteroids and ACTH, a 1-month washout is required before the MRI scan. For MRI performed after D1, a visit window of ±21 days is acceptable. The screening MRI scan should be performed as close as possible before starting the IMP. After it has been established that the participant meets all inclusion criteria and does not meet the exclusion criteria, the MRI scan should be performed as much as possible during the screening period. rWhen available, clinical outcome assessments were to be completed by participants prior to discussion of their health status and prior to administration of study treatment or other study-related procedures. s where available according to local regulations. tThe pharmacodynamic / biomarker samples collected are not timed samples. u If applicable locally, DNA testing can be performed at any time after signing the consent form (on Day 1 in cases where it may not be possible for some reason). vThis sample will be collected and stored for use in the event of any unexpected safety issues, to ensure pre-dose baseline values ​​are available for parameters not previously assessed (e.g., serology) and for biomarker studies (if agreed). w Samples for hematology and biochemistry testing on Day 1 (randomization) must be collected prior to administration of the first IMP dose.

[0302] The goals and endpoints of treatment are shown in Table 2B. Table 2B - Objectives and End Points

[0303] Overall design:

[0304] This was a phase 3, randomized, double-blind, double-dummy, 2-arm, active-controlled, parallel-group, multicenter, event-driven (6-month confirmed disability worsening [CDW]) trial with a variable treatment duration ranging from approximately 18 to 36 months.

[0305] Disclosure Statement:

[0306] This was a parallel treatment study with 2 groups, which was blinded / masked to the participants, any investigators, site staff, and the sponsor.

[0307] Number of participants:

[0308] Approximately 1200 people will be screened to achieve randomization of approximately 900 (±10%) participants to the study intervention, for a total sample size of at least 1800 patients in 2 RMS studies of identical design (EFC16033 and EFC16034).

[0309] Intervention Groups and Duration:

[0310] Participants will be randomized in a 1:1 ratio to receive either 60 mg of the selected dose (established from the dose-finding study DRI15928) of oral SAR442168 daily and placebo to match teriflunomide tablets daily or 14 mg of oral teriflunomide and placebo to match SAR442168 tablets daily. Randomization will be stratified by Expanded Disability Status Scale (EDSS) score at screening (<4 vs. ≥4) and geographic region (U.S. vs. non-U.S.).

[0311] Study Intervention

[0312] Experimental drugs Preparation: Tolebutinib film-coated tablets ·Route of administration: Oral Dosage regimen: 60 mg, once a day

[0313] Experimental drugs Preparation: Teriflunomide tablets ·Route of administration: Oral Dosage regimen: 14 mg, once a day

[0314] Experimental drugs Formulation: Placebo to match SAR442168 film-coated tablets ·Route of administration: Oral Dosage regimen: Once a day

[0315] Experimental drugs Formulation: Placebo to match teriflunomide tablets ·Route of administration: Oral Dosage regimen: Once a day

[0316] Non-investigational drugs Preparation: MRI contrast enhancement preparation ·Route of administration: Intravenous (IV) Dosage regimen: According to the corresponding label

[0317] Non-investigational drugs Preparation: Cholestyramine ·Route of administration: Oral Dosage regimen: For accelerated elimination program, 8 g 3 times a day for 11 days (In case of intolerance, 4 g 3 times a day for 11 days). The local labeling for teriflunomide should be followed.

[0318] Temporary Investigational Medicinal Product (IMP) Discontinuation Due to Surgery

[0319] If surgery is required during the study, consider the benefits and risks of withholding IMP for at least 3 to 7 days before and after surgery, depending on the type of surgery and the risk of bleeding.

[0320] The goal of this Phase 3 study is to evaluate SAR442168 in the RMS population. Efficacy will be assessed by adjudicating relapse rate, disability progression, and MRI findings of disease activity (Gd-enhanced lesions and new / enlarged T2 high-signal lesions). Together with the evaluation of other secondary and exploratory endpoints, this study will provide a comprehensive evaluation of the efficacy and safety of SAR442168 in the RMS population.

[0321] In ongoing Phase 3 and LTS studies, tolerinib has been generally well tolerated to date. The identified risks of tolerinib have been identified as follows: - SAEs of treatment-emergent drug-induced liver injury (DILI) were reported in the ongoing Phase 3 trial; however, all cases occurred between Months 2 and 3 and appeared to be reversible after treatment discontinuation, and potential confounding factors were identified for some cases.

[0322] Study Group

[0323] Inclusion criteria

[0324] Participants were eligible for inclusion in the study only if all of the following criteria as shown in Table 2C applied. Table 2C - Inclusion criteria

[0325] Exclusion criteria

[0326] Participants were excluded from the study if any of the following criteria as shown in Table 2D applied. Table 2D - Exclusion criteria Lifestyle considerations

[0327] Meals and dietary restrictions: Tolebrutinib (IMP) should be taken with regular meals. When possible, meals taken with IMP (e.g., breakfast, lunch, or dinner) should be consistent throughout the study. Typical meals taken with IMP will be recorded at each visit. In the event that meal times for IMP administration need to be changed, a minimum interval of 12 hours should be maintained between 2 doses.

[0328] Caffeine, Alcohol, and Tobacco: Participants should be advised not to consume heavy alcohol, defined as >14 g (1 standard drink) / day in female participants or >28 g (2 standard drinks) / day in male participants on a regular basis, throughout the study period. Study Intervention

[0329] A study intervention is defined as any experimental intervention(s), commercially available product(s), or placebo intended to be administered to study participants according to the study protocol.

[0330] Table 2E - Summary of Study Interventions Administered IMP: Investigational Medicinal Product, NIMP: Non-Investigational Medicinal Product

[0331] Between protocol-planned on-site visits, interim visits may be required for IMP dispensing. As an alternative to these visits or in lieu of on-site IMP dispensing, if desired, IMP may be supplied to participants from the site via a Sponsor-approved courier (direct-to-patient shipping), where permitted by local regulations and approved by the Sponsor.

[0332] Non-investigational drugs MRI contrast-enhancing agents ·Route of administration: IV Dosage regimen: According to the corresponding label Cholestyramine ·Route of administration: Oral Dosage regimen: For accelerated elimination program, 8 g 3 times a day for 11 days (in case of intolerance, 4 g 3 times a day for 11 days). The local label for teriflunomide should be followed. Concomitant therapy

[0333] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) that the participant is taking at the time of enrollment or receives during the study must be recorded along with the following: Reasons for use Date of application, including start and end dates Dosage information, including dose and frequency

[0334] Participants must abstain from taking prescription or over-the-counter medications (including vitamins and dietary or herbal supplements) for 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives, whichever is longer, before the start of the study intervention until completion of the follow-up visit unless the investigator determines that the medication will not interfere with the study.

[0335] Live (attenuated) vaccines should not be administered during the intervention period.

[0336] No MS-specific therapy documented in Exclusion Criteria E07 was permitted while participants continued on study treatment after randomization. Short-term use (3 to 5 days) of glucocorticoids (e.g., for treatment of MS relapses or acute illness) and topical corticosteroids (e.g., topical, nasal, ocular, aural, intra-articular) was permitted.

[0337] The Medical Monitor should be contacted if any questions arise regarding concomitant or prior therapy.

[0338] For some contraindicated concomitant medications (eg, aspirin >81 mg / day for headache), if use is not chronic, temporary discontinuation of IMP may be considered before deciding to permanently discontinue IMP.

[0339] If clinically feasible, medications used to treat MS symptoms (eg, impaired walking, fatigue, spasticity, incontinence, pain) should be maintained at stable doses prior to screening and for the duration of the treatment period.

[0340] Anticoagulant / antiplatelet therapy is not permitted concomitantly with IMP, including: - Acetylsalicylic acid (aspirin) > 81 mg / day -Antiplatelet drugs (eg, clopidogrel) -Warfarin (vitamin K antagonist) -Heparin, including low molecular weight heparin (antithrombin agent) -Dabigatran (direct thrombin inhibitor) -Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors)

[0341] Paracetamol / acetaminophen at a dose of ≤ 3 g / day was allowed at any time during the study. A short course (most often 5 days) of the lowest effective dose of a nonsteroidal anti-inflammatory drug (NSAID) (other than acetylsalicylic acid), preferably a selective cyclooxygenase-2 inhibitor, may be given during the study if clinically indicated for treatment of an existing medical condition or a new event. The investigator must record the use of NSAIDs (and any other concomitant medications) in the eCRF. CYP inhibitors / inducers:

[0342] Strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes were not permitted during the entire study period (see Appendix 8A [Section 10.8]). Tolebrutinib: Tolebrutinib is a substrate of both CYP3A4 and CYP2C8 isoenzymes. In healthy participants, a strong CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased tolebrutinib area under the curve (AUC) exposure by 1.8-fold (INT16385 study), and a strong CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased tolebrutinib (AUC) exposure by 8.4-fold (INT16726 study). Based on a favorable safety and tolerability profile and based on exposures observed in healthy participants who received tolebrutinib once daily at doses up to 240 mg for 14 days under fed conditions (TDR16862 study), drugs that strongly inhibit CYP3A4 were allowed and drugs that strongly inhibit CYP2C8 were not allowed. In healthy participants, strong CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) reduced tolerabine exposure by 6-fold (INT16726 study). Therefore, strong and moderate (based on prediction) CYP3A inducers are not allowed due to their potential to reduce tolerabine exposure and efficacy. See Table 2H for a list of drugs not to be used. Teriflunomide: Other strong CYP and transporter inducers should be avoided due to their potential to decrease teriflunomide exposure. Rifampin and other known strong CYP and transporter inducers such as carbamazepine, phenobarbital, phenytoin, avasimib, lumacato, rifapentine, rifabutin, and St. John's wort should be avoided. Leflunomide is contraindicated because teriflunomide is a metabolite of leflunomide.

[0343] The use of cholestyramine (and other bile acid sequestrants) and activated charcoal should be avoided as these may result in a significant decrease in plasma concentrations of teriflunomide.

[0344] Cholestyramine should only be used when an accelerated elimination process is required. In exceptional cases (e.g., when cholestyramine is not tolerated, or when cholestyramine is not available), the use of activated carbon may be considered (according to the current Aubagio SmPC).

[0345] Breast cancer resistance protein (BCRP) inhibitors (e.g., eltrombopag and gefitinib) should be avoided. Based on in vitro studies, teriflunomide is a substrate for the efflux transporter BCRP, and therefore these drugs may increase teriflunomide exposure (Appendix 8B [Section 10.9]).

[0346] Multiple drugs need to be used with caution because teriflunomide may alter their exposure. Appropriate arrangements need to be made to monitor their effects and ensure timely decisions about changes in medication. Medicinal products metabolized by CYP2C8 (e.g., repaglinide, pioglitazone, and rosiglitazone) should be used with caution during treatment with IMP due to the potential for increased concentrations of these drugs following inhibition of CYP2C8 by teriflunomide. Increased exposure to ethinyl estradiol and levonorgestrel has been observed following repeated doses of teriflunomide (Aubagio (teriflunomide) [package insert]. Genzyme Corporation. Cambridge, MA 02142; 2021.). Although this interaction with teriflunomide is not expected to adversely affect the efficacy of oral contraceptives, it should be considered when selecting or adjusting oral contraceptive therapy used during this trial. Medicinal products metabolized by CYP1A2 (e.g., duloxetine, alosetron, theophylline, and tizanidine) should be used with caution during treatment with IMP because teriflunomide can induce CYP1A2 and reduce the efficacy of these products. During the study period, the administration of substrates of organic anion transporter 3 (OAT3) (e.g., cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, and cimetidine) should be performed with caution as teriflunomide has the potential to increase the exposure of these medications through inhibition of OAT3. · Concomitant administration of teriflomide should be used with caution during the study period for substrates of BCRP (e.g., sulfasalazine) and substrates of the organic anion transporter polypeptide (OATP) family (e.g., rosuvastatin, svastatin, atorvastatin, pravastatin, naglinide, reglinide and rifampin), as teriflomide should be used with caution because teriflomide has the potential to increase the exposure of these products. Signs and symptoms of overexposure to the drug should be closely monitored and dose reduction should be considered. If used with IMP, the dose of rosuvastatin should not exceed 10 mg once a day. Dose Modifications

[0347] Dose reductions are not foreseen in this study. Interruption or permanent discontinuation of treatment may be necessary if considered necessary due to AEs (Sections 7 and 8.3). Discontinuation of study intervention

[0348] Explicit termination

[0349] The study intervention should be continued whenever possible.

[0350] Permanent intervention discontinuation is any treatment discontinuation associated with an explicit decision by the investigator or the participant not to re-expose the participant to the study intervention at any time.

[0351] In rare cases, it may be necessary for a participant to permanently discontinue the study intervention. If a study intervention is permanently discontinued, the participant should be asked to remain on study for evaluation until the EOS visit. This will be important for continued evaluation of safety. Data to be collected at the time of discontinuation of the study intervention are provided in the SoA (Tables 2A1 and 2A2). In the event of permanent discontinuation of the study intervention, the participant's MS should be treated according to local clinical practice and the investigator's best judgment.

[0352] The following may be valid reasons for the investigator or sponsor to discontinue a participant from study treatment: Adverse events that compromise the safety of the participant, or if discontinuation of the study intervention is desired or deemed necessary by the investigator and / or participant. If according to Figure 2-Figure 8 The laboratory abnormality follow-up guidelines in the IMP meet the IMP discontinuation criteria. In the investigator's opinion, the participant is no longer receiving therapeutic / clinical benefit. · Upon the participant's request, i.e., withdrawal of consent for treatment. If the female participant becomes pregnant or wishes to become pregnant during the study. If the male participant wishes to conceive during the study period. Any serious opportunistic infection (eg, PML [see Figure 6 ], HIV). • Continued need / chronic use of prohibited concomitant medications (see Concomitant Therapy in this Example and Table 2H).

[0353] After participants meet the algorithm ( Figure 4A and Figure 4B ) or if the investigator believes it is in the best interest of the participants, the investigator should consider discontinuing the study intervention for abnormal liver function.

[0354] Any clinically significant abnormal laboratory values ​​or ECG parameters will be rechecked immediately for confirmation 24 hours prior to a definitive decision to discontinue the IMP for the relevant participant.

[0355] If clinically significant findings are identified in the ECG (including but not limited to changes in the QT interval (QTc) [QTcF] corrected using the Fridericia formula from baseline after enrollment), the investigator or qualified designee will determine whether the participant can continue to participate in the study and whether any changes are required in the management of the participant. Review of the ECG findings by a cardiologist may be considered to decide to definitively discontinue the study intervention due to ECG changes. This review of the ECG findings recorded at the time of collection must be documented. Any new clinically relevant ECG findings should be reported as AEs.

[0356] Data to be collected at intervention discontinuation and follow-up, as well as any further evaluations to be completed, are provided in the SoA (Tables 2A1 and 2A2).

[0357] Additional testing may be performed at any time during the study if determined by the investigator to be necessary or required by local regulations. Table 2F - Laboratory Assessments Required by the Protocol ALT: alanine aminotransferase; anti-HBc; antibodies against the core antigen of hepatitis B; anti-HBs: hepatitis B surface antibodies; aPTT: activated partial thromboplastin time; AST: sacrificial aminotransferase; BUN: hepatitis nitrogen; β-hCG: human chorionic gonadotropin; FSH; follicle stimulating hormone; IEC: Independent Ethics Committee; INR: International Standardized Ratio; HBsAg: hepatitis B surface antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; Ig: Immunoglobulin; IRB: Institutional Review Committee; MCH: mean hemoglobin content; MCV: mean red blood cell volume; PT: prothrombin time; RBC: red blood cell; SGOT: serum glutamate aminotransferase; SGPT: serum glutamate aminotransferase; TB: tuberculosis; ULN: upper limit of normal value; WBC: white blood cell a Details of liver chemistry stopping criteria and required activities and follow-up assessments after ALT > 3×ULN is observed are in Figure 4A and Figure 4B Clinical laboratory findings that may suggest severe liver injury, such as ALT > 3 × ULN and bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT > 3 × ULN and international normalized ratio (INR) > 1.5 (if INR is measured), must be reported as a SAE. bOther renal function parameter, creatinine clearance (CrCl), will be calculated. cLocal urine testing for pregnancy will be standard of protocol (except for the Screening Visit when a serum pregnancy test is required) unless serum testing is required by local regulations or the IRB / IEC. Hepatic and other safety: activity and follow-up assessments

[0358] Table 2G-A and Figure 2-Figure 8 These activities described in the study were only required for the events of ALT increase and thrombocytopenia. For all other safety events described, these activities were recommended based on the medical judgment of the investigator.

[0359] Neutropenia should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0360] Thrombocytopenia should be recorded as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0361] Figure 4A Abbreviations: ALT: alanine aminotransferase; ANCA: anti-neutrophil cytoplasmic antibody; AST: aspartate aminotransferase; CMV: cytomegalovirus; CRF: case report form; DNA: deoxyribonucleic acid; dsDNA: double-stranded DNA; EBV: Epstein-Barr virus; GGT: gamma glutamyltransferase; HAV: hepatitis A virus; HBc: hepatitis B core; HBV: hepatitis B virus; HCV: hepatitis C virus; HEV: hepatitis E virus; IgM: immunoglobulin M; IMP: investigational medicinal product; INR: international normalized ratio; lab: laboratory; LFT: liver function test; PT: prothrombin time; RNA: ribonucleic acid; LKM: liver kidney microsome; ULN: upper limit of normal.

[0362] NOTE: "Baseline" refers to the ALT sampled at the Baseline Visit; or if a baseline value is not available, the most recent ALT sampled at the Baseline Visit. The algorithm is not applicable in the event of an increase in ALT during the Screening period. Table 2G-A Activities to confirm ALT elevation

[0363] Figure 5 Abbreviations: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, pharmacokinetics.

[0364] Increased serum creatinine should be reported as an AE only if at least 1 of the criteria listed in the general guidance for reporting AEs is met.

[0365] Figure 8 Abbreviations: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0366] CPK should be reported as an AE only if at least 1 of the criteria in the general guidance for reporting AEs is met.

[0367] Suspected PML: Recommended if the participant has clinical presentation or MRI features suggestive of PML Figure 6 The diagnostic and activity algorithms described in .

[0368] Figure 6 Abbreviations: Abbreviations: CSF, cerebrospinal fluid; Gd, gadolinium; IMP, investigational medicinal product; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.

[0369] Clinical manifestations or MRI lesion features suspected of PML are presented in Table 2G-B (based on Berger et al. Neurology 2013, 80, 1430-1438 and Kappos et al. Lancet Neurol. 2007, 6, 431-441). Table 2G-B - Clinical and MRI features suggestive of PML

[0370] Clinical or MRI features suggestive of PML should be recorded as AEs / AESIs / SAEs.

[0371] Examples of drugs with the potential to alter the metabolism of tolebrutinib

[0372] The following drugs have the potential to alter the kinetics of tolebrutinib due to their interactions with P450-mediated metabolism, being strong / moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes (listed according to the University of Washington Drug Interaction Database Program) and should be discontinued concomitantly with IMP during the study.

[0373] Please note that the list provided is not complete and the product information for drugs intended for concomitant use should be consulted. Table 2H - CYP3A inducers and CYP2C8 inhibitors abbreviation ADL: Activities of Daily Living AE: Adverse event AESI: Adverse events of special interest ALT: Alanine aminotransferase ARR: Annualized adjudicated relapse rate AUC: Area Under the Curve BCRP: Breast Cancer Resistance Protein BTK: Bruton's tyrosine kinase CDW: Confirmed Disability Worsening CFR: Code of Federal Regulations Chi3L1: Chitinase 3-like protein 1 CNS: Central nervous system CPK: Creatine phosphokinase CRF: Case Report Form CSR: Clinical Research Report C-SSRS: Columbia-Suicide Severity Rating Scale CYP: Cytochrome P450 DILI: Drug-induced liver injury DMC: Data Monitoring Committee DMT: disease modifying therapy DNA: deoxyribonucleic acid ECG: Electrocardiogram eCRF: Electronic Case Report Form EDSS: Expanded Disability Status Scale EOS: Research completed EQ-5D-5L: EuroQol 5-dimension 5-level questionnaire EU: European Union FSH: Follicle stimulating hormone GCP: Good Clinical Practice Guidelines Gd: Gadolinium HRT: Hormone Replacement Therapy ICF: Informed Consent ICH: International Council for Harmonization IEC: Independent Ethics Committee IMP: Investigational Medicinal Product INR: International Normalized Ratio IRB: Institutional Review Board IRT: Interactive Response Technology ITT: intention to treat IUD: intrauterine device IUS: intrauterine hormone-releasing system IV: Intravenous JCV: John Cunningham Virus LTS: Long Term Security MedDRA: Medical Dictionary for Regulatory Activities MRI: Magnetic resonance imaging MS: Multiple Sclerosis MSFC-3: Multiple Sclerosis Functional Composite-3 MSQol-54: Multiple Sclerosis Quality of Life-54 MTR: Magnetic Transfer Rate NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NEDA: No Evidence of Disease Activity-3 NfL: neurofilament light chain NIMP: Non-Investigational Medicinal Product NSAID: Nonsteroidal anti-inflammatory drug OAT3: Organic anion transporter 3 PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive multifocal leukoencephalopathy PPMS: Primary progressive multiple sclerosis QTcF: QT interval corrected using Fridericia's formula RMS: Relapsing multiple sclerosis SAE: Serious Adverse Event SAP: Statistical Analysis Program SEL: Slowly evolving lesions SmPC: Summary of Product Characteristics SoA: Schedule of Activities SPMS: Secondary progressive multiple sclerosis Research Manual: Research Reference Manual SWI: Susceptibility Weighted Imaging TEAE: Treatment-emergent adverse event ULN: Upper limit of normal US:United States USPI: United States Prescribing Information WOCBP: Women of childbearing potential Example 3 - A Phase 3, Randomized, Double-Blind, Efficacy and Safety Study Comparing SAR442168 with Placebo in Participants with Non-Relapsing Secondary Progressive Multiple Sclerosis (HERCULES)

[0374] Overall Design: This was a phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel-group, multicenter, event-driven (6-month CDP) trial in participants with NRSPMS, with a variable treatment duration ranging from approximately 24 to 48 months. A graphic scheme of the study design is shown in Figure 1C middle. Figure 1CAbbreviations used in: CDP, confirmed disability progression; EOS, end of study; MRI, magnetic resonance imaging; R, randomization. "Month 1 (D-28-D-1)" refers to the screening period as "Day -28 to Day -1"; "Month 0 (D1)" refers to randomization on Day 1.

[0375] Tables 3A1 and 3A2 shown below describe the timeline of activities during the course of the study. Table 3B that follows describes the overall study objectives and endpoints. Table 3A1: Timeline of Activities (SOA) - Screening to Year 2 Table 3A2: Schedule of Activities (SOA) - M27 to Follow-up Visit aPTT, activated partial thromboplastin time; β-HCG, β-human chorionic gonadotropin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Chi3L1, chitinase-3-like protein 1; C-SSRS, Columbia-Suicidality Severity Rating Scale; D, day; DNA, deoxyribonucleic acid; ECG, electrocardiogram; EDSS, expanded disability status scale; EOS, end of study; EOT, end of treatment; EQ-5D-5L, EuroQol 5-dimension 5-level instrument; FSH, follicle stimulating hormone; FUV, follow-up visit; ICF, informed consent; Ig, immunoglobulin; IRT, interactive response technology; HIV, human immunodeficiency virus; IMP, investigational product; INR, international normalized ratio; LTS, long-term safety study; M, month; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MRI: magnetic resonance imaging; MS: multiple sclerosis; SDMT, symbol-digit modalities test; CVLT-II, California Verbal Learning Test-II; MSQoL-54: multiple sclerosis quality of life-54; NfL: neurofilament light chain; pEOT: premature end of treatment; PK: pharmacokinetics; PT: prothrombin time; RBC, red blood cell; SWI, susceptibility-weighted imaging; TB, tuberculosis; TIBC: total iron binding capacity; V: visit; WBC, white blood cell. Note: All assessments should be performed as specified in this SoA unless not permitted according to local regulations. All visit assessments should be performed during the visit window unless otherwise specified in this protocol. aThe screening period may range from D-28 to D-1; the randomization visit may be performed only once. The IMP is available on site. The interval between the screening and randomization visit may range from 11 days (minimum) to 28 days (maximum). However, if necessary, the randomization visit may be performed earlier than 11 days after receipt of the IMP on site, assuming that the participant is eligible for randomization. In the event of any delay in screening (MRI re-planning, laboratory re-testing, etc.), an additional period of up to 2 weeks is allowed. b From D1 to EOS, the investigator may conduct unscheduled visits (e.g., for evaluation of adverse events) at any time. Assessments may be performed as needed to evaluate the participant based on the investigator's best judgment and in accordance with the study protocol. At a minimum, a physical examination should be performed, and temperature and vital signs should be measured. cAt the time of EOS, participants who have completed treatment with IMP (if eligible for CDP, double-blind or open-label) will be invited to participate in the LTS study. Only those participants who have completed treatment and do not wish to participate in the LTS study will be evaluated at the follow-up visit. dThese visits may be conducted as home health visits (where applicable) or on-site visits (preferably with testing performed in a central laboratory). In any case where this is not possible (to be documented in the source documents), the testing for these visits may be performed in a local laboratory. eIf the participant prematurely permanently discontinues treatment with IMP, the participant will experience a pEOT visit as soon as possible. If a pEOT visit can be planned within 24 hours after the final IMP dose, PK samples should also be collected. The participant will then be asked to continue with the planned study visits until a comprehensive EOS visit is reached. During these visits, all study procedures / assessments will be performed, except for IMP administration and blood sampling for PK and biomarkers (NfL, Chi3L1 and Ig levels). MRI scans for these participants will only be performed annually (using the next annual visit as a starting point). fFor participants continuing on study, a common EOS visit will be conducted when the pre-specified number of events at the 6-month CDP is expected to be reached. The timing and window of this visit will be communicated to the site. gAny disease-modifying therapy for MS taken at any time prior to signing the informed consent needs to be reported in the eCRF; other prior medications taken in the 6-month period prior to signing the ICF will be reported. hA complete physical examination should be performed at Screening, Baseline, Annually (M12, M24, M36, M48), and EOS; a simple physical examination is sufficient for the remaining visits (complete and simple physical examinations will include a neurological examination and collection of the following vital signs: arterial blood pressure, heart rate, temperature). iTo be performed on all participants at Screening. Tuberculosis testing will be repeated based on clinical judgement, equivocal results, or clinical suspicion for TB infection. See E 01, Table 3D for further details. Screening tests for TB are described in Table 2F. j ECG and 30-second rhythmogram will be obtained locally. kHematology (platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, reticulocytes, WBC differential count: neutrophils, lymphocytes, monocytes, eosinophils, basophils). Biochemistry (blood urea nitrogen [BUN], creatinine, glucose, sodium, potassium, bicarbonate, calcium, liver function tests [AST, ALT, ALP, total and direct bilirubin], total protein; creatine phosphokinase). Lipase will be tested at the screening visit and then quarterly. Monthly visits (M1, M2, M4, and M5) will include only hematology and a full liver profile. Additional safety assessments may be performed if required by local regulations. Such testing should be performed in a local laboratory. NOTE: If laboratory test abnormalities are considered transient, a one-time retest may be performed at Screening. Additional safety assessments may be performed if required by local regulations; such testing should be performed locally whenever possible. Additional visits may be added if required by local regulations. At the intermediate time points M1.5 and M2.5, only liver function tests will be collected (AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein, and creatine phosphokinase). mAt Screening, a serum beta-hCG pregnancy test will be performed in a central laboratory. Urine pregnancy testing will be performed at randomization and other scheduled visits during the study. At randomization, a pregnancy test will be performed prior to the first dose of IMP. Additional serum or urine pregnancy tests may be performed, as determined necessary by the Investigator or required by local regulations, to establish that the participant is not pregnant at any time during the study. Telephone communication with the site regarding the results of pregnancy tests performed at home is permitted. nAmong female participants only, if necessary to establish menopausal status. o Both the SDMT and the CVLT-II will be administered to all participants. If for some reason the CVLT-II is not available at a given site due to reasons such as lack of translation, local certification, etc., only the SDMT will be assessed for that participant. pA subset of sites with 3T MRI capabilities will perform additional sequences (e.g., SWI). Further details will be defined in the center MRI manual. qFor MRI performed after D1, a visit window of ±21 days is acceptable. For systemic corticosteroids and ACTH, a 1-month washout is required prior to the MRI scan. The screening MRI scan should be performed as close as possible prior to starting the IMP. The MRI scan should be performed as often as possible during the screening period, only after it has been established that the participant meets all inclusion criteria and does not meet exclusion criteria. rIf the results of the pilot assessment confirm feasibility, non-invasive activity monitoring (actimetry) may optionally be implemented by the Sponsor in a subset of participants during the course of the study. An actimetry baseline assessment will be performed at Screening. sClinical outcome assessments are to be completed by participants prior to discussion of their health status and prior to study treatment administration or other study-related procedures, when available and in accordance with local regulations. tOn the day of PK sampling, the IMP will need to be taken at the study site after a “regular meal.” Participants who forget to take the IMP at home or take the IMP before arriving at the site on the day of the PK sampling visit will be asked to repeat the assessment within 3 days of the missed PK sampling visit. PK assessments should be performed as soon as possible after an overdose or if otherwise specified per the protocol (e.g., to investigate abnormal laboratory test values). M6 and M12: two samples: one sample between 30 and 90 minutes after IMP administration, and one sample between 2.5 and 5 hours after IMP administration. M9: one sample, 30-90 minutes after IMP administration v Pharmacodynamic and biomarker samples will be collected only when permitted according to local regulations. wDNA testing will be allowed at any time after signing the consent form (on Day 1 in case it may not be possible for some reason). Participation is optional. Participants who do not wish to participate in genetic research may still participate in the study. The genetic analysis component of the study requires separate consent. x This sample will be collected and stored for use in the event of any unexpected safety issues, to ensure pre-dose baseline values ​​are available for parameters not previously assessed (e.g., serology), and for biomarker studies (if agreed). y Additional safety assessments may be performed if required by local regulations; whenever possible, such testing should be performed locally. Additional visits may be added if required by local regulations. z Samples for hematology and biochemistry testing on Day 1 (randomization) must be collected prior to administration of the first IMP dose. aa Samples must be shipped within 24 hours. bbBlood sample collection for lymphocyte phenotyping by flow cytometry will be performed in a subset of randomized participants. Participants who did not have a baseline sample collected will not have this test again; participants who did have a baseline sample collected will have a second sample collected at EOT / pEOT.

[0376] The goals and endpoints of treatment are shown in Table 3B. Table 3B - Objectives and End Points Abbreviations: 9-HPT, 9-hole column test; AE, adverse event; AESI, adverse event of special interest; CDI, confirmed disability improvement; CDP, confirmed disability progression; Chi3L1, chitinase-3-like protein 1; ECG, electrocardiogram; EDSS, expanded disability status scale; EOS, end of study; MRI, magnetic resonance imaging; MSQoL-54, multiple sclerosis quality of life-54 questionnaire; NfL, neurofilament light chain; PD, pharmacodynamics; PK, pharmacokinetic; nrSPMS, nonrelapsing secondary progressive multiple sclerosis; T25-FW, timed 25-foot walk.

[0377] Number of participants:

[0378] Approximately 1700 people will be screened to enable randomization of 1290 participants to the study intervention.

[0379] Enrolled participants will be randomized in a 2:1 ratio to 60 mg (established from the dose-finding study DRI15928) of oral daily SAR442168 or daily matching placebo.

[0380] Randomization will be stratified by age at screening (>40 years vs ≤40 years) and geographic region (U.S. vs non-U.S.).

[0381] Notice : "Enrollment" means that the participant or his / her legal representative agrees to participate in the clinical research after completing the informed consent process. Unless otherwise specified in the protocol, potential participants who are screened for study eligibility but do not participate in the study are not considered enrolled.

[0382] Intervention Groups and Duration:

[0383] Study Intervention

[0384] Experimental drugs Preparation: SAR442168 film-coated tablets ·Route of administration: Oral Dosage regimen: 60 mg once a day Experimental drugs Formulation: Placebo to match SAR442168 film-coated tablets ·Route of administration: Oral Dosage regimen: Once a day

[0385] Non-investigational drugs Preparation: MRI contrast enhancement preparation ·Route of administration: Intravenous (IV) Dosage regimen: According to the corresponding label

[0386] Temporary Investigational Medicinal Product (IMP) Discontinuation Due to Surgery

[0387] If surgery is required during the study, consider the benefits and harms of withholding IMP for at least 3 to 7 days before and after surgery, as well as the risk of bleeding

[0388] The duration of treatment will vary for individual participants, depending on the time of recruitment. With a planned recruitment period of approximately 24 months and assumed event rates (discussed below), the study duration should be approximately 48 months. All recruited participants will be followed in the study until the end of the co-study, which will be estimated and announced by the sponsor to ensure that approximately 288 events of a 6-month CDP have been observed before the end of the study.

[0389] Statistical considerations:

[0390] Primary endpoint:

[0391] The primary endpoint will be the treatment difference between SAR442168 and placebo in time to onset of 6-month CDP, regardless of completion of the treatment period. This endpoint corresponds to the "treatment policy strategy". This endpoint will be considered primarily to support regulatory decisions.

[0392] The time to 6-month CDP onset will be analyzed by Cox proportional hazards models with items for treatment, age at screening (>40 years, ≤40 years), and geographic region (US, non-US). Log-rank tests stratified by age at screening (>40 years, ≤40 years) and geographic region (US, non-US) will also be examined to compare SAR442168 to placebo.

[0393] In this primary ITT analysis: For participants who completed the study without initial disability progression or who prematurely discontinued the study before 6 months of confirmation of onset of disability progression, the participant's event time will be censored at the date of the last EDSS assessment. For participants who have an initial episode of disability progression before 6-month confirmation but reach the common study end date, the participant's event status will be determined by imputation. Because in this setting it is reasonable to assume that some of the missing data are missing at random, this approach utilizes partial information and follows the ITT principle. Event status within each treatment will be determined as an imputation model using a logistic model with items for age at screening (>40 years, ≤40 years) and geographic region (US, non-US). Multiple imputation will be used to summarize the results.

[0394] Only EDSS assessments measured more than 90 days after the adjudication of the onset of a relapse will be used to determine the onset of disability progression. In addition, for the purpose of confirmation, only EDSS scores measured more than 90 days after the adjudication of the onset of a relapse will be used. In the case of such MS relapses, the next quarterly EDSS assessment will be used for CDP confirmation. For any one or more non-confirmed (i.e., intervention) EDSS assessments between the initial (onset) and confirmed EDSS scores, the minimum score increase required for progression must also be maintained.

[0395] Key secondary endpoints:

[0396] Similar analyses to the primary analysis of the primary efficacy endpoint will be performed in the ITT population for the other time-to-event endpoints (time to sustained 20% increase in 9-HPT, sustained 20% increase in T25-FW, 3-month CDP, and CDI onset).

[0397] Continuous endpoints (percent change in brain volume loss at EOS, change in cognitive function, change in physical function, and change in MSQoL-54) will be analyzed using a repeated measures mixed effects model (MMRM) approach. The model will include the change / percent change value of the corresponding endpoint at each planned visit as the response variable, and treatment, age at screening (>40 years, ≤40 years), geographic region (US, non-US), visit, treatment-visit interaction, baseline value of the assessed endpoint, and baseline-visit interaction as covariates.

[0398] The negative binomial regression model will be used to analyze the clear efficacy endpoints with count data (new and / or enlarged T2 hyperintensities during the study period after baseline). The model will include the total counts occurring during the observation period as the response variable, and treatment group, age at screening (>40 years, ≤40 years), and geographic region (US, non-US) as covariates. The log-transformed scan number will be the displacement variable.

[0399] Analysis of safety data:

[0400] All safety summaries will be descriptive; safety data will not be tested for statistical significance. This includes treatment-emergent adverse events (TEAEs) and other safety information (e.g., clinical laboratory evaluations, electrocardiograms [ECGs], and vital signs). TEAEs are defined as adverse events (AEs) that occur or worsen or become serious during the treatment period. These analyses will be based on the safety population, defined as all participants who were randomly assigned and exposed to the study intervention, regardless of the amount of exposure, and analyzed according to the actual treatment received. Two participants had treatment-emergent transient increases in alanine aminotransferase (ALT) >3x ULN, 1 during the 30 mg SAR442168 treatment period (at Week 8, 105 U / L [normal range 6 to 34 U / L]), which returned to the normal range within 4 days, and 1 during the 60 mg SAR442168 treatment period (at Week 4, 107 U / L [normal range 6 to 34 U / L]). The participant in the 60 mg group had slightly elevated ALT at screening (48 U / L) and at baseline (50 U / L); ALT levels returned to the normal range in 8 weeks. Both participants continued study treatment during this time period. All other liver enzyme levels for both participants during the treatment period were within normal ranges; one event was assessed by the investigator as related to study drug and one event was assessed by the investigator as unrelated to study drug. Both participants completed the DRI15928 study and transitioned to the LTS follow-up study without adverse events. One mild petechiae event in 1 female participant (in the SAR442168 30 mg group at week 8) and 2 mild microscopic hematuria events in 2 male participants (1 event at week 16 in the SAR442168 30 mg group and 1 event at day 1 in the SAR442168 60 mg group with recorded occult blood in the urine) were reported during the treatment period in the SAR442168 Phase 2b trial. Hematology results were clinically insignificant for all 3 participants since the onset of the event. Participants with mild petechiae had benign pigmented lesions recorded during the screening period, and the events were assessed by the investigator to be related to the study drug. The 2 mild microscopic hematuria events were assessed to be unrelated to the study drug. All 3 events resolved spontaneously. No serious infections occurred. The most commonly reported infections (≥3 events in total) during the SAR442168 treatment period were upper respiratory tract infections, nasopharyngitis, gastroenteritis, and respiratory tract infections. Based on hematology laboratory results, no clinically significant cytopenias, including thrombocytopenia and neutropenia, were reported or detected, and no clinically significant arrhythmias were observed by ECG monitoring during the study. The identified risks of tolebrutinib have been identified as follows: • SAEs of treatment-emergent drug-induced liver injury (DILI) have been reported in the ongoing Phase 3 trial; however, all cases occurred between Months 2 and 3 and appeared to be reversible after treatment discontinuation, and potential confounding factors were identified for some cases.

[0401] Drug-induced liver injury has been identified in ongoing Phase 3 trials. The reported events occurred between the second and third months after starting IMP, and the liver enzyme elevations appeared to be reversible after discontinuation of IMP. Exclusion criteria and monitoring frequency have been updated in all actively enrolling programs to reduce the risk of liver injury.

[0402] This was a phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel-group, multicenter, event-driven (6-month CDP) trial in participants with NRSPMS, with a variable treatment duration ranging from approximately 24 to 48 months.

[0403] The study will consist of the following study periods:

[0404] Screening period: Day -28 to Day -1.

[0405] Randomization / Start IMP: Eligible participants will be randomized in a 2:1 ratio to receive daily oral SAR442168 (60 mg) or daily matching placebo.

[0406] Intervention Period: Double-blind treatment period to assess efficacy and safety until EOS, as described in the End of Study definition.

[0407] A month is conventionally defined as a period of 28 days.

[0408] Safety Follow-up Period / EOS: 4 to 8 weeks after the last dose of study treatment (for participants who complete IMP treatment [double-blind or open-label if rescue after 6-month CDP] and do not enter the LTS study) to collect safety data.

[0409] EOS: Participants were considered to have completed the study if they had completed all phases of the study, including the EOS visit, regardless of whether they were still taking the IMP.

[0410] Participants with 6 months of CDP were eligible for open-label active treatment (SAR442168) as rescue (under the heading Rescue Medicine).

[0411] The duration of the treatment period will vary for individual participants, depending on the timing of recruitment and end of study, as described below. All enrolled participants will be followed in the study until approximately 288 events are observed at a 6-month CDP. At a planned recruitment period of approximately 24 months and assumed event rates, the duration of the study should be approximately 48 months, with an estimated mean treatment duration of 33 to 36 months.

[0412] In the event that a participant prematurely discontinues the study intervention, the participant will be encouraged to remain in the study and comply with all study visits until the EOS.

[0413] To minimize possible bias in the study outcomes, the study will be double-blind. Participants, any investigators, site staff, and the sponsor will be kept blinded to the initial treatment until the end of the study. Study Group

[0414] Prospective approval of protocol deviations (also called protocol concessions or waivers) from recruitment and enrollment criteria was not permitted. Inclusion criteria

[0415] Participants were eligible for inclusion in the study only if all of the following criteria, as shown in Table 3C, applied: Table 3C - Inclusion criteria Exclusion criteria

[0416] Participants were excluded from the study if any of the following criteria as shown in Table 3D applied: Table 3D - Exclusion criteria Lifestyle considerations

[0417] Meals and dietary restrictions: SAR442168 should be taken with regular meals. When possible, meals taken with SAR442168 (e.g., breakfast, lunch, or dinner) should be consistent throughout the study. Typical meals taken with the IMP will be recorded at each visit. In the event that the meal times for IMP administration need to be changed, a minimum interval of 12 hours should be maintained between 2 doses.

[0418] Caffeine, Alcohol, and Tobacco: For each visit with a PK / PD assessment (see Tables 3A1 and 3A2), participants will abstain from products containing caffeine or xanthines (e.g., coffee, tea, cola drinks, and chocolate) for 2 hours prior to starting treatment and until the final PK and / or PD sample is collected later that day.

[0419] For each visit with PK / PD assessments (see Tables 3A1 and 3A2), participants will abstain from alcohol for 24 hours prior to starting treatment until the final PK and / or PD samples are collected later that day.

[0420] Participants should be advised not to consume heavy alcohol, defined as >14 g (1 standard drink) per day in female participants or >28 g (2 standard drinks) per day in male participants, on a regular basis throughout the study. Study Intervention

[0421] A study intervention is defined as any experimental intervention(s), commercially available product(s), or placebo intended to be administered to study participants according to the study protocol. Criteria for Temporary Delay of Enrollment and Administration of Study Intervention

[0422] During a regional or national emergency declared by a government agency, contingency measures should be considered for screening, enrollment, randomization, and administration of the study intervention if the site cannot fully follow the procedures required by the protocol. IMP: investigational medicinal product; NIMP: non-investigational medicinal product.

[0423] Between protocol-planned site visits, interim visits may be required for IMP dispensing. As an alternative to these visits or in lieu of on-site IMP dispensing, SAR442168 may be supplied from site to participants via a Sponsor-approved courier (direct-to-patient [DTP]), if required, where permitted by local regulations and approved by the Sponsor.

[0424] Non-investigational drugs

[0425] MRI contrast-enhancing agents ·Route of administration: IV Dosage regimen: According to the corresponding label Concomitant therapy

[0426] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) that the participant is taking at the time of enrollment or receives during the study must be recorded along with the following: Reason for use. Dates of application, including start and end dates. Dosage information, including dose and frequency.

[0427] Any live (attenuated) vaccines were prohibited within 2 months prior to the first treatment visit and during the intervention period.

[0428] No MS-specific therapy documented in Exclusion Criteria E 06 was permitted after randomization while participants continued on study treatment. Short-term use (3 to 5 days) of glucocorticoids (e.g., for treatment of MS relapses or acute illness) and topical corticosteroids (e.g., topical, nasal, ocular, aural, intra-articular) was permitted.

[0429] The Medical Monitor should be contacted if any questions arise regarding concomitant or prior therapy.

[0430] Participants must abstain from prescription or over-the-counter medications (including vitamins and dietary or herbal supplements) for 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives, whichever is longer, prior to the start of the study intervention until completion of the follow-up visit unless the investigator and sponsor determine that the medication will not interfere with the study.

[0431] If clinically feasible, medications used to treat MS symptoms (eg, impaired walking, fatigue, spasticity, incontinence, pain) should be maintained at stable doses prior to screening and for the duration of the treatment period.

[0432] Anticoagulant / antiplatelet therapy is not permitted concomitantly with IMP, including the following: Acetylsalicylic acid (aspirin) > 81 mg / day. Antiplatelet drugs (eg, clopidogrel). Warfarin (vitamin K antagonist). Heparin, including low molecular weight heparin (antithrombin agent). Dabigatran (a direct thrombin inhibitor). Apixaban, edoxaban, and rivaroxaban (direct factor Xa inhibitors).

[0433] Paracetamol / acetaminophen at a dose of ≤ 3 g / day was allowed at any time during the study. A short course (most often 5 days) of the lowest effective dose of a nonsteroidal anti-inflammatory drug (NSAID) (other than acetylsalicylic acid), preferably a selective cyclooxygenase-2 inhibitor, may be given during the study if clinically indicated for treatment of an existing medical condition or a new event. The investigator must record the use of NSAIDs (and any other concomitant medications) in the eCRF. CYP inhibitors and inducers:

[0434] Strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 liver enzymes were not permitted during the entire study period (Table 3I).

[0435] Based on nonclinical drug metabolism studies, SAR442168 is a substrate for CYP3A and CYP2C8 isozymes. In healthy participants, a strong CYP3A4 inhibitor (itraconazole 200 mg once a day for 4 days) increased the SAR442168 area under the curve AUC exposure by 1.8 times (study INT16385), and a strong CYP2C8 inhibitor (gemfibrozil 600 mg twice a day for 6 days) increased the SAR442168 AUC exposure by 8.4 times (study INT16726). Based on a satisfactory safety and tolerability profile and based on the exposure observed in healthy participants who received SAR442168 once a day for 14 days at a dose of up to 240 mg SAR442168 under fed conditions (study TDR16862), drugs that strongly inhibit CYP3A4 are allowed and drugs that strongly inhibit CYP2C8 are not allowed. In healthy participants, strong CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) reduced SAR442168 exposure 6-fold (Study INT16726). Therefore, strong and moderate (based on prediction) CYP3A inducers are not allowed due to their potential to reduce SAR442168 exposure and efficacy. See Table 3I for a list of drugs to avoid.

[0436] If any questions exist regarding concomitant or prior therapy, the sponsor should be contacted.

[0437] Rescue Medicine

[0438] If participants achieve the primary endpoint (6-month CDP), they can choose, in cooperation with the treating investigator, to receive one of the following: 1. Switch to open-label SAR442168 treatment and continue regularly scheduled study visits; 2. Switch to a non-study treatment approved for NRSPMS in their respective country. Participants will be encouraged to remain in the study for their planned clinic visits until the end of the co-study.

[0439] Participants and investigators will remain blinded to original treatment assignment if they choose to provide rescue medicine.

[0440] If possible, all individually blinded data will be reviewed and all inquiries will be addressed prior to switching to rescue to ensure data integrity for the primary assessment. Prior to initiating rescue therapy, the investigator should confirm that there have been no adjudicated relapses within 90 days prior to the onset or confirmation of a 6-month CDP. Based on individual symptoms and the assessed risk of further progression, the investigator and participant may choose to keep the participant on initial double-blind treatment after achieving a 6-month CDP.

[0441] Participants, any investigators, site staff, and the sponsor will be kept blinded to initial treatment assignment until the end of the study.

[0442] The supply of SAR442168 as a rescue medication will be regulated at the national level.

[0443] Multiple sclerosis relapses are not frequent in the NRSPMS population, but their occurrence during the study period cannot be completely ruled out. In the event of an MS relapse, treatment according to local routine practice is allowed (e.g., high-dose IV methylprednisolone for 3 to 5 days). The date and time of rescue medication administration and the name and dosage regimen of the rescue medication must be recorded.

[0444] Dose Modifications

[0445] No dose modifications were encountered in this study. Interruption or permanent discontinuation of treatment may be necessary if deemed necessary due to AEs.

[0446] Discontinuation of study intervention and participant discontinuation / withdrawal

[0447] Discontinuation of study intervention

[0448] Explicit termination

[0449] The study intervention should be continued whenever possible.

[0450] Permanent intervention discontinuation is any treatment discontinuation associated with an explicit decision by the investigator or the participant not to re-expose the participant to the study intervention at any time.

[0451] In rare cases, it may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant will be asked to remain in the study for evaluation until the EOS visit. For this set of participants (participants who discontinue IMP and / or switch to other DMTs), no PK or biomarker samples will be collected after the pEOT visit, and MRI assessments will only be performed annually, using the next annual visit as the starting point.

[0452] This will be important for continued evaluation of safety and efficacy. Data to be collected at the time of discontinuation of study intervention are provided in the SoA (Tables 3A1 and 3A2). In the event of permanent discontinuation of study intervention, the participant's MS should be treated according to local clinical practice and the investigator's best judgment.

[0453] The following may be valid reasons for the investigator or sponsor to discontinue treatment of a participant: Adverse events that compromise the safety of the participant, or if discontinuation of the study intervention is desired or deemed necessary by the investigator and / or participant. If the IMP discontinuation criteria are met according to the laboratory abnormality follow-up guidelines (Table 3F). In the investigator's opinion, the participant is no longer receiving therapeutic / clinical benefit. If the female participant becomes pregnant or wishes to become pregnant during the study. · Upon the participant's request, i.e., withdrawal of consent for treatment. Any serious opportunistic infection (eg, PML [see Figure 6 ], HIV) · Continued need / chronic use of prohibited concomitant medications (see Table 3I). Use of open-label SAR442168 or non-investigational disease-modifying therapy approved for NRSPMS in their respective country (e.g., after 6 months CDP). A brief physical examination will include, at a minimum, assessment of the skin, lungs, cardiovascular system, neurological examination, and abdomen (liver and spleen). Investigators should pay special attention to clinical signs associated with pre-existing serious illness. Any clinically significant new finding or worsening of a previously found finding should be reported as an AE at the investigator's discretion. Safety Assessment Physical examination

[0454] Physical examinations will be performed at the time points specified in the SoA (Tables 3A1 and 3A2). A complete physical examination will include at least an assessment of the general appearance, head and neck, abdomen, lymph nodes, skin, cardiovascular system, respiratory system, musculoskeletal system, and neurological examination by the treating investigator. Height (at screening) and weight will also be measured and recorded. Further details will be provided in the study brochure. A brief physical examination will include, at a minimum, assessment of the skin, lungs, cardiovascular system, neurological examination, and abdomen (liver and spleen). Investigators should pay special attention to clinical signs associated with pre-existing serious illness. Any clinically significant new finding or worsening of a previously found finding should be reported as an AE at the investigator's discretion.

[0455] The scope of the physical examination may be expanded at the discretion of the treating investigator to evaluate for AEs or abnormal clinical laboratory test values.

[0456] Vital signs ·Body temperature, heart rate, and blood pressure will be assessed. Blood pressure and pulse measurements will be assessed with fully automated devices while the participant is in the supine or sitting position. Manual techniques will be used only when automated devices are unavailable. Participants should rest in a quiet environment without distractions (e.g., television, mobile phones) for at least 5 minutes before blood pressure and pulse measurements. • Vital signs (to be performed prior to blood collection for laboratory testing) will consist of 1 heart rate measurement and 3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at least 1 minute apart).

[0457] Electrocardiogram A 12-lead ECG will be obtained as outlined in the SoA (see Tables 3A1 and 3A2) using an ECG machine that automatically calculates heart rate and measures PR, QRS, QT, and QTcF intervals. In cases where the ECG machine does not automatically calculate QTcF, manual calculation using a nomogram or an automated website calculator (e.g., https: / / reference.medscape.com / calculator / 48 / ecg-corrected-qt) is acceptable ECG and 30-second rhythmogram will be obtained locally. Further details will be included in the study brochure.

[0458] Clinical safety laboratory evaluation A list of clinical laboratory tests to be performed is provided in Table 3I. According to the SoA, serological testing for hepatitis B and hepatitis C will be performed during screening; testing for other infectious diseases should be performed during screening if locally required. In the case of an urgent safety event, the treating investigator may request urgent local laboratory data to allow appropriate treatment decisions to be made. All clinically relevant requested urgent local laboratory data will be recorded in the eCRF. The treating investigator must review the laboratory reports, document this review, and record any clinically relevant changes that occur during the study in the AE section of the eCRF. Laboratory reports must be archived with the original files. Clinically significant abnormal laboratory findings are those not related to the underlying disease unless judged by the investigator to be more serious than expected for the participant's condition. All laboratory tests with values ​​considered clinically significant abnormal during study participation or within 30 days after the last dose of study intervention should be repeated until the value returns to normal or baseline or is no longer considered clinically significant by the Investigator. -If abnormal laboratory values ​​do not return to normal / baseline within a period of time judged reasonable by the investigator, the cause should be identified and the Sponsor notified. All protocol-required laboratory assessments as defined in Table 3I must be performed in accordance with the laboratory manual and SoA (see Tables 3A1 and 3A2). Figure 2-Figure 8 In the event that laboratory evaluations indicate discontinuation of the IMP, a temporary discontinuation should be considered unless otherwise specified. - If laboratory values ​​from non-protocol-mandated laboratory evaluations performed at the institution's local laboratory require a change in the participant's management or are considered clinically significant by the investigator (e.g., SAE or AE or dose modification), the results must be recorded in the eCRF.

[0459] Suicidal ideation and behavior risk monitoring

[0460] SAR442168 crosses the blood-brain barrier. Assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation and behavior will be monitored using the C-SSRS during Study EFC16645. For safety reasons, the C-SSRS will be administered throughout the study by the treating investigator or authorized to an individual qualified to administer the scale.

[0461] If a participant scores "yes" on item 4 or 5 of the suicidal ideation section of the C-SSRS, or "yes" on any of the suicidal behavior sections, study drug administration must be discontinued. A psychiatric specialist will be consulted and decide whether study drug administration can be restarted and whether any additional risk reduction strategies (e.g., increased monitoring, antidepressant administration) are needed.

[0462] Adverse Events of Special Interest

[0463] AESIs are scientifically and medically relevant AEs (serious or nonserious) that are specific to the sponsor's product or procedure and require ongoing monitoring by the investigator and immediate notification to the sponsor. Such events may require further investigation to characterize and understand them. Adverse events of particular interest may be added, modified, or removed by protocol amendments during the study. Pregnancy in female participants enrolled in studies using IMP / NIMP and in female partners of male participants enrolled in studies - It will be considered a SAE only if it meets one of the severity criteria (see Appendix 3 [Section 10.3]), - In the event that a female participant becomes pregnant, the IMP should be discontinued. - Follow-up of pregnancy of female participants or female partners of male participants is mandatory until outcome has been determined. Symptomatic overdose (serious or minor) with IMP - Overdose (accidental or intentional) with IMP was an event suspected by the investigator or spontaneously notified by the participant (not based on systematic pill counts) and was defined as at least double the prescribed dose within the prescribed treatment interval (e.g., >2 tablets of IMP in a 12-hour interval). Increase in alanine aminotransferase (ALT) > 3× ULN - ALT increase >3×ULN confirmed by retesting within 72 hours or confirmed without retesting within 72 hours. ·One or more AESIs specific to other projects - ECG observation for atrial fibrillation or atrial flutter, - Serious infections (NCI CTCAE grade 3 or higher) infections that may or may not meet severity criteria (e.g., grade 3 opportunistic infections), - Moderate or severe bleeding events (NCI CTCAE grade 2 or higher), including but not limited to symptomatic bleeding, bleeding in critical areas or organs such as the CNS, or intraocular bleeding, -Thrombocytopenia, platelet count <75,000 / mm 3 (For the management flow chart, see Figure 3 ). Clinical laboratory tests

[0464] When feasible, the tests detailed in Table 3F will be performed by a central laboratory.

[0465] Local laboratory results are required only in the event that central laboratory results are not available in time for study intervention administration and / or response assessment.

[0466] In addition, if local laboratory results are used to make study intervention decisions or response assessments, these results must be entered in the eCRF.

[0467] Protocol-specific requirements for inclusion or exclusion of participants are detailed in Tables 3C and 3D.

[0468] Additional testing may be performed at any time during the study if determined necessary by the investigator or required by local regulations. Additional serum or urine pregnancy testing may be performed if determined necessary by the investigator or required by local regulations to confirm that the participant is not pregnant at any time during her / his participation in the study.

[0469] Table 3F - Laboratory Assessments Required by the Protocol ALT: alanine aminotransferase; anti-HBc: antibody against hepatitis B core antigen; anti-HBs: hepatitis B surface antibody; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BUN: blood urea nitrogen; β-hCG: human chorionic gonadotropin; FSH: follicle stimulating hormone; IEC: independent ethics committee; INR: international normalized ratio; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; IRB: institutional review board; MCH: mean corpuscular hemoglobin; MCV: mean corpuscular volume; PT: prothrombin time; RBC: red blood cell; SGOT: serum aspartate aminotransferase; SGPT: serum alanine aminotransferase; TB: tuberculosis; ULN: upper limit of normal; WBC: white blood cell a Details of liver chemistry stopping criteria and required activities and follow-up assessments after ALT > 3×ULN is observed are in Figure 2-Figure 8 Clinical laboratory findings that may suggest severe liver injury, such as ALT > 3 × ULN and bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT > 3 × ULN and international normalized ratio (INR) > 1.5 (if INR is measured), must be reported as a SAE. bLocal urine testing for pregnancy will be standard of care (except for the Screening Visit when a serum pregnancy test is required) unless serum testing is required by local regulations or the IRB / IEC.

[0470] The investigator must document his or her review of each laboratory safety report.

[0471] Laboratory / analyte results that could unblind the study will not be reported to the study site or other blinded personnel until the study has been unblinded. This includes PK assessments and any post-baseline biomarker or PD assessments. Hepatic and other safety: activity and follow-up assessments

[0472] Table 3G and Figure 2-Figure 8 These activities described in the study were only required for the events of ALT increase and thrombocytopenia. For all other safety events described, these activities were recommended based on the medical judgment of the investigator.

[0473] Neutropenia should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0474] Thrombocytopenia should be recorded as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0475] Figure 3 Abbreviations in the literature: aPTT: activated partial thromboplastin time; EDTA: ethylenediaminetetraacetic acid; INR: international normalized ratio; PK: pharmacokinetics; PT: prothrombin time.

[0476] Figure 4A Abbreviations: ALT: alanine aminotransferase; ANCA: anti-neutrophil cytoplasmic antibody; AST: aspartate aminotransferase; CMV: cytomegalovirus; CRF: case report form; DNA: deoxyribonucleic acid; dsDNA: double-stranded DNA; EBV: Epstein-Barr virus; GGT: gamma glutamyltransferase; HAV: hepatitis A virus; HBc: hepatitis B core; HBV: hepatitis B virus; HCV: hepatitis C virus; HEV: hepatitis E virus; IgM: immunoglobulin M; IMP: investigational medicinal product; INR: international normalized ratio; lab: laboratory; LFT: liver function test; PT: prothrombin time; RNA: ribonucleic acid; LKM: liver kidney microsome; ULN: upper limit of normal.

[0477] NOTE: "Baseline" refers to the ALT sampled at the Baseline Visit; or if a baseline value is not available, the most recent ALT sampled at the Baseline Visit. The algorithm is not applicable in the event of an increase in ALT during the Screening period. Table 3G Activities to confirm ALT elevation

[0478] Increased serum creatinine should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting Adverse Events in Appendix 3 (Section 10.3) is met.

[0479] CPK should be reported as an AE only if at least 1 of the criteria in the General Guidance for Reporting Adverse Events in Appendix 3 (Section 10.3) is met.

[0480] Figure 5 Abbreviations: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, pharmacokinetics.

[0481] Increased serum creatinine should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0482] Figure 8 Abbreviations: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0483] CPK should be reported as an AE only if at least 1 of the criteria in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0484] Suspected PML: Recommended if the participant has clinical presentation or MRI features suggestive of PML Figure 6 The diagnostic and activity algorithms described in .

[0485] Figure 6 Abbreviations: CSF, cerebrospinal fluid; Gd, gadolinium; IMP, investigational medicinal product; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy

[0486] Clinical manifestations or MRI lesion features suspected of PML are presented in Table 3H (based on Berger et al. Neurology 2013, 80, 1430-1438 and Kappos et al. Lancet Neurol. 2007, 6, 431-441).

[0487] In the event that PML is suspected based on imaging results, the local radiologist will inform the investigator directly, and a central review of the MRI will not be required. The investigator will obtain additional plasma, urine, and CSF samples for John Cunningham virus (JCV) analysis. The samples will be analyzed upon receipt, and the results will be provided directly to the study site and the sponsor. Other management will be at the discretion of the treating investigator. However, the next steps will include discontinuation of study treatment. Additional imaging will be performed at the discretion of the investigator, depending on the diagnostic workup and treatment plan. • The diagnosis of PML is established by detection of John Cunningham virus (JCV) DNA in the cerebrospinal fluid of patients with clinical and MRI features suggestive of PML. If JCV DNA is not detected in the CSF and if clinical suspicion for PML remains high, another lumbar puncture should be performed. If the diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may be considered to establish a definitive diagnosis. Table 3H - Clinical and MRI features suggestive of PML

[0488] Clinical or MRI features suggestive of PML should be recorded as AEs / AESIs / SAEs according to the definitions and procedures in Appendix 3 (Section 10.3). Examples of Drugs with the Potential to Alter the Metabolism or Absorption of SAR442168

[0489] The following drugs have the potential to alter the kinetics of SAR442168 due to their interactions with P450-mediated metabolism, being strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes (listed according to the University of Washington Drug Interaction Database program [www.druginteractioninfo.org]) and should be discontinued concomitantly with IMP during the study.

[0490] Please note that the list provided is not complete and the product information for drugs intended for concomitant use should be consulted. Table 3I - CYP3A inducers and CYP2C8 inhibitors abbreviation ADL: Activities of Daily Living AE: Adverse event AESI: Adverse events of special interest ALT: Alanine aminotransferase aPTT: activated partial thromboplastin time BTK: Bruton's tyrosine kinase CD: Cluster of differentiation CFR: Code of Federal Regulations Chi3L1: Chitinase 3-like protein 1 CNS: Central nervous system COVID-19: Coronavirus Disease 2019 CPK: Creatine phosphokinase CSF: cerebrospinal fluid CSR: Clinical Research Report C-SSRS: Columbia-Suicide Severity Rating Scale DDI: Drug-drug interaction DILI: Drug-induced liver injury DMC: Data Monitoring Committee DNA: deoxyribonucleic acid DNAM-1: DNAX accessory molecule 1 DTP: Direct to Patient EC: Ethics Committee eCRF: Electronic Case Report Form EDSS: Expanded Disability Status Scale EU: European Union FSH: Follicle stimulating hormone GCP: Good Clinical Practice Guidelines Gd: Gadolinium GM-CSF: Granulocyte-macrophage colony-stimulating factor GrA: human granzyme A GrB: human granzyme B GrK: human granzyme K GrM: human granzyme M HIV: Human Immunodeficiency Virus HR: Hazard ratio HRT: Hormone Replacement Therapy ICF: Informed Consent ICH: International Council for Harmonization IEC: Independent Ethics Committee IFNγ: interferon gamma IL: interleukin IMP: Investigational Medicinal Product INR: International Normalized Ratio IRB: Institutional Review Board IRT: Interactive Response Technology IUD: intrauterine device IUS: intrauterine hormone-releasing system IV: Intravenous IWRS: Interactive Web Response System JCV: John Cunningham Virus LTS: Long Term Security MCAM: Melanoma cell adhesion molecule MedDRA: Medical Dictionary for Regulatory Activities MRI: Magnetic resonance imaging MS: Multiple Sclerosis MSFC-3: Multiple Sclerosis Functional Composite-3 MTR: Magnetic Transfer Rate NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NEDA: No Evidence of Disease Activity-3 NfL: neurofilament light chain NRSPMS: Non-relapsing secondary progressive multiple sclerosis NSAID: Nonsteroidal anti-inflammatory drug PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive multifocal leukoencephalopathy PPMS: Primary progressive multiple sclerosis pTreg: peripheral regulatory T cells RMS: Relapsing multiple sclerosis RTE: New thymic emigrant cells SAP: Statistical Analysis Program SEL: Slowly evolving lesions SoA: Schedule of Activities SPMS: Secondary progressive multiple sclerosis SUSAR: Suspected unexpected serious adverse reaction SWI: Susceptibility Weighted Imaging TB: Tuberculosis TEAE: Treatment-emergent adverse event Tfh: T follicular helper cell Th 17: T helper 17 cells Th1: T helper 1 cells Th2: T helper 2 cells TIGIT: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain TNFα: Tumor necrosis factor alpha Treg: Regulatory T cells tTreg: thymus-derived Foxp3(+) regulatory T cells ULN: Upper limit of normal WBC: White blood cells WOCBP: Women of childbearing potential Example 4 - A Phase 3, Randomized, Double-Blind Efficacy and Safety Study Comparing SAR442168 with Placebo in Participants with Primary Progressive Multiple Sclerosis (PERSEUS)

[0491] The goal of this Phase 3 clinical trial is to demonstrate the efficacy and safety of SAR442168 compared to placebo in participants with PPMS. The primary endpoint is the time to onset of 6-month confirmed disability progression (CDP) assessed by the Expanded Disability Status Scale (EDSS) score, which is shown in Figure 7 middle.

[0492] A graphical scheme of the study design is shown in Figure 1D middle. Figure 1DAbbreviations used in the study: CDP, confirmed disability progression; DMT, disease-modifying therapy; EOS, end of study; MRI, magnetic resonance imaging.

[0493] Tables 4A1, 4A2, and 4A3 shown below describe the timeline of activities during the course of the study. Table 4B that follows describes the overall study objectives and endpoints. Table 4A1: Schedule of Activities (SOA) - Screening to Month 5 Table 4A2: Schedule of Activities (SOA) - Month 6 to Month 24 Table 4A3: Schedule of Activities (SOA) - Month 27 to Follow-up aPTT: activated partial thromboplastin time; β-HCG: β-human chorionic gonadotropin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; Chi3L1: chitinase-3-like protein 1; C-SSRS: Columbia-Suicidality Severity Rating Scale; D: day; DNA: deoxyribonucleic acid; ECG: electrocardiogram; EDSS: expanded disability status scale; EOS: end of study; EOT: end of treatment; EQ 5D5L: EuroQol 5-dimension 5-level questionnaire; FSH: follicle-stimulating hormone; HIV: human immunodeficiency virus; Ig: immunoglobulin; IMP: investigational medicinal product; INR: international normalized ratio; IRT: interactive response technology; LTS: long-term safety; M: month (28 days); MCV: mean corpuscular volume; MCH: mean corpuscular hemoglobin content; MRI: magnetic resonance imaging; MS: multiple sclerosis; MSQoL-54: multiple sclerosis quality of life-54; NfL: neurofilament light chain; OCT: optical coherence tomography; pEOT: premature end of treatment; PK: pharmacokinetics; PT: prothrombin time; RBC: red blood cell; SWI: susceptibility-weighted imaging; TB: tuberculosis; TIBC: total iron-binding capacity; V: visit; WBC: white blood cell. NOTE: All assessments should be performed as specified in this SoA unless not permitted under local regulations. All visit assessments should be performed during the visit window unless otherwise specified in this protocol. aThe Screening Period may range from D-28 to D-1; the Randomization Visit may be conducted only once. The IMP will be available on site. The interval between the Screening and Randomization Visits may range from 11 days (minimum) to 28 days (maximum). However, if necessary, the Randomization Visit may be conducted earlier than 11 days after receipt of the IMP on site, assuming the participant is eligible for randomization. In the event of any delay in Screening (MRI rescheduling, laboratory retesting, etc.), an additional period of up to 2 weeks is allowed. For other situations where a follow-up visit is required, please refer to the Study Manual. b From D1 to EOS, the investigator may conduct unscheduled visits (e.g., for evaluation of adverse events) at any time. Assessments may be performed as needed to evaluate the participant based on the investigator's best judgment and in accordance with the study protocol. At a minimum, a physical examination should be performed, and temperature and vital signs should be measured. cAt the time of EOS, all participants who have completed the study and are still treated with IMP (if meeting the 6-month CDP, double-blind or open-label) will be invited to participate in the LTS study. Only those participants who have completed treatment and do not wish to participate in the LTS study will be evaluated at the follow-up visit. For other situations requiring a follow-up visit, please refer to the study brochure. dThese visits may be conducted as home health visits (where applicable) or on-site visits (preferably with testing performed in a central laboratory). In any case where this is not possible (to be documented in the source documents), the testing for these visits may be performed in a local laboratory. eIf the participant prematurely permanently discontinues treatment with IMP, the participant will experience a pEOT visit as soon as possible. If a pEOT visit can be planned within 24 hours after the final IMP dose, PK samples should also be collected. The participant will then be asked to continue with the planned study visits until a comprehensive EOS visit is reached. During these visits, all study procedures / assessments will be performed, except for IMP administration and blood sampling for PK and biomarkers (NfL, Chi3L1 and Ig levels). MRI scans for these participants will only be performed annually (using the next annual visit as a starting point). fA common EOS visit will be conducted in anticipation of reaching the pre-specified number of events for the 6-month CDP. The timing and window for this visit will be communicated to the site. gIf no history is available, a CSF draw will be performed locally during the screening period. hAny disease-modifying therapy (DMT) for MS taken at any time prior to signing the informed consent needs to be reported in the case report form (CRF); other previous medications taken within the 6-month period prior to signing the informed consent (ICF) will be reported. iOn the day of PK sampling, the IMP will be taken at the study site after a “regular meal”. Participants who forget to take the IMP at home or take the IMP before arriving at the site on the day of the PK sampling visit will be required to undergo a PK assessment within 3 days of the missed PK sampling visit. The PK assessment should be performed as soon as possible after the overdose or if otherwise specified per the protocol (e.g., investigation of abnormal laboratory test values). jHematology (platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, reticulocytes, WBC differential count: neutrophils, lymphocytes, monocytes, eosinophils, basophils). Biochemistry will be tested (blood urea nitrogen [BUN], creatinine, glucose, potassium, sodium, chloride, bicarbonate, calcium, liver function tests [AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein; creatine phosphokinase]). Lipase will be tested only at screening. Monthly visits (M1, M2, M4, and M5) will include only hematology and a full liver profile. Additional safety assessments may be performed if required by local regulations; such testing should be performed in a local laboratory. Additional visits may be added if required by local regulations. NOTE: If abnormal laboratory test values ​​are believed to be transient, a one-time retest may be performed at screening. kAt intermediate time points (W2, W5, W6, W7, W9, W10, W11, M7, M8, M10, and M11), only liver function tests (AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein) will be collected and creatine phosphokinase; these can be performed at a central laboratory (preferred, as appropriate for site visits or home care) or at a local laboratory. For participants switching to open-label treatment, refer to the rescue medicine section. l A complete physical examination should be performed at Screening, Baseline, Annually, and EOS; a simple physical examination is sufficient for the remaining visits (a complete and simple physical examination will include a neurological examination and collection of the following vital signs: arterial blood pressure, heart rate, and temperature). mTo be performed for all participants at Screening. To be repeated based on clinical judgment, equivocal results, or clinical suspicion of TB infection. See E 01, Table 4D for details. Screening tests for TB are described in Table 4F. n ECG and 30-second rhythmogram will be obtained locally. o Urinalysis will be performed according to Table 4F. pA serum β-HCG pregnancy test will be performed at a central laboratory at Screening. A urine pregnancy test will be performed at randomization and other scheduled visits during the study. Pregnancy testing should be performed prior to the first dose of IMP. Additional serum or urine pregnancy testing may be performed, if determined necessary by the investigator or required by local regulations, to confirm that the participant is not pregnant at any time during the study. q In female participants only, if needed to establish menopausal status. Both the SDMT and the CVLT-II will be performed in all participants. If for some reason the CVLT-II is not available at a given site due to reasons such as lack of translation, local certification, etc., only the SDMT will be assessed for that participant. A subset of sites with 3T MRI capabilities will perform additional sequences (e.g., SWI). Further details will be defined in a separate manual. For MRI performed after D1, a visit window of ±21 days is acceptable. tFor MRI performed after D1, a visit window of ±21 days is acceptable. MRI scans should be performed as close as possible before starting the IMP. Screening MRI scans should be performed as often as possible during the Screening Period, only after it has been established that the participant meets all inclusion criteria and does not meet exclusion criteria. If the results of the pilot assessment confirm feasibility, non-invasive activity monitoring (actimetry) may optionally be implemented by the Sponsor in a subset of participants during the course of the study. An actimetry baseline assessment will be performed at Screening. vWhen available, clinical outcome assessments were to be completed by participants prior to discussion of their health status and prior to administration of study treatment or other study-related procedures. wWhere available according to local regulations. x M6 and M12: two samples: one sample between 30 and 90 minutes after IMP administration and one sample between 2.5 and 5 hours after IMP administration. M9: one sample, 30-90 minutes after IMP administration. yIf permitted according to local regulations, pharmacodynamic and biomarker samples will be collected at irregular intervals. z DNA testing can be done at any time after signing the consent form (on day 1 in case it may not be possible for some reason). Participation is optional. aa will collect and store this sample for use in the event of any unexpected safety issues, to ensure pre-dose baseline values ​​are available for parameters not previously assessed (e.g., serology) and for biomarker studies (if agreed). bb Samples for hematology and biochemistry testing on Day 1 (randomization) will be collected prior to administration of the first IMP dose. ccBlood sample collection for lymphocyte phenotyping by flow cytometry will be performed in a subset of randomized participants. Participants who did not have a baseline sample collected will not have this test again. Participants who did have a baseline sample collected will have a second sample collected at EOT / pEOT. dd samples must be shipped within 24 hours. ee will conduct sub-studies at selected sites.

[0494] The goals and endpoints of treatment are shown in Table 4B. Table 4B - Objectives and End Points Abbreviations: 9-HPT, 9-hole column test; AE, adverse event; BVL, brain volume loss; CDI, confirmed disability improvement; CDP, confirmed disability progression; Chi3L1, chitinase-3-like protein 1; CVLT-II, California Verbal Learning Test-II; ECG, electrocardiogram; EDSS, expanded disability status scale; EOS, end of study; MRI, magnetic resonance imaging; MSQoL-54, multiple sclerosis quality of life-54 questionnaire; NfL, neurofilament light chain; PK, pharmacokinetics; PPMS, primary progressive multiple sclerosis; SDMT, symbol-digit modality test; T25-FW, timed 25-foot walk

[0495] Dosage regimen

[0496] The choice of a 60 mg dose of BTK inhibitor taken with meals was based on the results of a phase 2b dose-finding trial of tolebrutinib in participants with relapsing multiple sclerosis (DRI15928). See, e.g., Reich, DS, et al., Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol, 2021. 20(9): p. 729-p. 738.

[0497] Analysis of PK data and the effect of fed state on tolerabine exposure showed a positive food effect and AUC 0-24In addition, the association between treatment response and tolebrutinib exposure showed that higher exposure was associated with a lower number of new gadolinium-enhancing T1-hyperintense lesions after 12 weeks of treatment. Taken together, these data support the recommendation to take tolebrutinib with food.

[0498] There was no association between the dose of tolebrutinib administered and the number of TEAEs. The most common events (priorities) observed in participants in the tolebrutinib-treated group were headache, upper respiratory tract infection, and nasopharyngitis. Low numbers of AESI and PCSA were observed. Overall, no new risks were identified in this trial.

[0499] Overall design:

[0500] This was a phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel-group, multicenter, event-driven (6-month CDP) trial in participants with PPMS, with a variable treatment duration ranging from approximately 24 to 48 months.

[0501] Disclosure Statement:

[0502] This was a parallel treatment study with 2 groups, which was blinded / masked to the participants, any investigators, site staff, and the sponsor.

[0503] Number of participants:

[0504] Approximately 1320 people will be screened to enable randomization of 990 participants to the study intervention.

[0505] Intervention Groups and Duration:

[0506] Participants will be randomized in a 2:1 ratio to receive 60 mg oral daily SAR442168 or daily matching placebo. Randomization will be stratified by age at screening (>40 years vs. ≤40 years), geographic region (United States [US] vs. non-US), and PPMS McDonald diagnostic criteria (2005 [Polman et al. Ann Neurol. 2005, 58, 840] and 2017 versions vs. 2017 versions [Thompson et al. Lancet Neurol. 2018, 17, 162]).

[0507] Study Interventions:

[0508] Experimental drugs Preparation: SAR442168 film-coated tablets ·Route of administration: Oral Dosage regimen: 60 mg once a day

[0509] Experimental drugs Formulation: Placebo to match SAR442168 film-coated tablets ·Route of administration: Oral Dosage regimen: Once a day

[0510] Non-investigational drugs Preparation: MRI contrast enhancement preparation ·Route of administration: Intravenous (IV) Dosage regimen: According to the corresponding label

[0511] Temporary IMP interruption due to surgery

[0512] If surgery is required during the study, consider the benefits and risks of withholding IMP for at least 3 to 7 days before and after surgery, depending on the type of surgery and the risk of bleeding.

[0513] The goal of this Phase 3 clinical trial is to confirm the efficacy and safety of SAR442168 in participants with PPMS compared to placebo. Six-month CDP was selected as the primary endpoint of this trial. It is widely used in clinical trials and is considered to be more clinically meaningful than 3-month CDP. Confirmed disability improvement (CDI) in at least 6 months measured by EDSS score will also be used as a secondary endpoint due to its clinical importance.

[0514] Magnetic resonance imaging outcomes will include changes in brain volume, which is considered a marker of CNS degenerative processes and is therefore recommended for use in progressive MS trials (EMA Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. London, March 26, 2015. EMA / CHMP / 771815 / 2011, Rev. 2 [cited February 13, 2020]).

[0515] Population pharmacokinetics (PK) will be performed to obtain a larger and more diverse population, to evaluate the PK of SAR442168 in the PPMS population, to assess sources of PK variability (ethnicity, special populations), and to establish the association of exposure with clinical efficacy, biomarkers, and safety endpoints. Analysis of population PK data will be performed once all participants complete the Month 12 visit (a separate unblinding team will be used to preserve blinding integrity).

[0516] In ongoing Phase 3 and LTS studies, tolerinib has been generally well tolerated to date. The identified risks of tolerinib have been identified as follows: - SAEs of treatment-emergent drug-induced liver injury (DILI) were reported in the ongoing Phase 3 trial; however, all cases occurred between Months 2 and 3 and appeared to be reversible after treatment discontinuation, and potential confounding factors were identified for some cases.

[0517] Definition of end of study

[0518] Participants were considered to have completed the study if they had completed all phases of the study, including the EOS visit, regardless of whether they were still undergoing the IMP.

[0519] This study will end when approximately 290 primary endpoint events have been observed at 6-month CDP. With a planned recruitment period of approximately 24 months, the estimated study duration is approximately 48 months.

[0520] Event rates based on blinded data will be monitored regularly to predict event timelines and estimate potential study end dates in a timely manner.

[0521] Study Group

[0522] Inclusion criteria

[0523] Participants were eligible for inclusion in the study only if all of the following criteria as shown in Table 4C applied. Table 4C - Inclusion criteria

[0524] Exclusion criteria

[0525] Participants were excluded from the study if any of the following criteria as shown in Table 4D applied. Table 4D - Exclusion criteria Lifestyle considerations

[0526] Meals and dietary restrictions: Tolebrutinib (IMP) should be taken with regular meals. When possible, meals taken with IMP (e.g., breakfast, lunch, or dinner) should be consistent throughout the study. Typical meals taken with IMP will be recorded at each visit. In the event that meal times for IMP administration need to be changed, a minimum interval of 12 hours should be maintained between 2 doses.

[0527] Caffeine, alcohol, and tobacco:

[0528] For each visit with PK / PD assessments, participants will abstain from caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 2 hours prior to starting treatment until the final PK and / or PD sample is collected later that day.

[0529] For each visit with PK / PD assessments, participants will abstain from alcohol for 24 hours prior to starting treatment until the final PK and / or PD samples are collected later that day.

[0530] Participants should be advised not to consume heavy alcohol, defined as >14 g (1 standard drink) per day in female participants or >28 g (2 standard drinks) per day in male participants, on a regular basis throughout the study.

[0531] Study interventions and concomitant therapies

[0532] A study intervention is defined as any experimental intervention(s), commercially available product(s), placebo, or medical device(s) intended to be administered to study participants according to the study protocol.

[0533] Table 4E - Summary of Study Interventions Administered

[0534] Dose Modifications

[0535] Dose reductions are not foreseen in this study. Interruption or permanent discontinuation of treatment may be necessary if deemed necessary due to AEs.

[0536] Concomitant therapy

[0537] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) that the participant is taking at the time of enrollment or receives during the study must be recorded along with the following: Reason for use. Dates of application, including start and end dates. Dosage information, including dose and frequency.

[0538] Live (attenuated) vaccines should not be administered during the intervention period. No therapy for MS recorded in Exclusion Criteria E 06 is allowed while participants continue study treatment after randomization. Short-term use (3 to 5 days) of glucocorticoids (e.g., for treatment of MS relapses or acute disease) and topical corticosteroids (e.g., topical, nasal, ocular, otic, intra-articular) is allowed.

[0539] The Medical Monitor should be contacted if any questions arise regarding concomitant or prior therapy.

[0540] Participants must abstain from prescription or over-the-counter medications (including vitamins and dietary or herbal supplements) for 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the start of the study intervention until completion of the follow-up visit unless the investigator and sponsor determine that the medication will not interfere with the study. If clinically feasible, medications used for MS treatment of MS symptoms (e.g., impaired walking, fatigue, spasticity, incontinence, pain) should be maintained at a stable dose prior to screening and for the duration of the treatment period.

[0541] Anticoagulant / antiplatelet therapy is not permitted concomitantly with IMP, including: Acetylsalicylic acid (aspirin) > 81 mg / day. Antiplatelet drugs (eg, clopidogrel). Warfarin (vitamin K antagonist). Heparin, including low molecular weight heparin (antithrombin agent). Dabigatran (a direct thrombin inhibitor). Apixaban, edoxaban, and rivaroxaban (direct factor Xa inhibitors).

[0542] Paracetamol / acetaminophen at a dose of ≤ 3 g / day was allowed at any time during the study. A short course (most often 5 days) of the lowest effective dose of a nonsteroidal anti-inflammatory drug (NSAID) (other than acetylsalicylic acid), preferably a selective cyclooxygenase-2 inhibitor, may be given during the study if clinically indicated for treatment of an existing medical condition or a new event. The investigator must record the use of NSAIDs (and any other concomitant medications) in the eCRF.

[0543] CYP inhibitors / inducers:

[0544] Strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 liver enzymes were not permitted throughout the study (Appendix 8 [Section 10.8]). Based on nonclinical drug metabolism studies, SAR442168 is a substrate for both CYP3A4 and CYP2C8 isoenzymes. In healthy participants, a strong CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased SAR442168 area under the curve (AUC) exposure by 1.8-fold (INT16385 study), and a strong CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased SAR442168 AUC exposure by 8.4-fold (INT16726 study). Based on satisfactory safety and tolerability profiles and based on the exposure observed in healthy participants who received SAR442168 once a day for 14 days at a dose of up to 240mg SAR442168 under fed conditions (TDR16862 study), drugs that strongly inhibit CYP3A4 are allowed and drugs that strongly inhibit CYP2C8 are not allowed. In healthy participants, strong CYP3A4 and moderate CYP2C8 induction by rifampicin (600mg, once a day for 8 days) reduced SAR442168 exposure by 6 times (INT16726 study). Therefore, strong and moderate (based on prediction) CYP3A inducers are not allowed due to their potential to reduce SAR442168 exposure and efficacy. The list of drugs to be avoided is shown in Appendix 8 (section 10.8).

[0545] If any questions exist regarding concomitant or prior therapy, the sponsor should be contacted.

[0546] Rescue Medicine

[0547] If participants achieve the primary endpoint (6-month CDP), they can choose, in cooperation with the treating investigator, to receive one of the following: 1. Switch to open-label SAR442168 treatment; or 2. Switch to a non-study treatment approved for PPMS in their respective country. In this case, the participant will permanently discontinue the IMP and will be encouraged to remain on the study for planned clinic visits until the end of the co-study.

[0548] In the event that a participant switches to open-label SAR442168 treatment, their liver function tests will need to be monitored at Weeks 2, 4, 5, 6, 7, 8, 9, 10, 11, and 12 after the first open-label dose, and then monthly for the next 9 months. Thereafter, scheduled visit time points according to the SoA (Tables 4A1 and 4A2) will be resumed (i.e., every 3 months) until the end of the co-study. Whenever a time point will coincide with a scheduled visit according to the SoA (Section 1.3), a full scheduled visit assessment will be performed in lieu of separate liver monitoring tests.

[0549] Participants and investigators will remain blinded to original treatment assignment if they choose to provide rescue medicine.

[0550] If possible, all individual blinded data will be reviewed and all inquiries will be addressed prior to switching to the selected rescue method to ensure data integrity for the primary assessment. Prior to initiating rescue therapy, the investigator should confirm that there were no adjudicated relapses within 90 days prior to the onset or confirmation of a 6-month CDP. Based on individual symptoms and the assessed risk of further progression, the investigator and participant may choose to keep the participant on initial double-blind treatment after achieving a 6-month CDP.

[0551] Discontinuation of study intervention and participant discontinuation / withdrawal

[0552] Discontinuation of study intervention

[0553] Explicit termination

[0554] The study intervention should be continued whenever possible.

[0555] Permanent intervention suspension is any treatment suspension associated with a clear decision made by the investigator or participant not to expose the participant to the study intervention again at any time. In rare cases, participants may need to permanently suspend the study intervention. If the study intervention is permanently suspended, the participant should be required to remain in the study for evaluation until the follow-up / EOS visit. For this participant set (participants who discontinue IMP and / or switch to another DMT), PK or biomarker samples will not be collected after the pEOT visit, and MRI assessments will be performed once a year, using the next annual visit as a starting point. This will be important for continuing to evaluate safety and efficacy. See SoA (Table 4A1 and Table 4A2) for data collected when the study intervention is suspended. In the case of permanent suspension of the study intervention, the MS of the participant should be treated according to the best judgment of local clinical practice and the treating investigator.

[0556] The following may be valid reasons for the investigator or sponsor to discontinue treatment of a participant: Adverse events that compromise the safety of the participant, or if discontinuation of the study intervention is desired or deemed necessary by the investigator and / or participant. If IMP discontinuation criteria are met according to the laboratory abnormality follow-up guidelines (Table 4F). In the investigator's opinion, the participant is no longer receiving therapeutic / clinical benefit. If the female participant becomes pregnant or wishes to become pregnant during the study. · Upon the participant's request, i.e., withdrawal of consent for treatment. Any serious opportunistic infection (eg, PML [see Figure 6 ], HIV) · Continued need / chronic use of prohibited concomitant medications (see Table 4I). Use of open-label SAR442168 or non-investigational disease-modifying therapy approved for PPMS in their respective country (e.g., after 6 months CDP). A brief physical examination will include, at a minimum, assessment of the skin, lungs, cardiovascular system, neurological examination, and abdomen (liver and spleen). Investigators should pay special attention to clinical signs associated with pre-existing serious illness. Any clinically significant new finding or worsening of a previously found finding should be reported as an AE at the investigator's discretion.

[0557] Investigators should consider discontinuing study interventions for abnormal liver function if a participant meets one of the criteria outlined in the algorithm (Table 4B) or if the investigator believes it is in the best interest of the participant.

[0558] Clinical laboratory tests

[0559] When feasible, the tests detailed in Table 4F will be performed by the central laboratory. Local laboratory results are required only in the event that the central laboratory results are not available in time for study intervention administration and / or response evaluation. In addition, if local laboratory results are used to make study intervention decisions or response evaluations, the results must be entered in the eCRF.

[0560] Protocol-specific requirements for inclusion or exclusion of participants are detailed in Tables 4C and 4D of the protocol.

[0561] Additional testing may be performed at any time during the study if determined necessary by the investigator or required by local regulations. Additional serum or urine pregnancy testing may be performed to confirm that the subject is not pregnant at any time during her participation in the study if determined necessary by the investigator or required by local regulations. Table 4F - Laboratory Assessments Required by the Protocol ALT: alanine aminotransferase; anti-HBc: antibody against hepatitis B core antigen; anti-HBs: hepatitis B surface antibody; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BUN: blood urea nitrogen; β-hCG: human chorionic gonadotropin; FSH: follicle-stimulating hormone; IEC: independent ethics committee; INR: international normalized ratio; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; IRB: institutional review board; MCH: mean corpuscular hemoglobin; MCV: mean corpuscular volume; PT: prothrombin time; RBC: red blood cell; SGOT: serum aspartate aminotransferase; SGPT: serum alanine aminotransferase; TB: tuberculosis; TIBC: total iron-binding capacity; ULN: upper limit of normal; WBC: white blood cell. a Details of liver chemistry stopping criteria and required activities and follow-up assessments after ALT > 3×ULN is observed are in Figure 2-Figure 8 Clinical laboratory findings that may suggest severe liver injury, such as ALT > 3 × ULN and bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT > 3 × ULN and international normalized ratio (INR) > 1.5 (if INR is measured), must be reported as a SAE. bLocal urine testing for pregnancy will be standard of care (except for the Screening Visit when a serum pregnancy test is required) unless serum testing is required by local regulations or the IRB / IEC. c Further details are provided in E 01, Table 4D.

[0562] The investigator must document his or her review of each laboratory safety report.

[0563] Laboratory / analyte results that could unblind the study will not be reported to the study site or other blinded personnel until the study has been unblinded. This includes PK assessments and any post-baseline biomarker or PD assessments. Hepatic and other safety: activity and follow-up assessments

[0564] Table 4G and Figure 2-Figure 8 These activities described in the study were only required for the events of ALT increase and thrombocytopenia. For all other safety events described, these activities were recommended based on the medical judgment of the investigator.

[0565] Neutropenia should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0566] Thrombocytopenia should be recorded as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0567] Figure 3 Abbreviations in the literature: aPTT: activated partial thromboplastin time; EDTA: ethylenediaminetetraacetic acid; INR: international normalized ratio; PK: pharmacokinetics; PT: prothrombin time.

[0568] NOTE: "Baseline" refers to the ALT sampled at the Baseline Visit; or if a baseline value is not available, the most recent ALT sampled at the Baseline Visit. The algorithm is not applicable in the event of an increase in ALT during the Screening period. Table 4G Activities to Confirm Elevated ALT

[0569] Increased serum creatinine should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting Adverse Events in Appendix 3 (Section 10.3) is met.

[0570] CPK should be reported as an AE only if at least 1 of the criteria in the General Guidance for Reporting Adverse Events in Appendix 3 (Section 10.3) is met.

[0571] Figure 5 Abbreviations: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, pharmacokinetics.

[0572] Increased serum creatinine should be reported as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0573] Figure 8 Abbreviations: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0574] CPK should be reported as an AE only if at least 1 of the criteria in the General Guidance for Reporting AEs in Appendix 3 (Section 10.3) is met.

[0575] Suspected PML: Recommended if the participant has clinical presentation or MRI features suggestive of PML Figure 6 The diagnostic and activity algorithms described in .

[0576] Figure 6Abbreviations: CSF, cerebrospinal fluid; Gd, gadolinium; IMP, investigational medicinal product; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy

[0577] Clinical manifestations or MRI lesion features suspected of PML are presented in Table 3H (based on Berger et al. Neurology 2013, 80, 1430-1438 and Kappos et al. Lancet Neurol. 2007, 6, 431-441).

[0578] In the event that PML is suspected based on imaging results, the local radiologist will inform the investigator directly, and a central review of the MRI will not be required. The investigator will obtain additional plasma, urine, and CSF samples for John Cunningham virus (JCV) analysis. The samples will be analyzed upon receipt, and the results will be provided directly to the study site and the sponsor. Other management will be at the discretion of the treating investigator. However, the next steps will include discontinuation of study treatment. Additional imaging will be performed at the discretion of the investigator, depending on the diagnostic workup and treatment plan. • The diagnosis of PML is established by detection of John Cunningham virus (JCV) DNA in the cerebrospinal fluid of patients with clinical and MRI features suggestive of PML. ●If JCV DNA is not detected in the CSF and if the clinical suspicion for PML remains high, another lumbar puncture should be performed. If the diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may be considered to establish a definitive diagnosis. Table 4H - Clinical and MRI features suggestive of PML

[0579] Clinical or MRI features suggestive of PML should be recorded as AEs / AESIs / SAEs according to the definitions and procedures in Appendix 3 (Section 10.3). Examples of Drugs with the Potential to Alter the Metabolism or Absorption of SAR442168

[0580] The following drugs have the potential to alter the kinetics of SAR442168 due to their interactions with P450-mediated metabolism, being strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes (listed according to the University of Washington Drug Interaction Database program [www.druginteractioninfo.org]) and should be discontinued concomitantly with IMP during the study.

[0581] Please note that the list provided is not complete and the product information for drugs intended for concomitant use should be consulted. Table 4I - CYP3A inducers and CYP2C8 inhibitors abbreviation 9-HPT: 9-hole column test ADL: Activities of Daily Living AE: Adverse event AESI: Adverse events of special interest ALT: Alanine aminotransferase aPTT: activated partial thromboplastin time ARR: Annualized relapse rate BTK: Bruton's tyrosine kinase BVL: Brain Volume Loss CD: Cluster of differentiation CDI: Confirmed Disability Improvement CDP: Confirmation of Disability Progression CFR: Code of Federal Regulations Chi3L1: Chitinase-3-like protein 1 CNS: Central nervous system CPK: Creatinine phosphokinase CRF: Case Report Form CSF: cerebrospinal fluid CSR: Clinical Research Report C-SSRS: Columbia-Suicide Severity Rating Scale CVLT-II: California Verbal Learning Test-II CYP: Cytochrome P450 DILI: Drug-induced liver injury DMC: Data Monitoring Committee DMT: disease modifying therapy DNA: deoxyribonucleic acid DNAM-1: DNAX accessory molecule 1 DTP: Direct to Patient ECG: electrocardiogram, electrocardiography eCRF: Electronic Case Report Form EDSS: Implementation of the Expanded Disability Status Scale number eGFR: estimated glomerular filtration rate EOS: Research completed EOT: End of Treatment EQ-5D-5L: EuroQol 5-dimension 5-level questionnaire FSH: Follicle stimulating hormone GCIPL: Ganglion cell-inner plexiform layer GCP: Good Clinical Practice Guidelines Gd: Gadolinium GM-CSF: Granulocyte-macrophage colony-stimulating factor GrA: human granzyme A GrB: human granzyme B GrK: human granzyme K GrM: human granzyme M HIV: Human Immunodeficiency Virus HR: Hazard ratio HRT: Hormone Replacement Therapy IB: Investigator's Handbook ICF: Informed Consent ICH: International Council for Harmonization IEC: Independent Ethics Committee IFNγ: interferon gamma Ig: immunoglobulin IL: interleukin IMP: Investigational Medicinal Product INR: International Normalized Ratio IRB: Institutional Review Board IRT: Interactive Response Technology ITT: intention to treat IUD: intrauterine device IUS: intrauterine hormone-releasing system IV: Intravenous IWRS: Interactive Web Response System JCV: John Cunningham Virus KM: Kaplan-Meier LLN: Lower limit of normal MCAM: Melanoma cell adhesion molecule MedDRA: Medical Dictionary for Regulatory Activities MMRM: Repeated measures mixed effects model MRI: Magnetic resonance imaging MS: Multiple Sclerosis MSFC-3: Multiple Sclerosis Functional Composite-3 MSQoL-54: Multiple Sclerosis Quality of Life-54 Questionnaire MTR: Magnetic Transfer Rate NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NEDA: No Evidence of Disease Activity-3 NfL: neurofilament light chain NIMP: Non-Investigational Medicinal Product NSAID: Nonsteroidal anti-inflammatory drug NYHA: New York Heart Association PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive multifocal leukoencephalopathy PPMS: Primary progressive multiple sclerosis pRNFL: peripapillary retinal nerve fiber layer pTreg: peripheral regulatory T cells QTcF: QT interval corrected using Fridericia's formula RMS: Relapsing multiple sclerosis RTE: New thymic emigrant cells SAE: Serious Adverse Event SAP: Statistical Analysis Program SDMT: Symbolic Digital Modal Testing SEL: Slowly evolving lesions SoA: Schedule of Activities SPMS: Secondary progressive multiple sclerosis SUSAR: Suspected unexpected serious adverse reaction SWI: Susceptibility Weighted Imaging T25-FW: Timed 25-Foot Walk TB: Tuberculosis TEAE: Treatment-emergent adverse event Tfh: T follicular helper cell Th 17: T helper 17 cells Th 17: T auxiliary 17 Th1: T helper 1 cells, T helper 1 Th2: T helper 2 cells Th2: T auxiliary 2 TIGIT: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain TNFα: Tumor necrosis factor alpha Treg: Regulatory T cells tTreg: thymus-derived Foxp3(+) regulatory T cells ULN: Upper limit of normal US:United States WOCBP: Women of childbearing potential

[0582] Embodiment No. 1: A method for treating MS in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels, and when the patient is found not to have elevated transferrin levels or elevated ferritin levels, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0583] Embodiment No. 2: A method for treating MG in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels, and when the patient is found not to have elevated transferrin levels or elevated ferritin levels, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0584] Embodiment No. 3: A method for treating MS in a patient in need thereof, the method comprising determining the iron status of the patient and, when the patient is found to have suitable iron status, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0585] Embodiment No. 4: A method for treating MG in a patient in need thereof, the method comprising determining the iron status of the ...

Claims

1. A method of treating MS in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels, and when the patient is found not to have elevated transferrin levels or elevated ferritin levels, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

2. A method of treating MG in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels, and if the patient is found not to have elevated transferrin levels or elevated ferritin levels, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

3. A method of treating MS in a patient in need thereof, the method comprising determining the patient's iron status and, upon finding that the patient has suitable iron status, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

4. A method of treating MG in a patient in need thereof, the method comprising determining the patient's iron status and, upon finding that the patient has suitable iron status, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

5. A method for treating MS, the method comprising administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient in need thereof, wherein the patient does not have elevated transferrin levels or elevated ferritin levels.

6. A method of treating MG, the method comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient does not have elevated transferrin or elevated ferritin levels.

7. A method for treating MS, the method comprising administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a patient in need thereof, wherein the patient has appropriate iron levels.

8. A method of treating MG, the method comprising administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient has suitable iron status.

9. A method for treating MS, comprising the following steps: (a) testing the patient's blood or serum for iron status; (b) detecting a level of said iron status test within a normal range; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the iron status test measures any one or more of the iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum, and wherein the normal range of the iron status test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of ≤500 μg / L, (iii) a transferrin saturation level of ≤50% in male patients or ≤40% in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

10. A method for treating MS, comprising the following steps: (a) detecting a transferrin saturation level in the patient's blood or serum within a normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, Wherein the transferrin saturation level in the blood or serum of a male patient within a normal range is ≤50% of transferrin saturation, and the transferrin saturation level in the blood or serum of a female patient within a normal range is ≤40% of transferrin saturation.

11. A method for treating MS, the method comprising the following steps: (a) detecting a ferritin level in the patient's blood or serum within a normal range; as well as (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, The ferritin level in the patient's blood or serum is within the normal range and is ≤500 μg / L.

12. A method for treating MS, comprising the following steps: (a) Perform liver function tests in patients; (b) detecting adequate liver function in said patient; as well as (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the liver function test measures one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein, and Patients with adequate liver function had one or more of the following: ALT ≤ 1.5 x upper limit of normal (ULN), AST level ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

13. A method for treating MS, comprising the following steps: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >8x upper limit of normal (ULN) were detected; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; as well as (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

14. A method for treating MS, the method comprising the following steps: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >5x upper limit of normal (ULN) detected during a period of at least two weeks; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; as well as (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

15. A method for treating MS, comprising the following steps: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; (e) one or more of total bilirubin >2x ULN and INR >1.5 was detected; (f) ceasing administration of the compound to the patient; and optionally (g) monitoring ALT levels in said patient; and (h) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

16. A method for treating MS, the method comprising the following steps: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) stopping administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally (e) monitoring ALT levels in said patient; as well as (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

17. The method according to any one of claims 13 to 16, wherein the ALT level in step (b) is determined at least monthly.

18. The method according to any one of claims 13 to 16, wherein the ALT level in step (d) is monitored at least weekly.

19. The method according to any one of claims 13 to 16, wherein the ALT level in step (d) is monitored every 2 to 3 days.

20. A method of treating MS in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not currently receiving a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 liver enzyme.

21. A method of treating MS in a patient in need thereof, the method comprising the steps of: (a) advising the patient to limit alcohol consumption during treatment; as well as (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is female and is advised to limit alcohol consumption to 14 grams per day or less, or the patient is male and is advised to limit alcohol consumption to 28 grams per day or less.

22. The method according to any one of claims 9 to 21, wherein the MS is selected from RMS, NRSPMS and PPMS.

23. A method for treating MG, the method comprising the steps of: (a) testing the patient's blood or serum for iron status; (b) detecting a level of said iron status test within a normal range; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the iron status test measures any one or more of the iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum, and wherein the normal range of the iron status test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of ≤500 μg / L, (iii) a transferrin saturation level of ≤50% in male patients or ≤40% in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

24. A method for treating MG, the method comprising the steps of: (a) detecting a transferrin saturation level in the patient's blood or serum within a normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, Wherein the transferrin saturation level in the blood or serum of a male patient within a normal range is ≤50% of transferrin saturation, and the transferrin saturation level in the blood or serum of a female patient within a normal range is ≤40% of transferrin saturation.

25. A method for treating MG, the method comprising the steps of: (a) detecting a ferritin level in the patient's blood or serum within a normal range; as well as (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, The ferritin level in the patient's blood or serum is within the normal range and is ≤500 μg / L.

26. A method for treating MG, the method comprising the steps of: (a) Perform liver function tests in patients; (b) detecting adequate liver function in said patient; as well as (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the liver function test measures one or more of the following levels in the patient's blood: aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein, and Patients with adequate liver function had one or more of the following: ALT ≤ 1.5 x upper limit of normal (ULN), AST level ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (unless caused by a non-liver related disorder or explained by a stable chronic liver disorder), and total bilirubin ≤ 1.5 x ULN (unless due to Gilbert's syndrome or a non-liver related disorder).

27. A method for treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >8x upper limit of normal (ULN) were detected; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; as well as (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

28. A method for treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >5x upper limit of normal (ULN) detected during a period of at least two weeks; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring ALT levels in said patient; as well as (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

29. A method for treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; (e) one or more of total bilirubin >2x ULN and INR >1.5 was detected; (f) ceasing administration of the compound to the patient; and optionally (g) monitoring ALT levels in said patient; and (h) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

30. A method for treating MG, the method comprising the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring alanine aminotransferase (ALT) levels in the patient; (c) ALT levels >3x upper limit of normal (ULN) were detected; (d) stopping administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally (e) monitoring ALT levels in said patient; as well as (f) upon determining that the patient's ALT level is <1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

31. The method according to any one of claims 27 to 30, wherein the ALT level in step (b) is determined at least monthly.

32. The method of any one of claims 27 to 30, wherein the ALT level in step (d) is monitored at least weekly.

33. The method according to any one of claims 27 to 30, wherein the ALT level in step (d) is monitored every 2 to 3 days.

34. A method of treating MG in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not currently receiving a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 liver enzyme.

35. A method of treating MG in a patient in need thereof, the method comprising the steps of: (a) advising the patient to limit alcohol consumption during treatment; as well as (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is female and is advised to limit alcohol consumption to 14 grams per day or less, or the patient is male and is advised to limit alcohol consumption to 28 grams per day or less.

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