Tyrosine kinase inhibitors for the treatment of 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 treating patients with MG or MS.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 357,465, filed Jun. 30, 2022, and U.S. Provisional Patent Application No. 63 / 433,866, filed Dec. 20, 2022, which are hereby incorporated by reference in their entireties for all purposes.

[0002] The present disclosure relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase (「BTK」) inhibitors, for treating multiple sclerosis (MS) and myasthenia gravis (MG).

Background Art

[0003] Multiple sclerosis (MS) is a neurological disease affecting over one million people worldwide. It is the most common cause of neurological disability in young and middle - aged adults, having a significant physical, psychological, social, and economic impact on the affected individuals 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 progression of the disease, sclerosis, i.e., lesions or scars, appear on the myelin sheaths of nerve cells, preventing the transmission of electrical signals. The sclerosis accumulates over time, leading to the debilitating symptoms experienced by MS patients.

[0004] Patients with MS generally experience one of four clinical courses of the disease: clinically isolated syndrome, relapsing-remitting, secondary progressive (non-relapsing secondary progressive multiple sclerosis (NRSPMS)), and primary progressive (PPMS), each of which can be mild, moderate, or severe. Approximately 85% of patients with MS have the relapsing-remitting form of the disease and experience distinct relapses (also called flare-ups or exacerbations), which are episodes of acute worsening of neurological function, followed by periods of partial or complete recovery (remission) without disease progression. Within the scope of the present disclosure, "relapsing multiple sclerosis", "relapsing MS" or "RMS" can 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; the 2013 revisions, Neurology 2014; 83:278-286.

[0005] Immunomodulatory drugs are the mainstay of MS therapy. Recent results from clinical trials have demonstrated the efficacy of agents that target B lymphocytes, particularly B cell depleting agents such as ocrelizumab (anti-CD20) (Hauser et al., N Engl J Med. 2017; 376(3):221-34).

[0006] Targeting B cells has demonstrated therapeutic benefit by modulating T cell activity and represents a departure from the general doctrine based on animal models that positions B cells at 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 present in the CNS is also well known and needs to be considered in the etiology of MS (Hemmer B et al, Nat Clin Pract Neurol. 2006; 2(4):201-11).

[0007] MG is a chronic autoimmune neuromuscular disease that causes skeletal muscle weakness that worsens after periods of activity and improves after periods of rest. These muscles are responsible for functions involving breathing and the movable parts of the body, including the arms and legs. The hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after periods of rest. Certain muscles, such as those that control eye and eyelid movement, facial expression, chewing, speaking, and swallowing, are often (but not always) involved in the disorder. The onset of the disorder can be sudden, and the symptoms are often not immediately recognized as myasthenia gravis. The degree of muscle weakness involved in myasthenia gravis varies widely among individuals. People with myasthenia gravis may experience the following symptoms: weakness of the eye muscles (called ophthalmoparesis), drooping of one or both eyelids (ptosis), blurred or double vision (diplopia), changes in facial expression, difficulty swallowing, shortness of breath, speech impairment (dysarthria), weakness in the arms, hands, fingers, legs, and neck.

[0008] 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 an error in the transmission of nerve impulses to the muscles. This occurs when normal communication between the nerve and the muscle is interrupted at the neuromuscular junction (the place where the nerve cell connects to the muscle it controls). Neurotransmitters are chemicals that nerve cells, or brain cells, use to transmit information. Normally, when an electrical signal or impulse travels down a motor nerve, the nerve terminal releases a neurotransmitter called acetylcholine that binds to a site on the muscle called the acetylcholine receptor. The binding of acetylcholine to its receptor activates the muscle and causes muscle contraction. In myasthenia gravis, antibodies block, modify, or destroy the acetylcholine receptors at the neuromuscular junction, preventing muscle contraction. This is most frequently caused by antibodies against the acetylcholine receptor itself, but antibodies against other proteins, such as the MuSK (muscle-specific kinase) protein, can also impair transmission at the neuromuscular junction.

[0009] Tolebrutinib is a BTK inhibitor that has been studied for both MG and MS. The Bruton's tyrosine kinase pathway is important for signal transduction in myeloid cells, including B lymphocytes and CNS microglia. Each of these cell types is involved in the pathophysiology of multiple sclerosis. Furthermore, since BTK signaling is essential for the maturation of B cells into antibody-secreting plasma cells, BTK inhibition can modulate both cellular and humoral immunity.

[0010] Therefore, inhibitors of BTK signaling represent a dual mechanism that targets both aspects of the immune system.

[0011] Therefore, compounds that inhibit BTK, which can inhibit antigen-induced B cell activation involved in neuroinflammation and regulate maladaptive microglial cells associated with neuroinflammation in the brain and spinal cord, may be useful for the treatment of MS and MG and have superior advantages compared to currently available treatments.

Summary of the Invention

Problems to be Solved by the Invention

[0012] Drug-induced liver injury has been identified in the ongoing tolebrutinib Phase 3 trial. The reported events occurred between 2 and 3 months after the start of tolebrutinib administration, and the increase in liver enzymes appears to be reversible after tolebrutinib discontinuation. Therefore, it is necessary to reduce the risk of liver injury and provide a safe treatment for MS or MG patients.

Means for Solving the Problems

[0013] The present disclosure relates to a method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or ferritin levels, and administering to the patient a therapeutically effective amount of Bruton's tyrosine kinase (BTK) comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one if the patient is found not to have elevated transferrin levels or ferritin levels.

[0014] The present disclosure relates to a method of treating MS, 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 levels or ferritin levels.

[0015] The present disclosure relates to a method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or ferritin levels, and administering to the patient a therapeutically effective amount of Bruton's tyrosine kinase (BTK) comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one if the patient is found not to have elevated transferrin levels or ferritin levels.

[0016] The present disclosure relates to 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 levels or ferritin levels.

[0017] The present disclosure relates to a method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining the patient's iron panel and administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (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 iron panel.

[0018] The present disclosure relates to a method of treating multiple sclerosis (MS), the method comprising administering to a patient in need thereof a therapeutically effective amount of a Bruton's tyrosine kinase (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 an appropriate iron panel.

[0019] The present disclosure relates to a method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining the patient's iron panel and administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (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 iron panel.

[0020] The present disclosure relates to a method of treating myasthenia gravis (MG), the method comprising administering to a patient in need thereof a therapeutically effective amount of a Bruton's tyrosine kinase (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 an appropriate iron panel.

[0021] The present disclosure relates to a method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining the patient's alcohol consumption and, if the patient is found to have appropriate alcohol consumption, administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0022] The present disclosure relates to a method of treating myasthenia gravis (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 an appropriate alcohol level.

[0023] The present disclosure relates to a method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining the patient's alcohol consumption and, if the patient is found to have 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.

[0024] The present disclosure relates to a method of treating myasthenia gravis (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 an appropriate alcohol consumption.

[0025] The present disclosure relates to a method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one when it is determined that 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 a method of treating multiple sclerosis (MS), the method comprising administering to a patient in need thereof a therapeutically effective amount of a Bruton's tyrosine kinase (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.

[0027] The present disclosure relates to a method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one when it is determined that the patient does not have an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system.

[0028] The present disclosure relates to a method of treating myasthenia gravis (MG), the method comprising administering to a patient in need thereof a therapeutically effective amount of a Bruton's tyrosine kinase (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.

[0029] The present disclosure relates to a method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining whether the patient has elevated alanine transaminase (ALT) enzyme, and administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0030] The present disclosure relates to a method of treating MS, 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 ALT enzyme.

[0031] The present disclosure relates to a method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining whether the patient has elevated ALT enzyme, and, if it is determined that the patient does not 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.

[0032] The present disclosure relates to 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 ALT enzyme.

[0033] In some embodiments, a dose of the BTK inhibitor from about 5 mg to about 60 mg is administered.

[0034] In some embodiments, the dose is 5 mg.

[0035] In some embodiments, the dosage is 15 mg.

[0036] In some embodiments, the dosage is 30 mg.

[0037] In some embodiments, the dosage is 60 mg.

[0038] In some embodiments, the dosage is once a day.

[0039] In some embodiments, the dosage is administered once a day with food.

[0040] In some embodiments, the dosage is 60 mg and is administered once a day with food.

[0041] In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0042] In some embodiments, the subject or patient is human.

[0043] In some embodiments, the subject or patient is a human subject or patient in the range of 12 to 55 years old.

[0044] 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.

[0045] The present disclosure also relates to a method of treating MS, comprising: (a) performing an iron panel test on the patient's blood or serum; (b) detecting levels of the iron panel test within the normal range; administering to a patient a therapeutically effective amount of a BTK inhibitor comprising (c)(R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; comprising wherein an iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum, and the normal range of the iron panel test comprises one or more of (i) an iron level of 60-170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240-450 μg / dL; relating to a method.

[0046] The present disclosure also relates to a method of treating MS, comprising: (a) detecting a transferrin saturation level in the patient's blood or serum within the normal range; (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; comprising wherein the normal range of the transferrin saturation level in the blood or serum of male patients is a transferrin saturation of 50% or less, and the normal range of the transferrin saturation level in the blood or serum of female patients is a transferrin saturation of 40% or less; relating to a method.

[0047] The present disclosure also relates to a method of treating MS, comprising: (a) detecting a level of ferritin in the patient's blood or serum within the normal range; (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; comprising a ferritin level within the normal range in the blood or serum of a patient being 500 μg / L or less, relating to a method.

[0048] The present disclosure also relates to a method of treating MS, (a) performing a liver function test in a patient; (b) detecting appropriate liver function in the patient; (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; comprising The liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the blood of the patient, and a patient having appropriate liver function has one or more of an ALT of 1.5x or less of the upper limit of normal (ULN), an AST of 1.5x or less of the ULN, an alkaline phosphatase of 2x or less of the ULN (except when caused by non-liver-related disorders or as explained by stable chronic liver disorders), and a total bilirubin of 1.5x or less of the ULN (except when due to Gilbert's syndrome or non-liver-related disorders), relating to a method.

[0049] The present disclosure also relates to a method of treating MS, (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 8x the upper limit of normal (ULN); (d) discontinuing administration of the compound to the patient, and optionally (e) Monitoring the ALT level of the patient; (f) When it is determined that the ALT level of the patient is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; relates to a method comprising the steps of.

[0050] The present disclosure also relates to a method for treating MS, (a) 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 (compound); (b) Measuring the level of alanine aminotransferase (ALT) in the patient; (c) Detecting an ALT level greater than 5x the upper limit of normal (ULN) during a period of at least two weeks; (d) Discontinuing the administration of the compound to the patient and optionally, (e) Monitoring the ALT level of the patient; (f) When it is determined that the ALT level of the patient is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; relates to a method comprising the steps of.

[0051] The present disclosure also relates to a method for treating MS, (a) 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 (compound); (b) Measuring the level of alanine aminotransferase (ALT) in the patient; (c) Detecting an ALT level greater than 3x the upper limit of normal (ULN); (d) Measuring one or more of the patient's total bilirubin and international normalized ratio (INR); (e) Detecting one or more of total bilirubin more than 2x the ULN and INR more than 1.5 in the patient, and (f) Discontinuing the administration of the compound to the patient, and optionally, (g) Monitoring the ALT level of the patient, and (h) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x the ULN, and relates to a method comprising.

[0052] The present disclosure also relates to a method of treating MS, comprising: (a) 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 (compound); (b) Measuring the level of alanine aminotransferase (ALT) in the patient; (c) Detecting an ALT level greater than 3x the upper limit of normal (ULN); (d) Discontinuing the 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 greater than 5%, and optionally, (e) Monitoring the ALT level of the patient; (f) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x the ULN; relates to a method comprising.

[0053] In some embodiments, the ALT level in step (b) is determined at least monthly.

[0054] In some embodiments, the ALT level in step (d) is monitored at least weekly.

[0055] In some embodiments, the ALT level in step (d) is monitored every 2-3 days.

[0056] The present disclosure also relates to a method of treating multiple sclerosis (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 has not been exposed to a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 liver enzyme.

[0057] The present disclosure also relates to a method of treating MS in a patient in need thereof, the method comprising: (a) advising the patient to limit alcohol consumption during treatment; (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 intake to 14 grams per day or less, or the patient is male and is advised to limit alcohol intake to 28 grams per day or less. The present disclosure also relates to a method of treating myasthenia gravis (MG), the method comprising:

[0058] (a) performing an iron panel test on the patient's blood or serum; (b) detecting levels of the iron panel test within the normal range; (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 method comprises The iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in a patient's blood or serum, and the normal range of the iron panel test includes one or more of (i) an iron level of 60-170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240-450 μg / dL. Relates to a method.

[0059] The present disclosure also relates to a method of treating MG, comprising: (a) detecting the transferrin saturation level in a patient's blood or serum within the 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 within the normal range in a male patient's blood or serum is 50% or less transferrin saturation, and the transferrin saturation level within the normal range in a female patient's blood or serum is 40% or less transferrin saturation. Relates to a method.

[0060] The present disclosure also relates to a method of treating MG, comprising: (a) detecting the level of ferritin in a patient's blood or serum within the 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 ferritin level within the normal range in the patient's blood or serum is 500 μg / L or less. Relates to a method.

[0061] The present disclosure also relates to a method for treating MG, comprising: (a) performing a liver function test in a patient; (b) detecting appropriate liver function in the patient; (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; comprising: The liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood, and a patient having appropriate liver function has one or more of ALT at 1.5x or less of the upper limit of normal (ULN), AST at 1.5x or less of the ULN, alkaline phosphatase at 2x or less of the ULN (except when caused by non-liver related disorders or when explained by stable chronic liver disorders), and total bilirubin at 1.5x or less of the ULN (except when due to Gilbert's syndrome or non-liver related disorders).

[0062] The present disclosure also relates to a method for treating MG, comprising: (a) 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 (the compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 8x the upper limit of normal (ULN); (d) discontinuing administration of the compound to the patient and optionally, (e) monitoring the ALT level of the patient; (f) restarting administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN. Relates to a method comprising.

[0063] The present disclosure also relates to a method of treating MG, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting, during a period of at least two weeks, an ALT level greater than 5x the upper limit of normal (ULN); (d) discontinuing administration of the compound to the patient; and optionally, (e) monitoring the ALT level of the patient; (f) restarting administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x the ULN. Relates to a method comprising.

[0064] The present disclosure also relates to a method of treating MG, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting an ALT level greater than 3x the ULN; (d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; (e) detecting one or more of total bilirubin greater than 2x the ULN and INR greater than 1.5; (f) discontinuing administration of the compound to the patient; and optionally, (g) monitoring the ALT level of the patient; (h) If it is determined that the patient's ALT level is less than 1.5x the ULN, a step of restarting the administration of a therapeutically effective amount of the compound to the patient; relates to a method comprising.

[0065] The present disclosure also relates to a method of treating MG, (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting an ALT level above 3x the upper limit of normal (ULN); (d) if the patient experiences one or more of fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash, and eosinophilia greater than 5%, stopping the administration of the compound to the patient; and optionally, (e) monitoring the patient's ALT level; (f) if it is determined that the patient's ALT level is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; relates to a method comprising.

[0066] In some embodiments, the ALT level in step (b) is determined at least monthly.

[0067] In some embodiments, the ALT level in step (d) is monitored at least weekly.

[0068] In some embodiments, the ALT level in step (d) is monitored every 2 - 3 days.

[0069] The present disclosure also relates to 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 has not been exposed to a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 liver enzyme.

[0070] The present disclosure also relates to a method of treating MG in a patient in need thereof, (a) advising the patient to limit alcohol consumption during treatment; (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; comprising wherein the patient is female and is advised to limit alcohol intake to 14 grams per day or less, or the patient is male and is advised to limit alcohol intake to 28 grams per day or less. BRIEF DESCRIPTION OF THE DRAWINGS

[0071]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 2

Figure 3

Figure 4A

Figure 4B

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0072] Here, specific embodiments are referred to in detail, and examples thereof are shown in the accompanying drawings. It will be understood that the present disclosure provides exemplary embodiments, but is not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to embrace all alternatives, modifications, and equivalents within the scope of the present disclosure as defined by the appended claims.

[0073] The section headings used herein are for organization purposes only and should in no way be construed as limiting the desired subject matter. Any document incorporated by reference shall be superseded by this specification if it conflicts with any term defined herein. The present teachings are described in conjunction with various embodiments, but the present teachings are not intended to be limited to such embodiments. On the contrary, the present teachings embrace various alternatives, modifications, and equivalents as would be understood by those skilled in the art.

[0074] I. Definitions Unless otherwise specified, the following terms used in this specification and the claims are defined for the purposes of this disclosure and have the following meanings.

[0075] 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 having the following structure:

Chemical formula

Chemical formula

[0076] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing a pharmaceutical composition, including carriers or excipients acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in this specification and the claims includes both one and two or more such excipients.

[0077] "Treating" or "treatment" of a disease includes the following. (1) Inhibiting a disease, e.g., arresting or reducing the onset of a disease or its clinical symptoms; or (2) Alleviating a disease, e.g., causing regression of a disease or its clinical symptoms.

[0078] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that its description includes both the case where the event or circumstance occurs and the case where it does not.

[0079] "Therapeutically effective amount" means an amount of a BTK inhibitor compound sufficient to affect such treatment of a disease when administered to a mammal for treating the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal being treated.

[0080] "Expanded Disability Status Scale (EDSS) score" is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments representing higher levels of disability. EDSS steps 1.0 through 4.5 refer to people with MS who can walk unaided and have a measurement of disability in eight functional systems (FS). Pyramidal - limb muscle weakness or motor difficulties; cerebellar ataxia, loss of balance, coordination or tremor; brainstem - speech, swallowing and nystagmus problems; sensory - numbness or loss of sensation; bowel and bladder function; visual function - vision problems; brain function - thinking and memory problems. EDSS steps 5.0 through 9.5 are defined by walking disability. See, for example, FIG. 7. Information regarding this score can be found in Kurtzke et al. Neurology 1983, 33, 1444 - 1452.

[0081] Before elaborating on the present teachings, it should be understood that the present disclosure is not limited to a particular composition or process step and may vary.

[0082] Also, as used in this specification and the appended claims, unless the context clearly indicates otherwise, singular forms such as "a", "an", and "the" include plural referents. Thus, for example, reference to "a complex" includes a plurality of complexes, reference to "a cell" includes a plurality of cells, and the like.

[0083] A numerical range includes the numbers defining the range. Measured values and measurable values are understood to be approximate values, taking into account significant figures and errors associated with the measurement. Also, the use of "comprise", "comprises", "comprising", "contain", "contains", "containing", "include", "includes", and "including" is not intended to be limiting. It should be understood that both the foregoing general description and the detailed description are merely illustrative and explanatory, and not restrictive of the teachings.

[0084] Unless otherwise specified in the above specification, embodiments in this specification that list various components "including" are also contemplated as "consisting of" or "consisting essentially of" the listed components; embodiments in this specification that list various components "consisting of" are also contemplated as "including" or "consisting essentially of" the listed components; embodiments in this specification that list various components "consisting essentially of" are also contemplated as "consisting of" or "including" the listed components (this interchangeability does not apply to the use of such terms in claims).

[0085] As used herein, the terms "or combinations thereof" and "or combinations thereof" refer to any and all substitutions and combinations of the terms listed prior to those terms. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, where order is important in a particular situation, also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB. Continuing with this example, combinations including repetitions of one or more items or terms such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. are explicitly included. Those skilled in the art will understand that, unless otherwise apparent from the context, there is typically no limit to the number of items or terms in any combination.

[0086] "Or" is used in an inclusive sense, i.e., is equivalent to "and / or", unless the context requires otherwise.

[0087] "Discontinuing" or "discontinuation", when used in connection with the administration of a BTK inhibitor compound, means that the BTK inhibitor compound is no longer being administered to the patient, either temporarily or permanently.

[0088] "Monitoring" with respect to the evaluation of a patient's ALT level means checking and / or detecting the patient's ALT level 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 once a week, in some embodiments, every five days, in some embodiments, every three days, in some embodiments, every two to three days, in some embodiments, every two days, in some embodiments, daily.

[0089] II. BTK Inhibitor Compound to be Administered In some embodiments, the BTK inhibitor compound (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to treat 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 dose of 5 to 60 mg of the BTK inhibitor compound is administered. In some embodiments, a dose of 60 mg of the BTK inhibitor compound is administered. In some embodiments, a dose of 60 mg of the BTK inhibitor compound is administered once daily.

[0090] In some embodiments, provided is 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 for use in a method of treating MS or MG in a patient in need thereof.

[0091] In some embodiments, provided is 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 for use in a method of reducing the frequency of MS or MG in a patient in need thereof.

[0092] The BTK inhibitor compound can be prepared, for example, according to the methods and schemes described in U.S. Patent No. 9,688,676B2, particularly according to the content from line 8 of column 62 to line 32 of column 65 and from line 28 of column 67 to column 69, which is incorporated herein by reference.

[0093] To enable those skilled in the art to prepare the BTK inhibitor compound, the preparation of the following compound of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is provided. The synthetic route should not be regarded as limiting the scope of the present disclosure, but rather as merely illustrative and representative thereof.

[0094] Exemplary synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one:

Chemical formula

[0095] III. A method of treatment for reducing the risk of liver injury A method of 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 is provided herein. However, the administration of the compound occurs (in certain embodiments) only when certain preconditions are met.

[0096] In one embodiment, the levels of transferrin or ferritin in a patient are measured. If it is determined that the patient's transferrin or ferritin level is not elevated, the patient receives a BTK inhibitor compound. However, if it is determined that the patient's transferrin or ferritin is elevated, the patient does not receive the compound. An increase in the transferrin level is determined by examining the saturation level of transferrin. In particular, an increase in the transferrin level is the case where the patient's transferrin saturation level is over 50% in males and over 40% in females. In other words, if the patient's transferrin saturation level is over 50% in males and over 40% in females, the patient does not receive the BTK compound, but if the patient's transferrin saturation level is measured and found to be 50% or less in males or 40% or less in females, the patient can receive the investigational drug. This measurement of transferrin saturation can be performed on either or both of MS patients and MG patients.

[0097] In some embodiments, the ferritin level of a patient is measured. If it is determined that the patient's ferritin level is not elevated, the patient receives a BTK inhibitor compound. An increase in the ferritin level means a level above 500 μg / L. In some embodiments, for the treatment of both MS and MG, if the patient's ferritin level is measured and found to be above 500 μg / L, the patient is not administered the BTK compound. However, if it is found to be 500 μg / L or less, the patient receives the BTK compound.

[0098] In some embodiments, for the treatment of both MG and MS, the iron panel of a patient is measured, which includes both iron levels, ferritin levels, and transferrin saturation in blood and serum. If either the ferritin level or the transferrin level exceeds the thresholds listed above, the patient does not receive the BTK inhibitor. However, if both the ferritin level and the transferrin level are below the thresholds listed above, the patient receives the BTK inhibitor.

[0099] In some embodiments, there is a method of treating MS and MG, comprising determining a patient's alcohol consumption and, if the patient is found to have appropriate alcohol consumption, administering to the 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. In some embodiments, appropriate alcohol consumption means that the patient has no history of active alcohol use disorder or alcohol or drug abuse within one year prior to the first visit. In other embodiments, appropriate alcohol consumption means that the patient's current alcohol intake is more than 2 drinks per day for males and more than 1 drink per day for females (1 drink = approximately 14 grams of alcohol = 350 mL of beer = 140 mL of wine = 40 mL of spirits). Thus, the patient needs to have an alcohol consumption of less than 2 drinks per day for males and less than 1 drink per day for females for the administration of the BTK compound.

[0100] In some embodiments, there is a method of treating MS and MG that measures whether a patient is taking a CYP3A enzyme inducer concomitantly. If the patient is taking such an inhibitor, the patient does not receive the BTK compound. Similarly, if the patient is taking an inhibitor of CYP3C8 concomitantly, the BTK compound is not administered to the patient.

[0101] In some embodiments, to treat both MS and MG, it is determined whether the patient has elevated ALT enzyme, and if so, the patient does not receive the BTK inhibitor. This refers to alanine aminotransferase (ALT) enzyme having an increased and / or greater than 3 times the starting value × upper limit of normal (ULN). Such patients do not receive the BTK compound.

[0102] In one embodiment, the level of the patient's transferrin or ferritin is measured. If it is determined that the patient's transferrin or ferritin level is not elevated, the patient continues to receive the BTK inhibitor compound. However, if it is determined that the patient's transferrin or ferritin is elevated, the patient discontinues receiving the compound (or the compound is no longer administered to the patient). Specifically, in some embodiments, if the patient's transferrin saturation level is greater than 50% in males and greater than 40% in females, the patient discontinues receiving the compound. Such discontinuation of treatment based on transferrin levels can be done for either or both MS and MG patients.

[0103] In some embodiments, the level of the patient's ferritin is measured. If it is determined that the patient's ferritin level is not elevated, the patient continues to receive the BTK inhibitor compound. However, if it is determined that the patient's ferritin is elevated, the patient discontinues receiving the compound (or the compound is no longer administered to the patient). Specifically, for treating both MS and MG, if the patient's ferritin level is measured and it is determined to be greater than 500 μg / L, the patient is not administered the BTK compound and / or the patient discontinues receiving the compound. However, if it is determined to be 500 μg / L or less, the patient continues to receive the BTK compound.

[0104] In some embodiments, for treating both MG and MS, the patient's iron panel is measured, which includes both iron levels, ferritin levels, and transferrin saturation in blood and serum. If either the ferritin level or the transferrin level exceeds the thresholds listed above, the patient does not receive the BTK inhibitor or discontinues receiving the compound. If both the ferritin level and the transferrin level exceed the thresholds listed above, the patient similarly does not receive the BTK inhibitor or discontinues receiving the compound.

[0105] In some embodiments, there is a method for treating MS and MG, comprising determining a patient's alcohol consumption and, if the patient is found to have appropriate alcohol consumption, administering to the 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. In some embodiments, appropriate alcohol consumption means that the patient has no history of active alcohol use disorder or alcohol or drug abuse within one year prior to the first visit. In other embodiments, appropriate alcohol consumption means that the patient's current alcohol intake is more than 2 drinks per day for men and more than 1 drink per day for women (1 drink = approximately 14 grams of alcohol = 350 mL of beer = 140 mL of wine = 40 mL of spirits). Thus, the patient needs to have an alcohol consumption of less than 2 drinks per day for men and less than 1 drink per day for women in order to receive the BTK compound.

[0106] In some embodiments, there is a method for treating MS and MG, comprising determining a patient's alcohol consumption and, if the patient is found to have a consumption higher than appropriate alcohol consumption, the patient is not administered the compound or the administration of the compound is discontinued. In some embodiments, a consumption higher than appropriate alcohol consumption means that the patient has a history of active alcohol use disorder or alcohol or drug abuse within one year prior to the first visit. In other embodiments, a consumption higher than appropriate alcohol consumption means that the patient has a current alcohol intake of more than 2 drinks per day for men and more than 1 drink per day for women (1 drink = approximately 14 grams of alcohol = 350 mL of beer = 140 mL of wine = 40 mL of alcohol). Thus, the patient needs to have an alcohol consumption of less than 2 drinks per day for men and less than 1 drink per day for women in order for the BTK compound to be administered or for the patient to continue receiving the compound.

[0107] In some embodiments, there is a method of treating MS and MG that measures whether a patient is concurrently taking an inducer of the CYP3A enzyme. If the patient is taking such an inhibitor, the patient does not receive the BTK compound and / or the administration of the compound is discontinued. Similarly, if the patient is concurrently taking an inhibitor of CYP3C8, the patient is not administered the BTK compound (or the administration of the compound is discontinued).

[0108] In some embodiments, to treat both MS and MG, it is determined whether a patient has elevated ALT enzyme, and if so, the patient does not receive the BTK inhibitor or discontinues receiving the compound. This refers to alanine aminotransferase (ALT) enzyme having an increased and / or greater than 3 times the starting value × upper limit of normal (ULN). Such a patient does not receive the BTK compound or the administration of the compound is stopped.

[0109] In one embodiment, for either an MG or MS patient, the patient is classified as having mild, moderate, or severe liver impairment as measured by the Child-Pugh class scale. In some embodiments, if it is determined that the patient has severe liver impairment, the patient does not receive the compound or the administration of the compound to the patient is stopped. In some embodiments, if it is determined that the patient has moderate liver impairment, the patient does not receive the compound or the administration of the compound to the patient is stopped. In some embodiments, if it is determined that the patient has mild liver impairment, the patient does not receive the compound or the administration of the compound to the patient is stopped.

[0110] In some embodiments, for both MS treatment and MG treatment, patients are screened to determine if they have ALT > 1.5 × ULN or AST > 1.5 × ULN or alkaline phosphatase > 2 × ULN (except when caused by non - liver - related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5 × ULN (except in the case of Gilbert's syndrome or non - liver - related disorders). Such patients having enzymes above these levels are not administered the compound, or if they are already receiving the compound, the receipt of the compound is discontinued.

[0111] In some embodiments, the dose is once daily. In some embodiments, the dose is administered once daily with food. In some embodiments, the dose is 60 mg and is administered once daily with food. In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0112] 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 in the range of 12 to 55 years old.

[0113] In some embodiments, the therapeutically effective amount is from 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 in the range of 12 to 55 years old.

[0114] In some embodiments, the therapeutically effective amount is from 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 in the range of 12 to 55 years old.

[0115] In some embodiments, the 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, the 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, the 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 at a dose of 60 mg as a monotherapy. In some embodiments, the 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 at a dose of 60 mg with food as a monotherapy.

[0116] In some embodiments, doses 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 are 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.

[0117] In some embodiments, the dosage is administered daily. The daily dosage can be delivered as a single dose or divided into multiple portions. For example, in some embodiments, the dosage is administered once a day (e.g., every about 24 hours). In some embodiments, the dosage is administered twice a day. In some embodiments, the dosage is subdivided into two portions that are administered twice a day (e.g., every about 12 hours). In some embodiments, the dosage is subdivided into three portions that are administered three times a day (e.g., every about 8 hours). In some embodiments, the dosage is subdivided into four portions that are administered four times a day (e.g., every about 6 hours).

[0118] 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, semi-solid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0119] In some embodiments, the patient is administered the BTK inhibitor compound for a period of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or for life. In some embodiments, the patient is administered the BTK inhibitor compound for a period of about 12 months. In some embodiments, the dosage is once a day. In one embodiment, provided is a method of treating MS or MG, the method comprising administering to a patient in need thereof a 60 mg BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0120] In some embodiments, the BTK inhibitor compound is administered as monotherapy. In some embodiments, the method comprises administering the BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent may be administered concurrently or sequentially with the BTK inhibitor compound.

[0121] The determination of the dosing frequency can be made by a person skilled in the art, such as the attending physician, taking into account the condition being treated, the age of the subject being treated, the severity of the condition being treated, the general health 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 typically depends on the weight of the subject being treated, the physical or health condition of that person, the extensiveness of the condition being treated, or the age of the subject being treated, the pharmaceutical formulation method, or the method of administration (e.g., administration time and route of administration).

[0122] In some embodiments, a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, comprises performing an iron panel test using the patient's blood or serum, and, when the patient has an appropriate iron panel, administering to the patient a pharmaceutically 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. In some embodiments, the iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, an appropriate iron panel comprises one or more of the following: (i) an iron concentration of 60 μg / dL to 170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240 μg / dL to 450 μg / dL.

[0123] In some embodiments, a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, comprising the steps of performing an iron panel test on a patient's blood or serum, detecting levels of the iron panel test within the normal range, and administering to the patient a pharmaceutically 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 is provided. In some embodiments, the iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range of the iron panel test includes one or more of (i) an iron level of 60-170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240-450 μg / dL.

[0124] 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 (the compound) for use in a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, comprising the steps of performing an iron panel test on a patient's blood or serum, detecting levels of the iron panel test within the normal range, and administering to the patient a pharmaceutically acceptable amount of the compound. In some embodiments, the iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range of the iron panel test includes one or more of (i) an iron level of 60-170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240-450 μg / dL.

[0125] In some embodiments, a method of treating multiple sclerosis (MS) including relapsing-remitting MS (RMS), non-relapsing / secondary progressive MS (NRSPMS), and primary progressive MS (PPMS), or myasthenia gravis (MG), comprises determining the transferrin saturation level in a patient's blood or serum, and, when the transferrin saturation level is appropriate, administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, an appropriate transferrin saturation level in the blood or serum of a male patient is a transferrin saturation of 50% or less. In some embodiments, an appropriate transferrin saturation level in the blood or serum of a female patient is a transferrin saturation of 40% or less.

[0126] In some embodiments, a method of treating multiple sclerosis (MS) including relapsing-remitting MS (RMS), non-relapsing / secondary progressive MS (NRSPMS), and primary progressive MS (PPMS), or myasthenia gravis (MG), comprises detecting the transferrin saturation level in a patient's blood or serum within a normal range, and administering to the patient a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, a transferrin saturation level within a normal range in the blood or serum of a male patient is a transferrin saturation of 50% or less. In some embodiments, a transferrin saturation level within a normal range in the blood or serum of a female patient is a transferrin saturation of 40% or less.

[0127] 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 detecting the transferrin saturation level in the blood or serum of a patient within the normal range and administering to the patient a therapeutically effective amount of the compound. In some embodiments, the transferrin saturation level within the normal range in the blood or serum of a male patient is 50% or less transferrin saturation. In some embodiments, the transferrin saturation level within the normal range in the blood or serum of a female patient is 40% or less transferrin saturation.

[0128] In some embodiments, there is provided a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising determining the level of ferritin in the blood or serum of a patient and, if the level of ferritin is appropriate, administering to the patient a pharmaceutically 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. In some embodiments, an appropriate ferritin level in the blood or serum of the patient is 500 μg / L or less.

[0129] In some embodiments, there is provided a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising detecting the level of ferritin in the blood or serum of a patient within the normal range and administering to the patient a pharmaceutically 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. In some embodiments, the ferritin level within the normal range in the blood or serum of the patient is 500 μg / L or less.

[0130] 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 detecting the level of ferritin in a patient's blood or serum within the normal range and administering to the patient a pharmaceutically acceptable amount of the compound. In some embodiments, the ferritin level within the normal range in the patient's blood or serum is 500 μg / L or less.

[0131] In some embodiments, provided is a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising performing a liver function test in a patient and, if the patient has appropriate liver function, administering to the patient a pharmaceutically 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. In some embodiments, the liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. In some embodiments, a patient having appropriate liver function has one or more of an ALT level of 1.5 times or less the upper limit of normal (ULN), an AST level of 1.5x or less the ULN, an alkaline phosphatase of 2x or less the ULN (except when caused by non-liver related disorders or explained by stable chronic liver disorders), and a total bilirubin of 1.5x or less the ULN (except in cases of Gilbert's syndrome or non-liver related disorders).

[0132] In some embodiments, a method of treating an MS, or MG, including RMS, NRSPMS, and PPMS, comprising the steps of performing a liver function test in a patient, detecting appropriate liver function, and administering to the patient a pharmaceutically 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 is provided. In some embodiments, the liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. In some embodiments, a patient having appropriate liver function has one or more of an ALT level of 1.5 times or less the upper limit of normal (ULN), an AST level of 1.5x or less the ULN, an alkaline phosphatase of 2x or less the ULN (except when caused by a non-liver-related disorder or explained by stable chronic liver disease), and a total bilirubin of 1.5x or less the ULN (except in the case of Gilbert's syndrome or a non-liver-related disorder).

[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 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 to the patient a therapeutically acceptable amount of the compound. In some embodiments, the liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. In some embodiments, a patient having appropriate liver function has one or more of an ALT level of 1.5 times or less the upper limit of normal (ULN), an AST level of 1.5x or less the ULN, an alkaline phosphatase of 2x or less the ULN (except when caused by a non-liver-related disorder or explained by stable chronic liver disease), and a total bilirubin of 1.5x or less the ULN (except in the case of Gilbert's syndrome or a non-liver-related disorder).

[0134] 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 monthly. 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 weekly.

[0135] In some embodiments, there is provided a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising 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 the level of alanine aminotransferase (ALT) in the patient; c) Detecting a level of ALT that is more than 8x the upper limit of normal (ULN); d) Discontinuing administration of the compound to the patient, and optionally, e) Monitoring the ALT level of the patient; f) Resuming administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN.

[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: a) Administering a therapeutically effective amount of the compound to a patient in need thereof; b) Measuring the level of alanine aminotransferase (ALT) in the patient; c) Detecting a level of ALT that is more than 8x the upper limit of normal (ULN); d) Discontinuing administration of the compound to the patient, and optionally, e) Monitoring the ALT level of the patient; f) Resuming administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN.

[0137] In some embodiments, a method of treating MS, including RMS, NRSPMS, and PPMS, or MG is provided, the method comprising: a) 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 (compound); b) Measuring the level of alanine aminotransferase (ALT) in the patient; c) Detecting, during a period of at least two weeks, an ALT level more than 5x the upper limit of normal (ULN); d) Discontinuing the administration of the compound to the patient, and optionally, e) Monitoring the ALT level of the patient; f) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN.

[0138] 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 multiple sclerosis (MS) including relapsing-remitting MS (RMS), non-relapsing / secondary progressive MS (NRSPMS), and primary progressive MS (PPMS), or myasthenia gravis (MG), the method comprising: a) Administering to a patient in need thereof a therapeutically effective amount of the compound; b) Measuring the level of alanine aminotransferase (ALT) in the patient; c) Detecting, during a period of at least two weeks, an ALT level more than 5x the upper limit of normal (ULN); d) Discontinuing the administration of the compound to the patient, and optionally, e) Monitoring the ALT level of the patient; f) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN.

[0139] In some embodiments, a method of treating MS including RMS, NRSPMS, and PPMS, or MG is provided, the method comprising: 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 the level of alanine aminotransferase (ALT) in the patient; c) Detecting a level of ALT that is more than 3x the upper limit of normal (ULN); d) Measuring one or more of the patient's total bilirubin and international normalized ratio (INR); e) Detecting one or more of a total bilirubin that is more than 2x the ULN and an INR that is more than 1.5; f) Discontinuing the administration of the compound to the patient, and optionally, g) Monitoring the ALT level of the patient; h) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN.

[0140] 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, and the method comprises a) Administering a therapeutically effective amount of the compound to a patient in need thereof; b) Measuring the level of alanine aminotransferase (ALT) in the patient; c) Detecting a level of ALT that is more than 3x the upper limit of normal (ULN); d) Measuring one or more of the patient's total bilirubin and international normalized ratio (INR); e) Detecting one or more of a total bilirubin that is more than 2x the ULN and an INR that is more than 1.5; f) Discontinuing the administration of the compound to the patient, and optionally, g) Monitoring the ALT level of the patient; h) If it is determined that the patient's ALT level is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; and

[0141] In some embodiments, a method of treating MS, including RMS, NRSPMS, and PPMS, or MG is provided, the method comprising: a) 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 (the compound); b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting an ALT level greater than 3x the upper limit of normal (ULN); d) if the patient experiences one or more of fatigue greater than 5%, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia, stopping the administration of the compound to the patient; and optionally, e) monitoring the patient's ALT level; f) if it is determined that the patient's ALT level is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; and

[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 (the compound) for use in a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising: a) administering a therapeutically effective amount of the compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting an ALT level greater than 3x the upper limit of normal (ULN); d) If the patient experiences one or more of fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash, and eosinophilia exceeding 5%, the step of discontinuing the administration of the compound to the patient, and optionally, e) the step of monitoring the patient's ALT level; f) the step of restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the patient's ALT level is less than 1.5x the ULN. A method for treating MOGAD is provided that includes these steps.

[0143] In some embodiments, the patient's ALT level 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 monthly. In some embodiments, the patient's ALT level 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 weekly.

[0144] In some embodiments, after stopping the administration of the compound, the patient's ALT level is monitored about every 2 - 3 days, about every 3 days, about every 2 days, or about daily.

[0145] In some embodiments, a method of treating an MS, or MG, including RMS, NRSPMS, and PPMS, comprising administering to a patient a pharmaceutically 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, wherein the patient has not been exposed to a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 hepatic enzyme, is provided. In some embodiments, the strong CYP3A inducer is selected from rifampin, carbamazepine, phenobarbital, St. John's wort extract, abacimib, lumacaftor, rifapentine, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semagacestat, asunaprevir, beclabuvir, daclatasvir, cenobamate, nafcillin, resinarate, modafinil, bosentan, telotristat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0146] In some embodiments, the present disclosure provides a BTK inhibitor for use in a method of treating MS or MG, including RMS, NRSPMS, and PPMS, the BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (the compound), and comprising administering to a patient a pharmaceutically acceptable amount of the compound, wherein the patient has not been exposed to a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 hepatic enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampin, carbamazepine, phenobarbital, St. John's wort extract, abacimib, lumacaftor, rifapentine, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semagacestat, asunaprevir, beclabuvir, daclatasvir, cenobamate, nafcillin, resinarate, modafinil, bosentan, telotristat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0147] In some embodiments, there is provided a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising advising a patient to limit alcohol consumption during treatment, and administering to the patient a pharmaceutically 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. In some embodiments, the patient is female and is advised to limit alcohol intake to one drink or less per day. In some embodiments, one drink is about 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of spirits). In some embodiments, the patient is male and is advised to limit alcohol intake to two drinks or less per day. In some embodiments, two drinks are about 28 grams of alcohol.

[0148] In some embodiments, the present disclosure provides a method of treating MS, including RMS, NRSPMS, and PPMS, or MG, the method comprising advising a patient to restrict alcohol consumption during treatment and administering to the patient a pharmaceutically 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. In some embodiments, the patient is female and is advised to limit alcohol intake to one drink or less per day. In some embodiments, one drink is about 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of spirits). In some embodiments, the patient is male and is advised to limit alcohol intake to two drinks or less per day. In some embodiments, two drinks are about 28 grams of alcohol.

[0149] The selection of a formulation depends on various factors such as the drug administration mode (for example, for oral administration, a formulation in the form of tablets, pills or capsules is preferred) and the bioavailability of the active ingredient. Recently, pharmaceutical formulations for drugs showing low bioavailability have been specifically developed based on the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing the particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 nm to 1,000 nm, wherein the active substance is supported on a polymeric crosslinked matrix. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation with significantly high bioavailability by grinding the active ingredient into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersing it in a liquid medium. The bioavailability of a drug that decomposes at the pH of the stomach can be increased by administering such a drug in a formulation that releases the drug into the duodenum.

[0150] The composition generally comprises a BTK inhibitor compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient such as a binder, surfactant, diluent, buffer, anti-adherent, flow promoter, hydrophilic or hydrophobic polymer, retardant, stabilizer or stabiliser, disintegrant or superdisintegrant, antioxidant, defoamer, filler, flavor, colorant, lubricant, adsorbent, preservative, plasticizer or sweetener, or a mixture thereof, facilitating the processing of the BTK inhibitor compound or a pharmaceutically acceptable salt thereof into a pharmaceutically usable preparation. Any well-known techniques and excipients are suitable and can be used as understood in the art, see, for example, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005); Liberman, H.A., Lachman, L., and Schwartz, J.B. Eds., Pharmaceutical Dosage Forms, Vol. 1-2 Taylor & Francis 1990; and R.I. Mahato, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Second Ed. (Taylor & Francis, 2012).

[0151] In certain embodiments, the formulation may include one or more pH adjusters or buffers such as acids like 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, tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride. Such buffers used as bases may have other counterions than sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases and buffers are included in an amount necessary to maintain the pH of the composition within an acceptable range.

[0152] In certain embodiments, the formulation may also include one or more salts in an amount necessary to bring the weight osmolality of the composition within 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, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0153] In certain embodiments, the formulation may also include one or more defoaming agents to reduce foaming during processing, which can result in coagulation of the aqueous dispersion, air bubbles in the finished film, or generally impair processing. Exemplary defoaming agents include silicone emulsions or sorbitan sesquioleate.

[0154] 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, the antioxidant enhances chemical stability as needed. Other agents such as citric acid or citrate or EDTA can also be added to retard oxidation.

[0155] 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, cetylpyridinium chloride.

[0156] In certain embodiments, the formulation may also include one or more binders. The binder imparts cohesiveness and includes, for example, alginic acid and its salts; carboxymethyl cellulose, methyl cellulose (e.g., Methocel®), hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and cellulose derivatives such as microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrins; amylose; magnesium aluminum silicate; polygalacturonic acid; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and sugars such as lactose; natural or synthetic rubbers including acacia, tragacanth, isapol husk ghatti gum mucilage, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegun®, polyethylene glycol, polyethylene oxide, wax, sodium alginate, and the like.

[0157] In certain embodiments, the formulation may also include a dispersant or a viscosity modifier. Dispersants or viscosity modifiers include materials that control the diffusion and uniformity of the drug in the liquid medium or by the granulation or blending method. In some embodiments, these agents also promote the effectiveness of the coating or erosion matrix. Exemplary diffusion promoters / dispersants include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP, known commercially as Plasdone®), and carbohydrate-based dispersants such as 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, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl-cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl-methylcellulose acetate stearate (HPMCAS), microcrystalline 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., Pluronics F68®, F88®, and F108®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is an ethylenediamine of propylene oxide and ethylene oxide (BASF Corporation, Parsippany, N.J.) A tetrafunctional block copolymer derived from sequential addition to), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol, for example, polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, for example, gum tragacanth and gum acacia, guar gum, xanthan gum including xanthan, sugars, cellulose-based, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginate, chitosan and combinations thereof. Plasticizers such as cellulose or triethylcellulose can also be used as dispersants. Dispersants particularly useful in liposome dispersions and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate. Generally, a binder level of about 10 to about 70% is used in powder-filled gelatin capsule formulations. The level of binder used in tablet formulations varies depending on either direct compression, wet granulation, roller compression, or the use of other excipients such as fillers that can themselves act as moderate binders. One skilled in the art can determine the binder level of the formulation, but a binder usage level of up to 90%, more typically up to 70%, is common in tablet formulations.

[0158] In certain embodiments, the formulation may also include one or more diluents that refer to chemical compounds used to dilute the compound of interest prior to delivery.

[0159] Diluents can also be used to stabilize the compounds because they can provide a more stable environment (they can also provide pH control or maintenance). Salts dissolved in buffer solutions, including but not limited to phosphate buffered saline, are utilized as diluents in the art. In certain embodiments, the diluent increases the bulk of the composition to facilitate compression or creates sufficient bulk for a homogeneous blend for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, dibasic calcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); hydroxypropyl-methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectionery; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0160] In certain embodiments, the formulation may also include one or more disintegrants that include both dissolution and dispersion of the dosage form when contacted with gastrointestinal fluids. The disintegrant or disintegrants facilitate the disintegration or breakup of the substance. Examples of disintegrants include starches such as natural starches like corn starch or potato starch, pregelatinized starches such as National 1551, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methylcellulose crystalline, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked cellulose such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose or cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), agar, guar, locust bean, karaya, pectin, tragacanth, gums such as sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0161] In certain embodiments, the formulation may also include an erosion promoter. The erosion promoter includes materials that control the erosion of certain 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.

[0162] In certain embodiments, the formulation may also include one or more fillers, such as compounds including lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0163] In certain embodiments, the formulation may also include one or more flavoring agents or sweeteners such as acacia syrup, acesulfame K,alitame, anise, apple, aspartame, banana, butterscotch, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream chocolate, cinnamon, bubble gum, citrus fruits, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizinate, glycyrrhizic acid (licorice) syrup, grape, grapefruit, honey, isomaltol, lemon, lime, lemon cream, monoammonium glycyrrhizinate, maltol, mannitol, maple, menthol, mint cream, mixed berries, 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, tangelo, thaumatin, tutti frutti, vanilla, walnut, watermelon, European cranberry, wintergreen, xylitol, or any combination of these flavor components such as anismenthol - menthol, cherry anis, cinnamon - orange, cherry - cinnamon, chocolate - mint, honey lemon, lemon - lime, lemon - mint, menthol - eucalyptus, orange - cream, vanilla - mint and mixtures thereof.

[0164] In certain embodiments, the formulation may also include one or more lubricants and flow promoters that are compounds that prevent, reduce or inhibit the adhesion or friction of materials.

[0165] Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl glutamate, hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil, higher fatty acids and their alkali metal and alkaline earth metal salts, such as 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 methoxypolyethylene glycol, such as Carbowax®, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid®, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

[0166] In certain embodiments, the formulation may also include one or more plasticizers that are compounds used to soften enteric or sustained-release coatings and reduce brittleness. Suitable plasticizers include, for example, polyethylene glycol such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethyl citrate, dibutyl sebacate, triethyl cellulose, and triacetin. In some embodiments, the plasticizer can also function as a dispersant or wetting agent.

[0167] In certain embodiments, the formulation may also include one or more solubilizing agents including compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium deoxycholate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin such as Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200 - 600, glycolfural, transcutol, propylene glycol, dimethyl isosorbide and the like. In one embodiment, the solubilizing agent is vitamin E TPGS or Captisol® or β-hydroxypropyl cyclodextrin.

[0168] In certain embodiments, the formulation may also include one or more suspending agents including compounds such as polyvinylpyrrolidone such as polyvinylpyrrolidone K112, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol such as polyethylene glycol can have a molecular weight of about 300 - about 6000, or about 3350 - about 4000, or about 7000 - about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum and gum arabic, xanthan gum including xanthan, xanthan gum, sugar, cellulose and the like, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, povidone and the like.

[0169] In certain embodiments, the formulation may also contain one or more surfactants including compounds such as sodium lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbate, polaxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide such as Pluronic® (BASF), etc. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil, as well as polyoxyethylene alkyl ethers and alkyl phenyl ethers such as octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0170] In certain embodiments, the formulation may also contain one or more thickeners including, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol alginate, acacia, chitosan, and combinations thereof.

[0171] In certain embodiments, the formulation may also contain 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, etc.

[0172] The pharmaceutical preparations disclosed herein can be obtained by mixing one or more solid excipients such as carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizing agents, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or combinations of one or more thereof with one or more of the compounds described herein, optionally grinding the resulting mixture, adding appropriate excipients if necessary, and then processing the mixture of granules to obtain tablets.

[0173] The pharmaceutical preparations disclosed herein also include gelatin capsules and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The capsules may also be made of a polymer such as hypromellose. The capsules may contain the active ingredient mixed with a binder such as lactose, starch, or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the case of soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, lipid, solubilizing agent, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All formulations for oral administration need to be in a dosage form appropriate for such administration.

[0174] These formulations can be manufactured by conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of methods. (1) Dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, (6) fusion, or (7) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd ed. (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 spray, tableting, extrusion, extrusion / spheronization, etc.

[0175] It should be recognized that there is a significant overlap among the excipients used in the solid dosage forms described herein. Accordingly, the additives listed above should be construed as merely illustrative of the types of excipients that can be included in the solid dosage forms described herein and not as limiting. The types and amounts of such excipients can be readily determined by those skilled in the art according to the particular desired properties.

[0176] In some embodiments, the solid dosage forms described herein are enteric-coated oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions described herein that utilize enteric coating to affect the release of the compound in the intestine of the gastrointestinal tract. An “enteric-coated” drug or tablet refers to a drug or tablet coated with a substance that remains intact in the stomach but dissolves and releases the drug upon reaching the intestine (in one embodiment, the small intestine). As used herein, “enteric coating” is a material such as one or more polymeric materials that encapsulates the therapeutic agent core either as a dosage form or as a particle. Typically, a substantial or all of the enteric coating material is dissolved before the therapeutic agent is released from the dosage form in order to achieve delayed dissolution of the therapeutic agent core or particle in the small or large intestine. For enteric coatings, see, for example, Loyd, V. Allen, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005); and P.J. Tarcha, Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991. Methods of applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, U.S. Patent Application Publication No. 2006 / 0045822.

[0177] An enteric-coated dosage form can be a compressed or molded or extruded tablet (coated or uncoated) that contains granules, powders, pellets, beads or particles of a BTK inhibitor compound or a pharmaceutically acceptable salt or other excipient thereof, which may or may not be itself coated, provided that at least the tablet or the BTK inhibitor compound is coated. An enteric-coated oral dosage form can also be a capsule (coated or uncoated) that contains pellets, beads or granules of a BTK inhibitor compound or a pharmaceutically acceptable salt or other excipient thereof, which may or may not be itself coated provided that at least one of them is coated. Some examples of coatings first used as enteric coatings are beeswax and glyceryl monostearate. Beeswax, shellac and cellulose; and cetyl alcohol, mastic, and shellac, and shellac and stearic acid (U.S. Patent No. 2,809,918); polyvinyl acetate and ethyl cellulose (see U.S. Patent No. 3,835,221). More recently, coatings used are neutral copolymers of polymethacrylic acid esters (Eudragit L30D). (F.W. Goodhart et al, Pharm. Tech., p. 64-71, April 1984); copolymers of methacrylic acid and methyl methacrylate ester (Eudragit S), or neutral copolymers of polymethacrylic acid esters containing metal stearates (Mehta et al, U.S. Patent Nos. 4,728,512 and 4,794,001), cellulose acetate succinate, and hypromellose phthalate.

[0178] Any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the intestine. In one embodiment, the delivery can be delivery to the small intestine. In another embodiment, the delivery can be delivery to the duodenum. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers, and their compatible mixtures, and some of their properties include, but are not limited to, the following.

[0179] Shellac: Also called refined lac, it is a refined product obtained from the resin secretion of insects. This coating dissolves in a medium with pH > 7.

[0180] Acrylic polymers: The performance of acrylic polymers (mainly their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include copolymers of methacrylic acid and ammonium methacrylate. The Eudragit series L, S, and RS (manufactured by Rohm Pharma, known as Evonik®) are available solubilized in organic solvents, aqueous dispersions, or dry powders. The RL, NE, and RS of the Eudragit series are insoluble but permeable in the gastrointestinal tract and are mainly used for colon targeting. The Eudragit series L, L-30D, and S are insoluble in the stomach, dissolve 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.

[0181] Cellulose derivatives: Examples of suitable cellulose derivatives are ethyl cellulose; a reaction mixture of a partial acetate ester of cellulose and phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH > 6. Aquateric is an aqueous system and a spray-dried CAP pseudo-latex having particles < 1 μm. Other components of Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methyl cellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, HP-55F are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose 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.

[0182] Polyvinyl acetate phthalate (PVAP): PVAP dissolves at pH > 5 and is much less permeable to water vapor and gastric juice. A detailed description of the above polymers and their pH-dependent solubility can be found in the article "Enteric coated hard gelatin capsules" by Professor 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 include a plasticizer and optionally other coating excipients well known in the art, such as colorants, talc, or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex2), triacetin (glyceryl triacetate), acetyltriethyl citrate (CitroflecA2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglyceride, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers usually contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as fluid bed or Urster coater, or spray or pan coating are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired site of local delivery in the intestinal tract.

[0183] In addition to the plasticizer, colorants, surfactants, anti-blocking agents, defoaming agents, lubricants (e.g., carnauba wax or PEG), and other additives can be added to the coating to solubilize or disperse the coating material and improve the coating performance and the coated product.

[0184] To promote the dissolution of the enteric coat, a double coat with a thickness half that of the enteric polymer (e.g., Eudragit L30D-55) may be applied. The inner enteric coat may have a buffer up to pH 6.0 in the presence of 10% citric acid, followed by a final layer of standard Eudragit L30D-55. Liu and Basit, who applied a two-layer enteric coat that is half the typical enteric coat thickness, were able to promote the dissolution of the enteric coating compared to a similar unbuffered coating system applied as a single layer (Liu, F. and Basit, A. Journal of Controlled Release. 147 (2010) 242-245).

[0185] The integrity of the enteric coating can be measured, for example, by the degradation of the drug within the micropellets. Enteric-coated dosage forms or pellets can be tested in dissolution tests first in gastric juice and separately in intestinal juice, as described in the USP, to determine their function.

[0186] Enteric-coated tablet 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 enterically coated with a coating solution containing Eudragit®, diethyl phthalate, isopropyl alcohol, talc, and water using a side-vented coating pan (Freund Hi-Coater).

[0187] Alternatively, a multi-unit dosage form containing enteric-coated pellets that can be incorporated into tablets or capsules can be prepared as follows.

[0188] Core material: The core material of the individually enteric-coated layered pellets can be configured according to different principles. The active agent (i.e., the BTK inhibitor compound or its pharmaceutically acceptable salt) and the layered seeds can optionally be mixed with an alkaline substance or buffer and used as the core material for further processing. The seeds to be layered with the active agent can be water-insoluble seeds containing different oxides, celluloses, organic polymers and other materials alone or in mixtures, or water-soluble seeds containing different inorganic salts, sugars, nonpareils and other materials alone or in mixtures.

[0189] Furthermore, the seeds may contain the active agent in the form of crystals, aggregates, compacts, etc. The size of the seeds is not essential for the present disclosure, but may be in the range of about 0.1 to 2 mm. The seeds laminated with the active agent are produced, for example, by either powder or solution / suspension lamination using a granulation or spray coating lamination apparatus. Before laminating the seeds, the active agent may be mixed with additional components.

[0190] Such components can be binders, surfactants, fillers, disintegrants, alkali additives or other pharmaceutically acceptable components alone or in mixtures. Binders are, for example, polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), or sugars, starches, or other pharmaceutically acceptable substances having aggregating properties. Suitable surfactants are found, for example, in the group of pharmaceutically acceptable non-ionic or ionic surfactants such as sodium lauryl sulfate.

[0191] Alternatively, the active agent can be optionally mixed with suitable components and incorporated into the core material. The core material may be produced by extrusion / spheronization, balling or compression using conventional processing equipment. The size of the incorporated core material is from about 0.1 to 4 mm, for example 0.1 to 2 mm. The produced core material can be further laminated with additional components containing the active agent or used for further processing.

[0192] The active agent is mixed with pharmaceutical ingredients to obtain favorable handling and processing characteristics and an appropriate concentration of the active agent in the final preparation. Pharmaceutical components such as fillers, binders, lubricants, disintegrants, surfactants, and other pharmaceutically acceptable additives can be used.

[0193] Alternatively, the above core material can be prepared using spray drying or spray congealing techniques.

[0194] Enteric coating layer: Before applying the enteric coating layer in the form of individual pellets onto the core material, the pellets may optionally be covered with one or more separating layers containing pharmaceutical excipients including alkaline compounds such as pH buffering compounds. This / These separating layer(s) separate(s) the core material from the outer enteric coating layer. This / These separating layer(s) protecting the core material of the active agent need to be water-soluble or rapidly disintegrate in water.

[0195] The separating layer can be optionally applied to the core material by coating or lamination procedures using suitable equipment such as coating pans, coating granulators, or fluid bed equipment using water or organic solvents for the coating process. Alternatively, the separating layer can be applied to the core material by using powder coating techniques. The material of the separating layer is a pharmaceutically acceptable compound, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, water-soluble salts of enteric coating polymers, etc., and is used alone or as a mixture. Additives such as plasticizers, colorants, pigments, fillers, anti-adhesion agents, and anti-static agents, such as magnesium stearate, titanium dioxide, talc, and other additives, may also be included in the separating layer.

[0196] When any separating layer is applied to the core material, it may constitute a variable thickness. The maximum thickness of the separating layer is usually limited only by the processing conditions. The separating layer can function as a diffusion barrier and can act as a pH buffering zone. The optionally applied separating layer is not essential for the embodiments of the present disclosure. However, the separating layer can improve the chemical stability of the active substance or the physical properties of the novel multi-unit tablet dosage form.

[0197] Alternatively, the separating layer may be formed in situ by the reaction between an enteric coating polymer layer applied on the core material and an alkali-reactive compound in the core material. Thus, the formed separating layer contains a water-soluble salt formed between the enteric coating layer polymer and the alkali-reactive compound located at the position forming the salt.

[0198] One or more enteric coating layers are applied onto the core material or the core material covered with the separating layer by using suitable coating techniques. The enteric coating layer material can be dispersed or dissolved in either water or a suitable organic solvent. As the enteric coating layer polymer, for example, one or more of a solution or dispersion of a methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable enteric coating polymers can be used separately or in combination.

[0199] The enteric coating layer contains a pharmaceutically acceptable plasticizer to obtain desired mechanical properties such as the flexibility and hardness of the enteric coating layer. Such plasticizers are, for example, but not limited to, triacetin, citrate esters, phthalate esters, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate or other plasticizers.

[0200] The amount of plasticizer is optimized for each enteric coating layer formulation with respect to the selected enteric coating layer polymer, the selected plasticizer, and the appropriate amount of the polymer such that the mechanical properties, i.e., the flexibility and hardness of the enteric coating layer, such as exemplified by Vickers hardness, are such that the acid resistance of the pellets coated with the enteric coating layer does not significantly decrease during compression of the pellets into tablets when tablets are desired. The amount of plasticizer is usually more than 5% by weight of the enteric coating layer polymer, such as 15 - 50%, more preferably 20 - 50%. Additives such as dispersants, colorants, pigment polymers, such as poly(ethyl acrylate, methyl methacrylate), anti-adhesion agents, and defoaming agents can also be included in the enteric coating layer. Other compounds may be added to increase the film thickness and reduce the diffusion of the acidic gastric juice into the acid-sensitive material. The maximum thickness of the applied enteric coating is usually limited only by the processing conditions and the desired dissolution profile.

[0201] Overcoat layer: The pellets coated with an enteric coating layer may optionally be further coated with one or more overcoat layers. The overcoat layer should be water-soluble or rapidly disintegrate in water. The overcoat layer can be applied to the enteric-coated laminated pellets by a coating or lamination procedure in a suitable apparatus such as a coating pan, a coating granulator, etc., or in a fluidized bed apparatus using water or an organic solvent for coating or lamination processes. The material of the overcoat layer is selected from pharmaceutically acceptable compounds such as sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc., and is used alone or as a mixture. Additives such as plasticizers, colorants, pigments, fillers, anti-adhesion agents, and anti-static agents, for example magnesium stearate, titanium dioxide, talc and other additives, may also be included in the overcoat layer. The overcoat layer can further prevent potential aggregation of the enteric-coated layer pellets, further protect the enteric coating layer from cracking during the compression process, and enhance the tableting process. The maximum thickness of the applied overcoat layer is usually limited by the processing conditions and the desired dissolution profile. The topcoat layer can also be used as a tablet film coating layer.

[0202] The enteric coating of a soft gelatin capsule can include an emulsion, oil, microemulsion, self-emulsifying system, lipid, triglyceride, polyethylene glycol, surfactant, other solubilizing agents, etc., and combinations thereof, in order to solubilize the active agent. The flexibility of the soft gelatin capsule is maintained by residual water and plasticizers. Further, in the case of gelatin capsules, spraying must be achieved at a relatively low relative humidity rate such that the gelatin is dissolved in water and can be achieved in a fluid bed or Wurster. Further, drying should be achieved without removing residual water or plasticizers and causing cracking of the capsule shell. Commercially available blends optimized for enteric coating of soft gelatin capsules such as Instamodel EPD (enteric polymer dispersion) are available from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a laboratory scale, enteric coated capsules can be prepared as follows. a) A step of rotating the capsules in a flask, or a step of immersing the capsules in a gently heated solution of an enteric coating material containing a plasticizer at the lowest possible temperature, or b) A step of rotating the capsules in a laboratory scale nebulizer / fluid bed and then drying them.

[0203] In the case of aqueous active agents, it may be particularly desirable to incorporate the drug into the aqueous phase of the emulsion. Such "water-in-oil" emulsions can provide a biophysical environment suitable for the drug and can provide an oil-water interface that protects the drug from the harmful effects of pH or enzymes that can degrade the drug. Further, such water-in-oil formulations can provide a lipid layer that can advantageously interact with the lipids in the body's cells and can increase the partitioning of the formulation onto the cell membrane. Such partitioning can increase the absorption of the drug in such a formulation into the circulation and thus increase the bioavailability of the drug.

[0204] In some embodiments, the water-in-oil emulsion contains an oil phase composed of medium-chain or long-chain carboxylic acids or their esters or alcohols, a surfactant or surface-active agent, and a water phase mainly containing water and an activator.

[0205] The medium-chain and long-chain carboxylic acids are in the range of C8 - C22 with up to 3 unsaturated bonds (and branches). 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.

[0206] Examples of these are oleic acid, gadoleic acid, and erucic acid. Unsaturated (polyolefinic) straight-chain monocarboxylic acids are also useful. Examples of these are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid, and behenolic acid. Examples of useful branched acids include, for example, diacetyl tartaric acid. The unsaturated olefin chains may also be hydroxylated or ethoxylated to prevent oxidation or to change the surface properties.

[0207] Examples of long-chain carboxylic acid esters include, but are not limited to, glyceryl monostearate; glyceryl monopalmitate; a mixture of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoate; glyceryl monooleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate and glyceryl monolinoeate; glyceryl linolenate; glyceryl monogaduate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoeate, glyceryl linolenate and glyceryl monogaduate; acetylated glycerides such as distilled acetylated monoglyceride; a mixture of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactate and silicon dioxide; d-alpha tocopherol polyethylene glycol 1000 succinate; a mixture of mono- and di-glyceride esters such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and di-glycerides; lactic acid mono- and di-glycerides; lactic acid carboxylic acid esters of glycerin and propylene glycol; lactic 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 monoglyceride; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of waxes; stearyl octanoate; C8-C30 cholesterol / lanosterol esters; and sucrose long-chain carboxylic acid esters.

[0208] Examples of the self-emulsifying long-chain carboxylic acid esters include those of the group such as stearic acid ester, palmitic acid ester, ricinoleic acid ester, oleic acid ester, behenic acid ester, ricinoleic acid ester, myristic acid ester, lauric acid ester, caprylic acid ester, caproic acid ester, and the like. In some embodiments, the oily phase may include a combination of two or more long-chain carboxylic acids or their esters or alcohols. In some embodiments, a medium-chain surfactant may be used, and the oil phase may include a mixture of caprylic / capric triglyceride and a C8 / C10 mono- / di-glyceride of caprylic acid, glyceryl caprylate or propylene glycol monocaprylate or a mixture thereof.

[0209] The alcohols that can be used are also exemplified by the hydroxyl forms of the carboxylic acids exemplified above and stearyl alcohol.

[0210] A surfactant (Surface active agent) or a surfactant is a long-chain molecule that accumulates at the hydrophilic / hydrophobic (water / oil) interface and can reduce the surface tension of the interface. As a result, the emulsion can be stabilized. In some embodiments, the surfactant is of the Tween® (polyoxyethylene sorbitan) family of surfactants, the Span® (sorbitan long-chain carboxylic acid ester) family of surfactants, the Pluronic® (ethylene or propylene oxide block copolymer) family of surfactants, the Labrasol®, Labrafil® and Labrafac® (each polyglycolized glyceride) family of surfactants, oleic acid, stearic acid, lauric acid or sorbitan esters of other long-chain carboxylic acids, poloxamer (a polyethylene - polypropylene glycol block copolymer or Pluronic®), other sorbitan or sucrose long-chain carboxylic acid esters, mono- and diglycerides, PEG derivatives of caprylic / capric triglyceride and mixtures thereof or mixtures of two or more of the above. In some embodiments, the surfactant phase may include a mixture of polyoxyethylene (20) sorbitan monooleate (Tween80®) and sorbitan monooleate (Span80®).

[0211] The aqueous phase may optionally contain an active agent and a buffer suspended in water.

[0212] In some embodiments, such emulsions are coarse emulsions, microemulsions and liquid crystal emulsions. In other embodiments, such emulsions may optionally contain a permeation enhancer. In other embodiments, spray-dried dispersions or microparticles or nanoparticles containing encapsulated microemulsions, coarse emulsions or liquid crystals can be used.

[0213] In some embodiments, the solid dosage forms described herein are parenterally administered time-delayed release dosage forms. As used herein, the term "parenterally administered time-delayed release" refers to delivery such that drug release is achieved at some generally predictable location in the distal intestine, more distal than would have been achieved in the absence of the delayed release modification. In some embodiments, the method for delaying release is a coating that becomes permeable, dissolves, ruptures, or is otherwise breached after a designed duration. The coating in a time-delayed release dosage form can have a defined period of erosion after which the drug is released (suitable coatings include polymer coatings such as HPMC, PEO, etc.), or has a core composed of a superdisintegrant or osmotic agent, or salts, hydrophilic polymers, typically water attractants such as polyethylene oxide or alkylcellulose, salts such as sodium chloride, magnesium chloride, sodium acetate, sodium citrate, sugars such as glucose, lactose or sucrose, or acids such as citric acid or gas generating agents such as citric acid and sodium bicarbonate that draw water through a semipermeable membrane, with or without any of the aforementioned acids incorporated into the dosage form. The semipermeable membrane is substantially impermeable to both drug and osmotic agent, but is permeable to water, which enters the dosage form at a substantially constant rate, increasing the pressure, and rupturing after the swelling pressure exceeds a specific threshold over the desired delay time. The permeability of the drug through this membrane should be less than 1 / 10 that of water, and in one embodiment less than 1 / 100 that of water permeability. Alternatively, the membrane can become porous by leaching out extractable aqueous phase over the desired delay time.

[0214] Osmotic dosage forms are described in Theeuwes U.S. Patent No. 3,760,984, and osmotic burst dosage forms are described in Baker U.S. Patent No. 3,952,741. These osmotic burst dosage forms can provide a single release pulse or multiple pulses when different devices with different timings are used. The timing of the osmotic burst can be controlled by the choice of polymer and the thickness or area of the semipermeable membrane surrounding the core containing both the drug and the osmotic agent or attractant. As the pressure in the dosage form increases with additional permeating water, the membrane stretches to its breaking point and then the drug is released. Alternatively, a specific break region can be created in the membrane by having a thinner and weaker region of the membrane or by adding a weaker material to a region of the coating membrane. Some preferred polymers with high water permeability that can be used as semipermeable membranes are cellulose acetate, cellulose acetate butyrate, cellulose nitrate, crosslinked polyvinyl, alcohol, polyurethane, nylon 6, nylon 6.6, and aromatic nylon. Cellulose acetate is a particularly preferred polymer.

[0215] In another embodiment, the time-delay coating that initiates the delay of drug release after at least partial dissolution of the enteric coating is composed of a hydrophilic erodible polymer that gradually begins to erode over time upon contact with water. Examples of such polymers include hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, microcrystalline cellulose; polysaccharides and their derivatives; 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); polyurethane; hydrogel; crosslinked polyacrylic acid; and cellulose polymers and their derivatives including but not limited to any combination or blend of the above.

[0216] Some preferred erodible hydrophilic polymers suitable for forming an 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 a linear polymer of unsubstituted ethylene oxide. The molecular weight of the poly(ethylene oxide) polymer can range from about 10 5 Daltons to about 10 7 Daltons. The preferred molecular weight range of the poly(ethylene oxide) polymer is from about 2x10 5 to 2x10 6 Daltons and is commercially available from The Dow Chemical Company (Midland, Mich.) under the name SENTRYR POLYOX™ water-soluble resin, NF (National Formulary) grade. When higher molecular weight polyethylene oxide is used, other hydrophilic agents, such as salts or sugars, such as glucose, sucrose, or lactose, which promote erosion or disintegration of this coating, are also included.

[0217] The time-delayed dosage form can be an enterion® capsule or a mechanical pill, such as a pH-sensitive capsule, that can release the drug after a pre-programmed time, or when a signal that can be transmitted is received, or when leaving the stomach.

[0218] The amount of the compounds of the present disclosure in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains from about 0.01 to 99.99 weight % of the BTK inhibitor compound on a weight percent (wt%) basis based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80 weight %.

[0219] The foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding. Accordingly, it is to be understood that the above description is intended to be illustrative and not limiting. Accordingly, the scope of the present disclosure should not be determined with reference to the above description, but instead should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. Additionally, the appended examples provide exemplary test protocols showing how clinical trials may be conducted.

Example

[0220] The following examples are provided to illustrate certain disclosed embodiments and should in no way be construed as limiting the scope of the present disclosure. In the examples discussed below, the BTK inhibitor defined above may also be interchangeably referred to as a "compound" or a "drug".

[0221] Example 1 - Phase 3 Randomized Double - Blind Placebo - Controlled Parallel - Group Trial to Evaluate the Efficacy and Safety of Tolebrutinib (SAR442168) in Adults with Generalized Myasthenia Gravis The objective of this trial is to evaluate the efficacy and safety of tolebrutinib 60 mg compared to placebo in adult participants with moderate - to - severe generalized myasthenia gravis (gMG) receiving standard of care (SoC).

[0222] The schematic diagram of the trial design is shown in Figure 1A. Abbreviations used in Figure 1A: DB: Double - Blind; EOT: End of Treatment; MMS: Minimal Manifest Status; OLE: Open - Label Extension; R: Randomized; SoC: Standard of Care; W: Week. Tables 1A1 and 1A2 shown below describe the activity schedule during the trial. Table 1B below describes the objectives and endpoints of the entire trial.

[0223]

Table 1

[0224]

Table 2

[0225]

Table 3

[0226]

Table 4

[0227]

Table 5

[0228]

Table 6

[0229]

Table 7

[0230]

Table 8

[0231]

Table 9

[0232]

Table 10

[0233]

Table 11

[0234]

Table 12

[0235]

Table 13

[0236]

Table 14

[0237]

Table 15

[0238]

Table 16

[0239]

Table 17

[0240]

Table 18

[0241]

Table 19

[0242] The treatment objectives and endpoints are shown in Table 1B.

[0243]

Table 20

[0244]

Table 21

[0245]

Table 22

[0246] 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 in MG; IgG: immunoglobulin G; IgM: immunoglobulin M; MG-ADL: myasthenia gravis activities of daily living; MGFA-PIS: Myasthenia Gravis Foundation of America post-intervention status; MG-QoL15: myasthenia gravis quality of life 15-item scale; MGII: myasthenia gravis impairment index; Musk: muscle-specific kinase; OCS: oral corticosteroid; OLE: open-label extension; PD: pharmacodynamics; PK: pharmacokinetics; QMG: quantitative myasthenia gravis; QoL: quality of life; SoC: standard of care.

[0247] Brief Overview This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and safety of 60 mg of trelbudivac once daily compared with placebo in adult participants aged 18 to 85 years with moderate to severe gMG receiving SoC. The 26-week double-blind treatment period includes a 2-year OLE period with quarterly visits following 7 site visits.

[0248] The efficacy of trelbudivac versus placebo during the double-blind period is evaluated by clinical assessments including physician examination or direct participant feedback, i.e., scales based on clinical outcome assessments. These assessments are continued during the OLE to measure long-term efficacy and safety.

[0249] Number of Participants Approximately 192 participants are screened to achieve 154 participants randomized to the trial intervention at a 1:1 randomization ratio (assuming a 20% screening failure rate).

[0250] Intervention Group and Duration The double-blind period includes a screening period (maximum 28 days), after which eligible participants are randomized to the treatment group, 60 mg oral, daily trelbudivac or matching placebo.

[0251] The treatment period is 26 weeks.

[0252] OLE includes all eligible participants who have completed the DB period of treatment. Participants receive 60 mg of oral, daily trebananib over a period of up to 2 years.

[0253] Post-trial access may be considered if needed and as approved by local regulations.

[0254] Trial Intervention Investigational Medicinal Product: - Formulation: Trebananib film-coated tablets - Route of administration: Oral - Dosage regimen: Take 60 mg once daily with food

[0255] Investigational Medicinal Product: - Formulation: Placebo matching trebananib film-coated tablets - Route of administration: Oral - Dosage regimen: Take once daily with food

[0256] The modified intention-to-treat (mITT) population includes all randomized and treated participants who have baseline values and at least one post-baseline value for any efficacy assessment. Participants are analyzed as randomized. This becomes the primary efficacy population.

[0257] Trial Population Inclusion Criteria Participants are eligible for inclusion in the trial only if all of the following criteria apply as shown in Table 1C.

[0258]

Table 23

[0259]

Table 24

[0260]

Table 25

[0261]

Table 26

[0262] Exclusion Criteria If any of the following criteria are applied as shown in Table 1D, the participant will be excluded from the study.

[0263]

Table 27

[0264]

Table 28

[0265]

Table 29

[0266]

Table 30

[0267]

Table 31

[0268]

Table 32

[0269]

Table 33

[0270]

Table 34

[0271]

Table 35

[0272] Considerations Regarding Lifestyle Diet and Dietary Restrictions: Trabectedin should be taken with a normal diet. If possible, the meal at which trabectedin is taken (e.g., breakfast, lunch, or dinner) should be consistent throughout the trial. The typical meal at which the study intervention is taken is recorded at each visit. If it is necessary to change the meal time for study intervention administration, a minimum 12-hour gap should be maintained between two administrations.

[0273] Caffeine, Alcohol, and Tobacco For each visit with PK / PD evaluation, participants should refrain from consuming caffeine or xanthine-containing products (e.g., coffee, tea, cola beverages, and chocolate) from 2 hours before treatment initiation until late in the day after collection of the final PK and / or PD samples.

[0274] For each visit with PK / PD evaluation, participants should refrain from consuming alcohol from 24 hours before treatment initiation until late in the day after collection of the final PK and / or PD samples.

[0275] Throughout the trial, participants should be warned not to consume a significant amount of alcohol, defined as less than 14 grams per day (standard 1 cup) for female participants or less than 28 grams per day (standard 2 cups) for male participants, on a regular basis.

[0276] Individuals who do not meet the inclusion criteria for this trial may be re-screened up to two times. New participant numbers need to be assigned to the re-screened participants. There is no need to set a waiting period between the screening ineligibility date and the re-screening.

[0277] If a participant does not meet the inclusion criteria for specific dynamic laboratory tests at screening (Visit 1), these laboratory evaluations can be repeated at the discretion of the principal investigator of the clinical trial if it is determined that the parameter results may return to an acceptable range for trial inclusion within the baseline / randomization screening period (Visit 2). If the trial ultimately meets the inclusion criteria, it is not necessary to consider such participants as screening ineligible.

[0278] Trial Intervention and Concomitant Therapy The trial intervention was defined as any investigational intervention, marketed product, placebo, or medical device intended to be administered to trial participants in accordance with the trial protocol.

[0279]

Table 36

[0280]

Table 37

[0281] Dose Modification A decrease in dose is not anticipated in this trial. If it is considered necessary due to an AE, treatment may need to be interrupted or permanently discontinued.

[0282] Concomitant Therapy Prohibited Agents Any medications (including over-the-counter or prescription drugs, recreational drugs, vitamins, and / or herbal supplements), vaccines, or medical procedures that a participant is receiving at the time of enrollment or during the trial must be recorded together with the following: - Reason for use - Administration dates including start date and end date - Dosage information including dosage and frequency If there are questions regarding concomitant therapy or previous therapy, it is necessary to contact the sponsor of the clinical trial.

[0283] Participants should refrain from taking prescription or over-the-counter herbal medications containing St. John's wort within 14 days of the start of the trial intervention until the completion of the last visit.

[0284] Live (attenuated) vaccines should not be administered during the trial.

[0285] For some prohibited concomitant medications (e.g., aspirin for headache), if the use is not chronic, a temporary suspension of the IMP can be considered before making a decision to permanently discontinue the IMP.

[0286] Prohibited treatments during the trial also include the following: - IV CS and OCS > 20 mg / day (except when used as rescue therapy) - Cyclosporine and cyclophosphamide. - Rituximab and other B-cell depletion therapies (anti-CD20 or anti-CD19), eculizumab and other complement pathway targeting drugs, anti-FcRn, or any monoclonal antibody.

[0287] Anticoagulant / antiplatelet therapy is not permitted to be conducted simultaneously with the IMP including the following: - Acetylsalicylic acid (aspirin) > 81 mg / day - Antiplatelet drugs (e.g., 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 inhibitor / inducer: Potent and moderate inducers of CYP3A or potent inhibitors of the CYP2C8 hepatic enzyme are not permitted throughout the trial.

[0288] Tretinib is a substrate of the CYP3A4 and CYP2C8 isoenzymes. In healthy participants, a potent CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased tretinib (area under the curve [AUC]) exposure 1.8-fold, and a potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased tretinib (AUC) exposure 8.4-fold. Based on the satisfactory safety and tolerability profile and on the observed exposures in healthy participants who received tretinib once daily at a maximum dose of 240 mg for 14 days under fed conditions, drugs that strongly inhibit CYP3A4 are permitted, and drugs that strongly inhibit CYP2C8 are not permitted. In healthy participants, potent CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) decreased tretinib exposure 6-fold. Therefore, strong and moderate (predicted) CYP3A inducers are not permitted as they may decrease tretinib exposure and efficacy.

[0289] Other drugs permitted with some restrictions: Anticoagulants / antiplatelets - Acetylsalicylic acid (aspirin) ≤ 81 mg / day - Paracetamol / acetaminophen at a dose of 3 grams / day or less is permitted for use at any time during the trial. If clinically necessary for the treatment of existing medical conditions or new events, non-steroidal anti-inflammatory drugs (NSAIDs) (other than acetylsalicylic acid) at the recommended dose may be administered for a short period (maximum 5 days) during the trial. The trial physician must record the use of NSAIDs (and any other medications) in the eCRF. The trial physician needs to evaluate the signs of bleeding events for participants taking NSAIDs together with the IMP. For bleeding events of grade 2 or higher, the non-steroidal anti-inflammatory drug should be discontinued.

[0290] Rescue Therapy The use of rescue therapy for gMG exacerbation is permitted at any time between the DB and OLE parts of the trial, at the discretion of the trial physician-in-charge, if there is an increase of at least 2 points in at least one of the individual non-ocular MG-ADL items compared to the MG-ADL value on day 1, or in case of new or worsening respiratory / ocular symptoms. Rescue therapy may include IVIg, plasma exchange, change in the SoC OCS dose, or any use of a new CS. If rescue therapy is needed, the sponsor of the trial should be notified, if possible, before administration of the treatment, without compromising the safety of the participant. The date and time of administration of rescue therapy, as well as the name and dosing regimen, must be recorded. If rescue therapy is used during the DB period, the trial intervention needs to be permanently discontinued.

[0291] The provision of rescue therapy is specified at the national level. The use of rescue therapy must be recorded in the eCRF.

[0292] Liver Chemistry Stop Criteria If a participant meets one of the conditions outlined in the algorithm (see Figures 4A and 4B), it is necessary to discontinue the trial intervention due to abnormal liver function tests. Abnormal liver chemistry that does not meet the stop rules defined in the trial protocol may also require discontinuation if the trial physician-in-charge determines that discontinuation is in the best interest of the participant.

[0293] QTc Stop Criteria If clinically significant findings (including, but not limited to, changes from baseline in the QTc interval corrected using Fridericia's formula [QTcF]) are confirmed by ECG after enrollment, the trial physician-in-charge or a qualified designee will determine whether the participant can continue to receive the trial intervention and whether any changes in the management of the participant are necessary. Review of the ECG findings by a cardiologist may be considered for the final decision to discontinue the trial intervention due to ECG changes. This review of the ECG printed at the time of collection must be documented. Any clinically important new findings must be reported as AEs.

[0294] Temporary suspension The principal investigator of the clinical trial may consider temporarily suspending the intervention if an AE is suspected or if the clinical trial is interrupted due to a regional or national emergency declared by a government agency. For all temporary suspensions of the intervention, the principal investigator of the clinical trial must record the period on the appropriate page of the eCRF.

[0295] If surgery is necessary during the trial, the benefit-risk and bleeding risk of suspending the IMP for at least 3 to 7 days before and after surgery should be considered.

[0296] The following lead to temporary treatment suspension: · Cytopenia: It is necessary to follow the algorithm of the sponsor for neutropenia and thrombocytopenia according to Figures 2 and 3. · Increase in serum creatinine, creatine phosphokinase (CPK), and liver enzymes: Follow the corresponding algorithm according to Figure 5. · Cardiac arrhythmia (atrial fibrillation): Any grade 3 event (symptomatic, requiring urgent intervention, device [e.g., pacemaker], ablation, new onset). · Suicide risk according to C-SSRS: When the participant scores "Yes" in item 4 or 5 of the suicidal ideation section, or "Yes" in any item of the suicidal behavior section.

[0297] If necessary, the principal investigator of the clinical trial or the participant may consider temporarily suspending the treatment for other reasons, such as interruption of the trial due to an emergency in a region or country declared by a government agency like COVID-19, interruption of the trial due to other diseases, or safety concerns due to the need for a prohibited concomitant medication. The treatment can be resumed later if it is considered safe and appropriate.

[0298] If the participant no longer wishes to take the IMP, the participant is advised to remain in the trial.

[0299] The principal investigator should discuss with the participant about the major visits. It is emphasized that the value of all research data collected during the continuing involvement is important for the public health value of the trial.

[0300] Participants who discontinue the trial intervention should be clearly questioned about the possible AE contribution to their decision, and information on the induced AEs must all be documented.

[0301] All trial terminations must be recorded by the principal investigator in the appropriate screening of the CRF or eCRF and the participant's medical records. The medical records should document at least the termination date and reason.

[0302] In addition, the participant can withdraw consent to discontinue participation in the trial. Withdrawal of consent for the intervention should be distinguished from withdrawal of consent for FU visits and withdrawal of consent for non-participant contact FU (e.g., checking medical records). The facility should document all cases of withdrawal of consent.

[0303] Participants who discontinue the trial cannot be randomized / reassigned (treatment) again in the trial. Their incorporation and intervention numbers must not be reused.

[0304]

Table 38

[0305]

Table 39

[0306]

Table 40

[0307] Liver and Other Safety: Behavior and Follow-up Assessments The actions described in Table 1H and Figures 2-8 are necessary only for the events of increased ALT and thrombocytopenia. For all other safety events described, these are suggested by the medical judgment of the principal investigator of the clinical trial.

[0308] Neutropenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting is met.

[0309] Thrombocytopenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0310] Abbreviations in Figure 4A: 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; HBV: 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.

[0311] Note: "Baseline" refers to the ALT sampled at the time of baseline visit, or, if the baseline value is not available, the most recent ALT sampled before the baseline visit. This algorithm does not apply to examples of increased ALT during screening.

[0312]

Table 41

[0313]

Table 42

[0314] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the AE reporting general guidelines in Appendix 3 (Section 10.3) is met.

[0315] An increase in CPK is recorded as an AE only if at least one of the criteria of the general guidelines for reporting adverse events is met.

[0316] Examples of drugs that may alter trebrutinib metabolism The following drugs are strong / moderate inducers of CYP3A or strong inhibitors of the CYP2C8 hepatic enzyme and may alter the pharmacokinetics of trebrutinib by interaction with P450-mediated metabolism, and should not be taken concomitantly with the IMP during the trial (according to the list of the University of Washington's drug interaction database program).

[0317] Note that the list provided is not exhaustive and it is necessary to refer to the product information of the drugs intended for combination use.

[0318]

Table 43

[0319] Abbreviations AChEI: Acetylcholinesterase inhibitor AChR: Acetylcholine receptor ADL: Activities of daily living AE: Adverse event AESI: Adverse event of special interest ALT: Alanine aminotransferase ANCOVA: Analysis of covariance AUC: Area under the curve BCR: B-cell receptor BTK: Bruton 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: Corticosteroid 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 Delivery of Investigational Drug ECG: Electrocardiogram eCRF: Electronic Case Report Form EOS: End of Study 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: Fcγ Receptor FcεR: Fcε Receptor FSH: Follicle-Stimulating Hormone FU: Follow-Up GCP: Good Clinical Practice GDPR: General Data Protection Regulation gMG: Generalized Myasthenia Gravis HCRU-MG: Healthcare Resource Utilization in Myasthenia Gravis HIV: Human Immunodeficiency Virus HRT: Hormone Replacement Therapy IA: Interim Analysis IB: Investigator's Brochure ICE: Incident ICF: Informed Consent Form ICH: International Conference on 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 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 Status: MGII: Myasthenia Gravis Impairment Index MG-QoL15: Myasthenia Gravis - Quality of Life 15-item Scale mITT: Modified Intention to Treat MMRM: Mixed Model for Repeated Measures MS: Multiple Sclerosis MuSK: Muscle-Specific Kinase NCI: National Cancer Institute NSAID: Non-Steroidal Anti-Inflammatory Drug OCS: Oral Corticosteroid OLE: Open-Label Extension PCSA: Potentially Clinically Significant Abnormality PD: Pharmacodynamics pEOT: Premature End of Treatment PGIS: Patient Global Impression of Severity: PK: Pharmacokinetics QMG: Quantitative Myasthenia Gravis QoL: Quality of Life QTcF: QTc Interval Corrected Using Fridericia's Formula RMS: Relapsing Multiple Sclerosis SAE: Serious Adverse Event SAP: Statistical Analysis Plan SD: Standard Deviation SoA: Schedule of Activities SoC: Standard of Care SUSAR: Suspected Unexpected Serious Adverse Reaction TE: Treatment Emergent TEAE: Treatment Emergent Adverse Event TLR: Toll-Like Receptor ULN: Upper Limit of Normal US: United States of America VAS: Visual Analog Scale WOCBP: Women of Childbearing Potential

[0320] Example 2 - Phase 3 Randomized Double-Blind Efficacy and Safety Trial Comparing SAR442168 and Teriflunomide (Aubagio®) in Participants with Relapsing-Remitting Multiple Sclerosis (GEMINI 2) The objective of this Phase 3 trial is to evaluate SAR442168 in the RMS population. Efficacy is evaluated by the judged relapse rate, disability progression, and MRI findings of disease activity (Gd-enhancing lesions and new / enlarged T2 hyperintense lesions). Along with the evaluation of other secondary and exploratory endpoints, this trial provides a comprehensive assessment of the efficacy and safety of SAR442168 in the RMS population.

[0321] The schema of the trial design is shown in Figure 1B. Abbreviations used in Figure 1B: EOS, End of Study; MRI, Magnetic Resonance Imaging; R, Randomization. “Month - 1 (D - 28 to D - 1)” refers to the screening period as “Day - 28 to Day - 1”, and “Month 0 (D1)” refers to the randomization on Day 1.

[0322] Tables 2A1 and 2A2 shown below describe the schedule of activities during the trial. The following Table 2B describes the objectives and endpoints of the whole trial.

[0323]

Table 44

[0324]

Table 45

[0325]

Table 46

[0326]

Table 47

[0327]

Table 48

[0328]

Table 49

[0329]

Table 50

[0330]

Table 51

[0331]

Table 52

[0332]

Table 53

[0333]

Table 54

[0334]

Table 55

[0335]

Table 56

[0336]

Table 57

[0337]

Table 58

[0338]

Table 59

[0339]

Table 60

[0340]

Table 61

[0341]

Table 62

[0342]

Table 63

[0343]

Table 64

[0344] The treatment objectives and endpoints are shown in Table 2B.

[0345]

Table 65

[0346]

Table 66

[0347]

Table 67

[0348]

Table 68

[0349]

Table 69

[0350]

Table 70

[0351] Overall Design: This is an active - control, parallel - group, multi - center, event - driven (6 - month confirmed disability worsening (CDW)) trial with a variable treatment period in the range of about 18 to 36 months, using a 3 - phase, randomized, double - blind, double - dummy, 2 - arm design.

[0352] Disclosure Statement: This is a parallel treatment trial using two arms that are blinded / masked for participants, investigators, site staff, and sponsors.

[0353] Number of Participants: Approximately 1200 people will be screened to achieve approximately 900 (±10%) participants who are randomly assigned to the trial intervention with a total sample size of at least 1800 patients across two RMS trials (EFC16033 and EFC16034) of the same design.

[0354] Intervention group and period: Participants are randomly assigned in a 1:1 ratio to receive either a selected dose of 60 mg of oral SAR442168 (established from dose setting study DRI15928), placebo matching to either teriflunomide tablets or 14 mg of oral teriflunomide, and placebo matching to SAR442168 tablets daily. Randomization is stratified by the Expanded Disability Status Scale (EDSS) score at screening (<4 vs. ≥4) and geographical region (US vs. non-US).

[0355] Study Intervention Investigational drug: · Formulation: Trebltinib film-coated tablets · Route of administration: Oral · Dosage regimen: 60 mg once daily

[0356] Investigational drug: · Formulation: Teriflunomide tablets · Route of administration: Oral · Dosage regimen: 14 mg once daily

[0357] Investigational drug: · Formulation: Placebo matching to SAR442168 film-coated tablets · Route of administration: Oral · Dosage regimen: Once daily

[0358] Investigational drug: · Formulation: Placebo matching to teriflunomide tablets · Route of administration: Oral · Dosage regimen: Once daily

[0359] Non-investigational drug · Formulation: MRI contrast agent · Route of administration: Intravenous (IV) · Dosage regimen: According to each label

[0360] Non-investigational drug · Formulation: Cholestyramine · Route of administration: Oral · Administration regimen: For accelerated removal treatment sequence, 8 g three times daily for 11 days (4 g three times daily for 11 days in case of intolerance). Should follow the local label of teriflunomide.

[0361] Temporary interruption of investigational medicinal product (IMP) by surgery If surgery is necessary during the trial, consider the benefit / risk of withholding IMP for at least 3 - 7 days before and after surgery according to the type of surgery and the risk of bleeding.

[0362] The objective of this Phase 3 trial is to evaluate SAR442168 in the RMS population. Efficacy is evaluated by the determined recurrence rate, disability progression, and MRI findings of disease activity (Gd - enhancing lesions and new / enlarging T2 - hyperintense lesions). Together with the evaluation of other secondary and exploratory endpoints, this trial provides a comprehensive assessment of the efficacy and safety of SAR442168 in the RMS population.

[0363] In ongoing Phase 3 trials and LTS trials, trebranitinib has generally shown good tolerance to date. The risks identified for trebranitinib are identified as follows. - SAEs that occurred under treatment for drug - induced liver injury (DILI) were reported in the ongoing Phase 3 trial, but all cases occurred between the second and third months, appeared to be reversible after treatment discontinuation, and potential confounding factors were identified for some cases.

[0364] Trial population Inclusion criteria Participants are eligible for inclusion in the trial only if all of the following criteria are applied as shown in Table 2C.

[0365]

Table 71

[0366]

Table 72

[0367]

Table 73

[0368] Exclusion Criteria If any of the following criteria are applied as shown in Table 2D, the participant will be excluded from the study.

[0369]

Table 74

[0370]

Table 75

[0371]

Table 76

[0372]

Table 77

[0373]

Table 78

[0374]

Table 79

[0375]

Table 80

[0376]

Table 81

[0377]

Table 82

[0378]

Table 83

[0379] Considerations Regarding Lifestyle Diet and Dietary Restrictions: Trebananib (IMP) shall be taken with a normal diet. If possible, the meal at which IMP is taken (e.g., breakfast, lunch, or dinner) should be consistent throughout the entire study. The typical meal at which IMP is taken is collected at each visit. If it is necessary to change the meal time for IMP administration, a minimum 12-hour gap should be maintained between two administrations.

[0380] Caffeine, Alcohol, and Tobacco: Throughout the study, participants should be warned not to consume a significant amount of alcohol, defined as less than 14 grams (standard 1 cup) per day for female participants or less than 28 grams (standard 2 cups) per day for male participants, on a regular basis.

[0381] Study Interventions Study interventions are defined as any investigational intervention, marketed product, or placebo intended to be administered to study participants in accordance with the study protocol.

[0382]

Table 84

[0383] During protocol-scheduled on-site visits, intermediate visits may be required for IMP dispensing. As an alternative to these visits, or as an alternative to on-site IMP dispensing, if necessary, IMP may be supplied to participants from the site via a courier company approved by the sponsor for home delivery (direct shipment to the patient), if permitted by local regulations and approved by the sponsor of the study.

[0384] Non - investigational drug MRI contrast agent · Route of administration: IV · Dosage regimen: According to each label Cholestyramine · Route of administration: Oral · Dosage regimen: 8 g once a day for 11 days (4 g once a day for 11 days in case of intolerance), 3 times. Should follow the local label of teriflunomide.

[0385] Combination therapy Any drug or vaccine (including over - the - counter or prescription drugs, vitamins, and / or herbal supplements) that the participant is receiving at the time of registration or during the trial must be recorded together with the following: · Reason for use · Date of administration (including start and end dates) · Dosage information including dose and frequency

[0386] Participants should refrain from taking prescription or non - prescription drugs (including vitamins and dietary or herbal supplements) within 7 days before the start of the trial intervention (or 14 days if the drug is a potential enzyme inducer) or within 5 half - lives (whichever is longer) until the completion of the follow - up visit, provided that, in the opinion of the principal investigator of the clinical trial, the drug does not interfere with the trial.

[0387] Live (attenuated) vaccines should not be administered during the intervention period.

[0388] The treatment of MS described in exclusion criterion E07 is not permitted after randomization while the participant is on trial treatment. Short - term use (3 - 5 days) of glucocorticoids (e.g., for MS relapse treatment or acute diseases) and topical corticosteroids (e.g., topical, nasal, ocular, otic, intra - articular) is permitted.

[0389] If there are questions regarding combination therapy or previous therapy, it is necessary to contact the medical monitor.

[0390] For some prohibited combinations (e.g., aspirin > 81 mg / day for headache), if the use is not chronic, a temporary suspension of IMP can be considered before making a decision to permanently discontinue IMP.

[0391] Drugs for the treatment of MS symptoms (e.g., walking disorder, fatigue, spasm, incontinence, pain) should be maintained at a stable dose before screening and during the treatment period, if clinically feasible.

[0392] Anticoagulant / antiplatelet therapy is not permitted to be carried out simultaneously with IMPs including the following: - acetylsalicylic acid (aspirin) > 81 mg / day - antiplatelet drugs (e.g., clopidogrel) - warfarin (vitamin K antagonist) - heparin (including low molecular weight heparin (antithrombin agent)) - dabigatran (direct thrombin inhibitor) - apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors)

[0393] Paracetamol / acetaminophen at a dose of 3 grams / day or less is permitted for use at any point during the trial. If clinically necessary for the treatment of existing medical conditions or new events, during the trial, non-steroidal anti-inflammatory drugs (NSAIDs) (other than acetylsalicylic acid), preferably the selective cyclooxygenase-2 inhibitor at the lowest effective dose, may be administered for a short period (maximum 5 days). The treating physician must record the use of NSAIDs (and any other drugs) in the eCRF.

[0394] CYP inhibitor / inducer: Strong and moderate inducers of CYP3A or strong inhibitors of the CYP2C8 hepatic enzyme are not permitted throughout the trial (see Appendix 8A (Section 10.8)). · Tolebrutinib: Tolebrutinib is a substrate of CYP3A4 and CYP2C8 isoenzymes. In healthy participants, a potent CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased tolebrutinib area under the curve (AUC) exposure 1.8-fold (INT16385 study), and a potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased tolebrutinib (AUC) exposure 8.4-fold (INT16726 study). Based on the satisfactory safety and tolerability profile, and on the observed exposure in healthy participants who received tolebrutinib once daily at a maximum dose of 240 mg over 14 days under fed conditions (TDR16862 study), drugs that strongly inhibit CYP3A4 are tolerated, while drugs that strongly inhibit CYP2C8 are not permitted. In healthy participants, potent CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) decreased tolebrutinib exposure 6-fold (INT16726 study). Therefore, strong and moderate (predicted) CYP3A inducers are not permitted as they may decrease tolebrutinib exposure and efficacy. See Table 2H for the list of drugs not to be used. · Teriflunomide: Other potent CYP and transporter inducers should be avoided as they may decrease teriflunomide exposure. Rifampicin and other known potent CYP and transporter inducers (e.g., carbamazepine, phenobarbital, phenytoin, abacimibe, lumacaftor, rifapentine, rifabutin, and St. John's wort) should be avoided. Since teriflunomide is a metabolite of leflunomide, leflunomide is prohibited.

[0395] The use of cholestyramine (and other bile acid sequestrants) and activated charcoal should be avoided as they may cause a significant decrease in the plasma concentration of teriflunomide.

[0396] Cholestyramine can only be used if an accelerated removal procedure sequence is required. In exceptional circumstances (for example, if cholestyramine is not tolerated or not available), the use of activated carbon (as per the current Aubagio SmPC) can be considered.

[0397] Inhibitors of breast cancer resistance protein (BCRP) (e.g., eltrombopag and gefitinib) should be avoided. Based on in vitro studies, teriflunomide is a substrate of the efflux transporter BCRP, and these drugs may increase teriflunomide exposure (Appendix 8B (Section 10.9)).

[0398] Many drugs need to be used with caution as their exposure can be altered by teriflunomide. Appropriate adjustments need to be made to monitor the effect and ensure timely decisions regarding drug changes. ·Medicines metabolized by CYP2C8 (e.g., repaglinide, pioglitazone, and rosiglitazone) should be used with caution during treatment with IMP as their concentrations may increase after CYP2C8 inhibition by teriflunomide. ·An increase in ethinyl estradiol and levonorgestrel exposure has been observed after repeated doses of teriflunomide (Aubagio (Teriflunomide) (Package Insert). Genzyme Corporation. Cambridge, MA 02142; 2021.). ·This interaction of teriflunomide is not expected to adversely affect the effectiveness of oral contraceptives, but should be considered when selecting or adjusting the oral contraceptive used during this trial. ·Medicines metabolized by CYP1A2 (e.g., duloxetine, alosetron, theophylline, and tizanidine) should be used with caution during treatment with IMP due to the ability of teriflunomide to induce CYP1A2 and decrease the effectiveness of these products. · Administration of substrates of organic anion transporter 3 (OAT3) (e.g., cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, and cimetidine) should be carried out with caution during the trial because teriflunomide may increase exposure to these drugs through inhibition of OAT3. · Co - administration of teriflunomide with substrates of BCRP (e.g., sulfasalazine) and the organic anion transporting polypeptide (OATP) family (e.g., rosuvastatin, simvastatin, atorvastatin, pravastatin, nateglinide, repaglinide, and rifampicin) should be used with caution during the trial because teriflunomide may increase exposure to these products. Participants should be closely monitored for signs and symptoms of excessive drug exposure and dose reduction should be considered. When used with the IMP, the dose of rosuvastatin should not exceed 10 mg once daily.

[0399] Dose modification A decrease in dose is not anticipated in this trial. If it is considered necessary due to an AE, treatment may need to be interrupted or permanently discontinued (Sections 7 and 8.3).

[0400] Discontinuation of trial intervention Final discontinuation Trial intervention should be continued for as long as possible.

[0401] Permanent interruption of intervention is any interruption of treatment related to the final decision by the principal investigator or the participant not to re - expose the participant to the trial intervention at any time.

[0402] In rare cases, it may be necessary for a participant to permanently discontinue the trial intervention. If the trial intervention is permanently discontinued, the participant is required to remain in the trial being evaluated until the EOS visit. This is important to continue to assess safety. For data collected at the time of discontinuation of the trial intervention, refer to the SoA (Tables 2A1 and 2A2). If the trial intervention is permanently interrupted, the participant should be treated for MS according to the best judgment of the local clinical practice and principal investigator of the clinical trial.

[0403] The legitimate reasons for the principal investigator of the clinical trial to discontinue the participant's trial treatment may be as follows. · An adverse event that poses a risk to the participant's safety, or when the principal investigator of the clinical trial and / or the participant considers it desirable or necessary to discontinue the trial intervention. · When the IMP discontinuation criteria are met according to the guidance for follow-up of abnormal test results (Figures 2 to 8). · In the opinion of the principal investigator of the clinical trial, the participant is no longer deriving a therapeutic / clinical benefit. · At the participant's request, i.e., withdrawal of consent to treatment. · When a female participant becomes pregnant during the trial or wishes to become pregnant. · When a male participant wishes to impregnate a child during the trial. · Severe opportunistic infections (e.g., PML (see Figure 6), HIV). · Continuing need for / chronic use of prohibited concomitant medications (see combination therapies in this example and Table 2H).

[0404] When a participant meets one of the conditions outlined in the algorithm (Figures 4A and 4B), or when the principal investigator of the clinical trial considers it to be in the best interest of the participant, the principal investigator of the clinical trial should consider discontinuing the trial intervention for abnormal liver function.

[0405] Clinically significant abnormal clinical test values or ECG parameters are immediately retested for confirmation 24 hours later before determining the final discontinuation of the IMP for the relevant participant.

[0406] If clinically significant findings are identified on the ECG after registration (including changes from the baseline of the corrected QT interval (QTc), using, but not limited to, the Fridericia formula [QTcF]), the principal investigator or qualified designee will determine whether the participant can continue in the study and whether any changes to the participant's management are required. Review of the ECG findings by a cardiologist may be considered for the final decision to discontinue the study intervention due to ECG changes. This review of the ECG findings recorded at the time of collection must be documented. Any clinically important new ECG findings must be reported as AEs.

[0407] For data collected at the time of intervention discontinuation and follow-up and additional evaluations that need to be completed, refer to the SoA (Tables 2A1 and 2A2).

[0408] Additional tests can be performed at any time during the study if the principal investigator determines it is necessary or if required by local regulations.

[0409]

Table 85

[0410]

Table 86

[0411] ALT: Alanine aminotransferase; anti-HBc: antibody against hepatitis B core antigen; anti-HB: 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 glutamate-oxaloacetate transaminase; SGPT: serum glutamate-pyruvate transaminase; TB: tuberculosis; ULN: upper limit of normal; WBC: white blood cell Details of the liver chemistry stopping criteria, necessary actions, and follow-up evaluations after observation of a ALT > 3×ULN are shown in FIGS. 4A and 4B. If the INR is measured, clinical laboratory findings of ALT > 3×ULN and bilirubin ≥ 2×ULN (> 35% direct bilirubin), or ALT > 3×ULN and international normalized ratio (INR) > 1.5 may suggest severe liver injury and must be reported as an SAE. b Calculate other renal function parameters, creatinine clearance (CrCl). c Local urine testing for pregnancy is the standard of the protocol unless serum testing is required by local regulations or the IRB / IEC (except for screening visits where a serum pregnancy test is necessary).

[0412] Liver and other safety: Actions and follow-up evaluations The treatments described in Tables 2G-A and FIGS. 2-8 are only required for events of increased ALT and thrombocytopenia. For all other safety events described, these are suggested by the medical judgment of the investigator-in-charge of the clinical trial.

[0413] Neutropenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0414] Thrombocytopenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0415] Abbreviations in Figure 4A: 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; HBV: Hepatitis B core; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; IgM: Immunoglobulin M; IMP: Investigational drug; 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

[0416] Note: "Baseline" refers to the ALT sampled at baseline visit, or, if the baseline value is not available, the most recent ALT sampled before the baseline visit. This algorithm does not apply to examples of increased ALT during screening.

[0417]

Table 87

[0418]

Table 88

[0419] Abbreviations in Figure 5: ARF, Acute renal failure; ULN, Upper limit of normal; DIC, Disseminated intravascular coagulation; CPK, Creatine phosphokinase; ECG, Electrocardiogram; PK, Pharmacokinetics.

[0420] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting is met.

[0421] Abbreviations in Figure 8: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0422] An increase in CPK is recorded as an AE only if at least one of the criteria of the general guidelines for reporting AEs is met.

[0423] Suspected PML: If either the clinical symptoms or MRI features of the participant suggest PML, the diagnostic and action algorithm described in Figure 6 is recommended.

[0424] Abbreviations in Figure 6: Abbreviations: CSF, cerebrospinal fluid; GD, gadolinium; IMP, investigational drug; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.

[0425] Propose the characteristics of clinical symptoms or MRI lesions suspected of PML in Table 2G-B (based on Berger et al. Neurology 2013, 80, 1430-1438 and Kappos et al. Lancet Neurol. 2007, 6, 431-441).

[0426]

Table 89

[0427] Clinical or MRI features suggesting PML should be recorded as AE / AESI / SAE.

[0428] Examples of drugs that may alter trebranib metabolism The following drugs are strong / moderate inducers of CYP3A or strong inhibitors of the CYP2C8 hepatic enzyme and may alter the pharmacokinetics of trebrutinib through interaction with P450-mediated metabolism, and should not be taken concurrently with the IMP during the trial (according to the list of the University of Washington's Drug Interaction Database program).

[0429] It should be noted that the list provided is not exhaustive, and it is necessary to refer to the product information of the drugs for combination use.

[0430]

Table 90

[0431] Abbreviations ADL: Activities of Daily Living AE: Adverse Event AESI: Adverse Event of Special Interest ALT: Alanine Aminotransferase ARR: Annualized Relapse Rate AUC: Area Under the Curve BCRP: Breast Cancer Resistance Protein BTK: Bruton Tyrosine Kinase CDW: Confirmed Disability Progression CFR: Code of Federal Regulations Chi3L1: Chitinase-3-like Protein-1 CNS: Central Nervous System CPK: Creatine Phosphokinase CRF: Case Report Form CSR: Clinical Study 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: End of test EQ-5D-5L: EuroQol 5-Dimension 5-Level Questionnaire EU: European Union FSH: Follicle-stimulating hormone GCP: Good Clinical Practice Gd: Gadolinium HRT: Hormone replacement therapy ICF: Informed consent form ICH: International Council for Harmonisation 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 system IV: Intravenous JCV: John Cunningham virus LTS: Long-term safety 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: Magnetization transfer ratio 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: Non-steroidal anti-inflammatory drug OAT3: Organic anion transporter 3 PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive multifocal leukoencephalopathy PPMS: Primary progressive multiple sclerosis QTcF: QTc interval corrected using Fridericia's formula RMS: Relapsing remitting multiple sclerosis SAE: Serious adverse event SAP: Statistical analysis plan SEL: Slowly expanding lesion SmPC: Summary of product characteristics SoA: Schedule of activities SPMS: Secondary progressive multiple sclerosis Test manual: Test reference manual SWI: Susceptibility weighted imaging TEAE: Treatment-emergent adverse event ULN: Upper limit of normal US: United States of America USPI: US prescribing information WOCBP: Women of childbearing potential

[0432] Example 3 - Phase 3 randomized double-blind efficacy and safety trial comparing SAR442168 with placebo in participants with non-relapsing secondary progressive multiple sclerosis (HERCULES) Overall design: This is a phase 3, randomized, double-blind, two-arm, placebo-controlled, parallel-group, multi-center, event-driven (6-month confirmed disability progression (CDP)) trial with a variable treatment period in the range of approximately 24 to 48 months. The schematic diagram of the trial design is shown in Figure 1C. Abbreviations used in Figure 1C: CD, confirmed disability progression; EOS, end of study; MRI, magnetic resonance imaging; R, randomization. "-1 month (D-28 to D-1)" refers to the screening period as "-28 days to -1 day", and "0 month (D1)" refers to randomization on day 1.

[0433] Tables 3A1 and 3A2 shown below describe the schedule of activities during the trial. The following Table 3B describes the objectives and endpoints of the entire trial.

[0434]

Table 91

[0435]

Table 92

[0436]

Table 93

[0437]

Table 94

[0438]

Table 95

[0439]

Table 96

[0440]

Table 97

[0441]

Table 98

[0442]

Table 99

[0443]

Table 100

[0444]

Table 101

[0445]

Table 102

[0446]

Table 103

[0447]

Table 104

[0448]

Table 105

[0449]

Table 106

[0450]

Table 107

[0451]

Table 108

[0452]

Table 109

[0453]

Table 110

[0454]

Table 111

[0455]

Table 112

[0456]

Table 113

[0457]

Table 114

[0458]

Table 115

[0459]

Table 116

[0460]

Table 117

[0461] The treatment objectives and endpoints are shown in Table 3B.

[0462]

Table 118

[0463]

Table 119

[0464]

Table 120

[0465]

Table 121

[0466]

Table 122

[0467] Number of participants: Screen approximately 1,700 participants and achieve 1,290 who are randomly assigned to receive the test intervention.

[0468] Enrolled participants are randomly assigned in a 2:1 ratio to receive either oral daily SAR442168 at 60 mg (established from dose-setting study DRI15928) or a matching daily placebo.

[0469] Randomization is stratified by age at screening (over 40 years vs. 40 years and younger) and geographical region (United States vs. non-United States).

[0470] Note: “Enrolled” means that after completion of the informed consent process, the participant or his or her legally acceptable representative agrees to participate in the clinical trial. Potential participants who are screened for eligibility in the trial but who have not yet participated in the trial are not considered enrolled unless otherwise specified in the clinical trial protocol.

[0471] Intervention groups and duration: Test intervention Investigational drug: · Formulation: SAR442168 film-coated tablets · Route of administration: Oral · Dosage regimen: 60 mg once daily

[0472] Investigational drug: · Formulation: Placebo matching SAR442168 film-coated tablets · Route of administration: Oral · Dosage regimen: Once daily

[0473] Non-investigational drug · Formulation: MRI contrast agent · Route of administration: Intravenous (IV) · Dosage regimen: According to each label

[0474] Temporary interruption of the investigational medicinal product (IMP) due to surgery If surgery is necessary during the trial, the benefit-risk and bleeding risk of discontinuing IMP for at least 3 - 7 days before and after surgery should be considered.

[0475] The treatment period varies for individual participants depending on the recruitment time. With an approximately 24 - month planned recruitment period and assumed event rates (described below), the trial period should be approximately 48 months. All recruited participants will be followed up in the trial until the general trial end, which is estimated and announced by the sponsor to ensure that approximately 288 events of 6 - month CDP are observed before the trial end.

[0476] Statistical considerations: Primary endpoint: The primary endpoint is the treatment difference between SAR442168 and placebo in the time to onset of 6 - month - CDP, regardless of the completion of the treatment period. This endpoint corresponds to the "treatment strategy". This endpoint is considered the main one to support regulatory decision - making.

[0477] The time to onset of 6 - month CDP is analyzed by a Cox proportional hazards model that includes terms for treatment, age at screening (over 40 years, 40 years or less), and geographical region (USA, non - USA). A log - rank test stratified by age at screening (over 40 years, 40 years or less) and geographical region (USA, non - USA) is also examined to compare SAR442168 with placebo.

[0478] In this primary ITT analysis: · For participants who completed the trial without progression of the initial disability or who discontinued the trial midway before the onset of progression of the disability was confirmed at 6 months, the event time of the participant is censored at the date of the last EDSS assessment. · For participants who initially had an onset of disease progression but reached the common study end date before 6 months of follow-up, the participant's event status is determined by the imputation approach. In this setting, it is reasonable to assume that the partially missing data are missing at random, so this approach uses partial information and follows the ITT principle. A logistic model with terms for age at screening (over 40 years, 40 years or younger) and geographical region (US, non-US) is used to determine the event status as the imputation model within each treatment. A multiple imputation approach is used to summarize the results.

[0479] Only the EDSS assessment measured more than 90 days after the onset of the determined relapse is used to determine the onset of disease progression. In addition, for confirmation purposes, only the EDSS score measured more than 90 days after the onset of the determined relapse is used. In the case of such an MS relapse, the next quarter's EDSS assessment is used for CDP confirmation. The minimum increase in score required for progression must also be maintained for any non-confirmatory (i.e., intervening) EDSS assessments between the initial (onset) EDSS score and the confirmatory EDSS score.

[0480] Primary secondary endpoints: For other endpoints of time to event (sustained 20% increase in 9HPT, sustained 20% increase in T25-FW, 3-month CDP, and time to onset of CDI), analyses similar to the primary analysis of the primary efficacy endpoint are performed in the ITT population.

[0481] Continuous endpoints (rate of change in brain volume loss at EOS, change in cognitive function, change in physical function, and change in MSQoL-54) are analyzed using a mixed-effects model with a repeated measures (MMRM) approach. The model includes, as response variables, the change / rate of change values of each endpoint at each scheduled visit, treatment, age at screening (over 40 years, 40 years or younger), geographic region (US, non-US), visit, treatment-by-visit interaction, baseline value of the endpoint being evaluated, and the interaction of baseline value-by-visit as a covariate.

[0482] Categorical efficacy endpoints with count data (new and / or enlarged T2 hyperintensities over the post-baseline study period) are analyzed using a negative binomial regression model. The model includes, as the response variable, the total count occurring during the observation period, with treatment group, age at screening (over 40 years, 40 years or younger) and geographic region (US, non-US) as covariates. The logarithmically transformed number of scans is the offset variable.

[0483] Analysis of safety data: Safety summaries are all descriptive, and no statistical significance tests are performed on safety data. 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, worsen, or become severe during the treatment period. These analyses are based on a safety population defined as all participants who are randomly assigned, exposed to the study intervention regardless of exposure amount, and analyzed according to the treatment actually received. · Two participants, one during the treatment period with 30 mg of SAR442168 (week 8, 105 U / L [normal range 6 - 34 U / L]) (returned to the normal range within 4 days), and one during the treatment period with 60 mg of SAR442168 (week 4, 107 U / L [normal range 6 - 34 U / L]), had a transient increase in alanine aminotransferase (ALT) > 3×ULN that developed under treatment. The participant in the 60 mg group had slightly elevated ALT at screening (48 U / L) and baseline (50 U / L), and the ALT level returned to the normal range within 8 weeks. Both participants continued the investigational treatment during this period. All other liver enzyme levels in both participants were within the normal range during the treatment period; one event was evaluated by the study physician as related to the investigational drug and one was evaluated as unrelated. Both participants completed the DRI15928 trial and successfully rolled over to the LTS follow-up trial. · During the treatment period of the SAR442168 Phase 2b trial, in the SAR42168 30 mg group, one event of mild petechial hemorrhage in a female participant (week 8 in the SAR442168 30 mg group) and two events of mild microscopic hematuria in two male participants (one event at week 16 in the SAR42168 30 mg group and one event on day 1 in the SAR442168 60 mg group, occult blood in urine was detected) were reported. Hematological results were not clinically significant for all three participants from the onset of the events. The participant with mild petechial hemorrhage had a benign pigmented lesion detected during screening, and the event was evaluated by the study physician as related to the investigational drug. The two events of mild microscopic hematuria were evaluated as unrelated to the investigational drug. All three events resolved spontaneously. · No severe infections occurred. The most frequently reported ones (a total of 3 or more events) during the SAR442168 treatment period were upper respiratory tract infection, nasopharyngitis, gastroenteritis, and airway infection. · Clinically significant cytopenias, including thrombocytopenia and neutropenia, were not reported or detected based on blood test results, and no clinically significant arrhythmias were observed by ECG monitoring during the trial. The identified risks of trebrutinib are identified as follows. · SAE events that occurred under the treatment of drug-induced liver injury (DILI) were reported in the ongoing Phase 3 trial. However, all cases occurred between the second and third months, appeared to be reversible after treatment discontinuation, and potential confounding factors were identified in some cases.

[0484] Drug-induced liver injury has been identified in the ongoing Phase 3 trial. The reported events occurred 2 - 3 months after the start of the IMP, and the increase in liver enzymes appears to be reversible after IMP interruption. Exclusion criteria and monitoring frequencies have been updated in all active recruitment protocols to reduce the risk of liver injury.

[0485] This is a Phase 3, randomized, double-blind, two-arm, placebo-controlled, parallel-group, multi-center, event-driven (6-month confirmed disability progression (CDP)) trial with a variable treatment period ranging from approximately 24 to 48 months.

[0486] The trial consists of the following trial periods: Screening period: from the 28th day before to the 1st day before.

[0487] Randomization / IMP start: Eligible participants are randomly assigned in a 2:1 ratio to receive oral SAR442168 (60 mg) daily or a matching placebo daily.

[0488] Intervention period: A double-blind treatment period for the evaluation of efficacy and safety until the end of study (EOS) defined in the trial end definition.

[0489] One month is defined as a 28-day period by convention.

[0490] Safety follow-up period / EOS: 4 - 8 weeks after the last dose of the trial treatment (for participants who have completed IMP treatment (double-blind or non-blind, rescued after 6 months of CDP) and are not in LTS) to collect safety data.

[0491] EOS: Participants are considered to have completed the trial if they have completed all stages of the trial, including EOS visits, regardless of whether they are continuing IMP.

[0492] Participants with 6 months of CDP are eligible for open-label active treatment as rescue (SAR442168) (under the heading of rescue medication).

[0493] The duration of the treatment period varies for individual participants depending on the time of recruitment and trial completion, as described below. All recruited participants will be followed in the trial until approximately 288 events of 6 months of CDP are observed. With an estimated recruitment period of about 24 months and an assumed event rate, the duration of the trial should be about 48 months, and the estimated mean treatment period should be 33 - 36 months.

[0494] If a participant discontinues the trial intervention early, they will be encouraged to remain in the trial until EOS and comply with all trial visits.

[0495] To minimize potential bias in the trial results, the trial will be double-blinded. The blinding of the initial treatment will not be known to the participants, the facility staff of the principal investigator, and the sponsor until the end of the trial.

[0496] Trial Population Future approval of protocol deviations from the recruitment and registration criteria (also called protocol waivers or exclusions) is not permitted.

[0497] Inclusion Criteria Participants are eligible to be included in the trial only if all of the following criteria are applied as shown in Table 3C.

[0498]

Table 123

[0499]

Table 124

[0500]

Table 125

[0501] Exclusion Criteria If any of the following criteria are applied as shown in Table 3D, the participant will be excluded from the study.

[0502]

Table 126

[0503]

Table 127

[0504]

Table 128

[0505]

Table 129

[0506]

Table 130

[0507]

Table 131

[0508]

Table 132

[0509]

Table 133

[0510] Considerations Regarding Lifestyle Diet and Dietary Restrictions: SAR442168 should be taken with a normal diet. If possible, the meal at which SAR442168 is taken (e.g., breakfast, lunch, or dinner) should be consistent throughout the entire study. The typical meal at which the IMP is taken is collected at each visit. If it is necessary to change the meal time for IMP administration, a minimum 12-hour gap should be maintained between two administrations.

[0511] Caffeine, Alcohol, and Tobacco: For each visit with PK / PD evaluation (see Tables 3A1 and 3A2), participants should refrain from consuming caffeine or xanthine-containing products (e.g., coffee, tea, cola beverages, and chocolate) from 2 hours before the start of treatment until late in the day after collection of the final PK and / or PD samples.

[0512] For each visit with PK / PD evaluation (see Tables 3A1 and 3A2), participants should refrain from alcohol from 24 hours before the start of treatment until late in the day after collection of the final PK and / or PD samples.

[0513] Throughout the study, participants should be warned not to consume a significant amount of alcohol, defined as less than 14 grams per day (standard 1 cup) for female participants or less than 28 grams per day (standard 2 cups) for male participants.

[0514] Study Interventions Study interventions are defined as any investigational intervention, marketed product, or placebo intended to be administered to study participants according to the study protocol.

[0515] Criteria for Temporarily Delaying Enrollment and Administration of Study Interventions During a declared regional or national emergency by a government agency, if the facility is unable to appropriately follow the procedures mandated by the protocol, emergency measures for screening, registration, randomization, and administration of the test intervention should be considered.

[0516]

Table 134

[0517] During the protocol-scheduled on-site visits, intermediate visits may be required for IMP dispensing. As an alternative to these visits, or as an alternative to on-site IMP dispensing, if necessary, SAR442168 may be supplied from the site to the participants via a courier company approved by the sponsor for direct-to-patient (DTP) shipping, if permitted by local regulations and approved by the sponsor of the clinical trial.

[0518] Non-test drug MRI contrast agent · Route of administration: IV · Dosage regimen: According to each label

[0519] Combination therapy Any medications or vaccines (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements) that the participant received at the time of registration or during the trial must be recorded together with the following: · Reason for use · Date of administration (including start and end dates) · Dosage information including dosage and frequency.

[0520] Any live (attenuated) vaccines within 2 months of the first treatment visit and during the intervention period are prohibited.

[0521] Treatment of MS described in exclusion criterion E06 is not permitted after randomization while the participant is on test treatment. Short-term use (3 - 5 days) of glucocorticoids (e.g., for MS relapse treatment or acute disease) and topical corticosteroids (e.g., topical, nasal, ocular, otic, intra-articular) is permitted.

[0522] If there are any questions regarding combination therapy or previous therapy, it is necessary to contact the medical monitor.

[0523] Participants must refrain from taking prescription or over-the-counter medications (including vitamins and dietary or herbal supplements) within 7 days before the start of the trial intervention (or 14 days if the drug is a potential enzyme inducer) or within 5 half-lives (whichever is longer) until the completion of the follow-up visit, as long as the drug does not interfere with the trial, in the opinion of the principal investigator and the sponsor of the clinical trial.

[0524] Medications for the treatment of MS symptoms (e.g., walking impairment, fatigue, spasticity, incontinence, pain) should be maintained at a stable dose before screening and during the treatment period, if clinically feasible.

[0525] Anticoagulant / antiplatelet therapy is not permitted to be carried out simultaneously with IMPs including the following: · Acetylsalicylic acid (aspirin) > 81 mg / day. · Antiplatelet drugs (e.g., clopidogrel). · Warfarin (vitamin K antagonist). · Heparin (including low molecular weight heparin (antithrombin agent)). · Dabigatran (direct thrombin inhibitor). · Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors).

[0526] Paracetamol / acetaminophen at a dose of 3 grams / day or less is permitted for use at any time during the trial. If clinically necessary for the treatment of existing medical conditions or new events, non-steroidal anti-inflammatory drugs (NSAIDs) (other than acetylsalicylic acid), preferably selective cyclooxygenase-2 inhibitors at the lowest effective dose, may be administered for a short period (maximum 5 days) during the trial. The principal investigator must record the use of NSAIDs (and any other medications) in the eCRF.

[0527] CYP Inhibitors and Inducers: Potent and moderate inducers of CYP3A or potent inhibitors of the CYP2C8 hepatic enzyme are not permitted throughout the trial (Table 3I).

[0528] Based on non - clinical drug metabolism studies, SAR442168 is a substrate of the CYP3A and CYP2C8 isoenzymes. In healthy participants, a potent CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased the SAR442168 area under the curve (AUC) exposure 1.8 - fold (Study INT16385), and a potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased the SAR442168 AUC exposure 8.4 - fold (Study INT16726). Based on a satisfactory safety and tolerability profile and on the observed exposures in healthy participants who received SAR442168 once daily at a dose of up to 240 mg SAR442168 over 14 days under fed conditions (Study TDR16862), drugs that strongly inhibit CYP3A4 are permitted, while drugs that strongly inhibit CYP2C8 are not permitted. In healthy participants, strong CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) decreased the SAR442168 exposure 6 - fold (Study INT16726). Therefore, potent and moderate (predicted) CYP3A inducers are not permitted as they may decrease SAR442168 exposure and efficacy. See Table 3I for the list of drugs to be avoided.

[0529] If there are questions regarding concomitant or previous therapies, it is necessary to contact the sponsor of the clinical trial.

[0530] Rescue Medication If a participant achieves the primary endpoint (6 - month CDP), the participant may choose, in collaboration with the treating investigator of the trial, to receive any of the following. 1. Switch to open - label SAR442168 treatment and continue with regularly scheduled trial visits, 2. Switch to non - experimental treatment approved for NRSPMS in each country. Participants are encouraged to stay in the trial for their scheduled clinical visits until the general trial end.

[0531] If the participant and the principal investigator select the provision of rescue medication, they remain blinded to the original treatment assignment.

[0532] To ensure data integrity for primary evaluation, before switching to rescue, all individual blinded data are reviewed and all queries are resolved if possible. Before starting rescue treatment, the principal investigator must confirm that there has been no recurrence determined within 90 days before the onset or confirmation of 6 - month CDP. Based on the individual symptoms and the assessed risk of further progression, the principal investigator and the participant may choose for the participant to continue the initial double - blinded treatment even after achieving 6 - month CDP.

[0533] The initial treatment assignment is not known to the participant, the facility staff of the principal investigator, and the sponsor until the end of the trial.

[0534] The provision of SAR442168 as rescue medication is specified at the country level.

[0535] Relapses of multiple sclerosis are not frequent in the NRSPMS population, but their occurrence during the trial cannot be completely excluded. In case of an MS relapse, treatment is allowed according to the local routine practice (e.g., 3 - 5 days of high - dose IV methylprednisolone). It is necessary to record the date and time of rescue medication administration as well as the name and dosing regimen of the rescue medication.

[0536] Dose change Dose changes are not anticipated in this trial. If considered necessary due to an AE, it may be necessary to interrupt or permanently discontinue the treatment.

[0537] Withdrawal of trial intervention and participant discontinuation / withdrawal Termination of trial intervention Final termination Trial intervention should be continued for as long as possible.

[0538] Permanent interruption of intervention is any interruption of treatment related to a final decision by the principal investigator of the clinical trial or the participant not to re-expose the participant to the trial intervention at any time.

[0539] In rare cases, it may be necessary for the participant to permanently discontinue the trial intervention. If the trial intervention is permanently discontinued, the participant is required to remain in the trial to be evaluated until the follow-up visit. For this group of participants (participants who discontinued the IMP and / or switched to another DMT), PK or biomarker samples are not collected after the pEOT visit, and MRI evaluations are only performed annually starting from the next annual visit.

[0540] This is important to continue to evaluate safety and efficacy. For data collected at the time of termination of trial intervention, see SoA (Tables 3A1 and 3A2). If the trial intervention is permanently interrupted, the participant should be treated for MG according to the best judgment of the local clinical practice and the principal investigator of the clinical trial.

[0541] The legitimate reasons for the principal investigator of the clinical trial or the sponsor of the clinical trial to discontinue the treatment of the participant may be as follows. · An adverse event that poses a risk to the safety of the participant, or when the principal investigator of the clinical trial and / or the participant believes that the termination of the trial intervention is desired or necessary. · When the IMP discontinuation criteria are met according to the guidance for follow-up of test abnormalities (Table 3F). · In the opinion of the principal investigator of the clinical trial, the participant is no longer obtaining therapeutic / clinical benefits. · When a female participant becomes pregnant during the trial or wishes to become pregnant. · At the request of the participant, i.e., withdrawal of consent to treatment. · Severe opportunistic infections (e.g., PML (see Figure 6), HIV). · Continuing need for / Chronic use of prohibited concomitant medications (see Table 3I). · Use of open-label SAR442168 or non-study disease-modifying therapies approved for NRSPMS in each country (e.g., after 6 months of CDP). · Simple physical examinations should include at least an evaluation of the skin, lungs, cardiovascular system, neurological examination, and abdomen (liver and spleen). · The principal investigator of the clinical trial should pay special attention to clinical signs related to previous serious illnesses. · Clinically significant new findings or exacerbation of previous findings should be reported as AEs according to the judgment of the principal investigator of the clinical trial.

[0542] Safety assessment Physical examination Physical examinations are conducted at the time points specified in the SoA (Tables 3A1 and 3A2). · Complete physical examinations should include at least an evaluation of general appearance, head and neck, abdomen, lymph nodes, skin, cardiovascular system, respiratory system, musculoskeletal system, and neurological examination by the principal investigator of the treatment clinical trial. Height (at screening) and weight are also measured and recorded. Further details are described in the study manual. · Simple physical examinations should include at least an evaluation of the skin, lungs, cardiovascular system, neurological examination, and abdomen (liver and spleen). · The principal investigator of the clinical trial should pay special attention to clinical signs related to previous serious illnesses. · Clinically significant new findings or exacerbation of previous findings should be reported as AEs according to the judgment of the principal investigator of the clinical trial.

[0543] The scope of the physical examination can be expanded at the discretion of the principal investigator of the treatment clinical trial to evaluate AES or abnormal clinical test values.

[0544] Vital signs · Evaluate body temperature, heart rate, and blood pressure. · Blood pressure and pulse measurements are evaluated by participants in the supine or seated position using a fully automated device. Manual techniques are used only when automated devices are not available. · Prior to measurement of blood pressure and pulse, participants should be given a break of at least 5 minutes in a quiet environment without distraction (e.g., TV, mobile phone). · Vital signs (performed prior to blood sampling for laboratory tests) consist of one heart rate and three blood pressure measurements (three consecutive blood pressure measurements are recorded at intervals of at least 1 minute).

[0545] Electrocardiogram · Use an ECG device that automatically calculates the heart rate and measures the PR, QRS, QT, and QTcF intervals to obtain a 12-lead ECG as outlined in the SoA (see Tables 3A1 and 3A2). If the ECG device does not automatically calculate QTcF, manual calculation using a nomogram or an automated web-based calculator (e.g., https: / / reference.medscape.com / calculator / 48 / ecg-corrected-qt) is permitted. · The ECG and 30-second rhythm strip are obtained locally. Further details are included in the test manual.

[0546] Clinical Safety Laboratory Evaluation · See Table 3I for the list of clinical tests to be performed. For each SoA, serological tests for hepatitis B and C should be performed during screening and, if necessary, other infectious disease tests should be performed locally during screening. · The treating investigator can request urgent local test data in cases of urgent safety events that enable appropriate treatment decisions. All clinically relevant requested urgent local test data are recorded in the eCRF. ·The principal investigator of the treatment trial shall review the clinical examination reports, document this review, and record any clinically relevant changes that occur during the trial in the AE section of the eCRF. The examination reports must be submitted together with the source documents. Clinically significant abnormal examination findings are those not related to underlying diseases unless the principal investigator of the trial determines that they are more severe than expected for the participant's condition. ·All clinical examinations with values considered to be clinically significantly abnormal during the trial or within 30 days after the last dose of the trial intervention should be repeated until the values return to normal or baseline or until the principal investigator of the trial no longer considers them to be clinically significant. - If the abnormal test values do not return to normal / baseline within the period determined by the principal investigator of the trial to be reasonable, the cause should be identified and the sponsor of the trial notified. ·All test evaluations required by the protocol as defined in Table 3I must be carried out in accordance with the laboratory manual and the SoA (see Tables 3A1 and 3A2). If the test evaluations in Figures 2 - 8 indicate discontinuation of the IMP, a temporary discontinuation should be considered unless otherwise specified. - If test values from laboratory evaluations not specified in the protocol, which are carried out in the local laboratory of the facility, require a change in the management of the participant or are considered clinically important by the principal investigator of the trial (e.g., SAE or AE or dose change), the results must be recorded in the eCRF.

[0547] Monitoring of the risk of suicidal thoughts and behavior SAR442168 crosses the blood - brain barrier. The assessment of suicidal thoughts and behavior and suicidal thoughts and behavior that develop during treatment will be monitored using the C - SSRS during Trial EFC16645. For safety reasons, the C - SSRS will be administered throughout the trial by the principal investigator of the treatment trial or delegated to an individual who is certified to administer the scale.

[0548] If a participant scores "Yes" on item 4 or 5 of the Suicide Ideation section of the C-SSRS, or "Yes" on any item of the Suicide Behavior section, the administration of the investigational drug must be interrupted. Consult a psychiatrist to determine whether the investigational drug can be restarted and whether additional risk mitigation strategies (e.g., increased monitoring, administration of antidepressants) are necessary.

[0549] Adverse Events of Special Interest An AESI is an AE (severe or non-severe) of scientific and medical concern specific to the sponsor's product or program that requires ongoing monitoring and immediate notification by the Investigator-in-Charge to the Sponsor. Such events may require further investigation to characterize and understand them. Adverse Events of Special Interest can be added, amended, or removed during the trial by amending the protocol. · Pregnancy of female participants who participated in the trial, and pregnancy of female partners of male participants who participated in the trial using IMP / NIMP. - Is eligible as an SAE only if it meets one of the severity criteria (see Appendix 3 (Section 10.3)). - If a female participant becomes pregnant, the IMP should be discontinued. - Observation of the course of pregnancy of female participants or female partners of male participants is essential until the results are determined. · Symptomatic overdose (severe or non-severe) with IMP. - Overdose of IMP (accidental or intentional) is an event suspected by the Investigator-in-Charge or spontaneously reported by the participant (not based on the total number of pills in the body) and is defined as at least twice the intended dose within the intended treatment interval (e.g., more than 2 tablets of IMP within 12 hours). · Increase in alanine transaminase (ALT) > 3 × ULN. - An increase in ALT exceeding 3 × ULN was confirmed by retesting within 72 hours or the absence of retesting within 72 hours. · Other project-specific AESIs - ECG observation of atrial fibrillation or atrial flutter - Severe infections (NCI CTCAE grade 3 or higher) that may or may not meet the severity criteria (e.g., opportunistic infection of grade 3). - Moderate or severe hemorrhagic events (NCI CTCAE grade 2 or higher) (including, but not limited to, symptomatic bleeding, bleeding in important regions or organs such as the CNS, or intraocular bleeding). - Thrombocytopenia, platelet count < 75,000 / mm 3 (See Figure 3 for the management flowchart).

[0550] Clinical examinations The tests detailed in Table 3F, if feasible, are performed by the central laboratory.

[0551] Local test results are only required when the central test results are not in time for either the test intervention administration and / or response evaluation.

[0552] Furthermore, if local test results are used to make either a test intervention decision or a response evaluation, the results must be entered into the eCRF.

[0553] Protocol-specific requirements regarding the inclusion or exclusion of participants are detailed in Tables 3C and 3D.

[0554] Additional tests can be performed at any time during the trial if the principal investigator of the clinical trial deems it necessary or if required by local regulations. An additional serum or urine pregnancy test can be performed at any time during the participation of a trial participant to establish the absence of pregnancy if the principal investigator of the clinical trial deems it necessary or if required by local regulations.

[0555]

Table 135

[0556]

Table 136

[0557] The principal investigator of the clinical trial must document the review of each laboratory safety report.

[0558] Test results / analysis results that may unblind the trial are not reported to the trial site or other blinded staff until the trial is blinded. This includes PK assessments and any post-baseline biomarker or PD assessments.

[0559] Liver and other safety: Behavioral and follow-up evaluations The actions described in 3G and Figures 2 - 8 are only required for increases in ALT and thrombocytopenia events. For all other safety events described, these are suggested by the medical judgment of the principal investigator of the clinical trial.

[0560] Neutropenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0561] Thrombocytopenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0562] Abbreviations in Figure 3: aPTT: Activated partial thromboplastin time; EDTA: Ethylenediaminetetraacetic acid; INR: International normalized ratio; PK: Pharmacokinetics; PT: Prothrombin time.

[0563] Abbreviations in Figure 4A: 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; HBV: Hepatitis B core; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; IgM: Immunoglobulin M; IMP: Investigational drug; 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.

[0564] Note: "Baseline" refers to the ALT sampled at the time of baseline hospital visit, or, if the baseline value is not available, the most recent ALT sampled before the baseline hospital visit. This algorithm does not apply to examples of increases in ALT during screening.

[0565]

Table 137

[0566]

Table 138

[0567] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0568] An increase in CPK is recorded as an AE only if at least one of the criteria of the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0569] Abbreviations in Figure 5: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, pharmacokinetics.

[0570] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0571] Abbreviations in Figure 8: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0572] An increase in CPK is recorded as an AE only if at least one of the criteria of the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0573] Suspected PML: When either the clinical symptoms or MRI features of the participant suggest PML, the diagnostic and action algorithm described in Figure 6 is recommended.

[0574] Abbreviations in Figure 6: Abbreviations: CSF, cerebrospinal fluid; GD, gadolinium; IMP, investigational drug; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy

[0575] Propose the characteristics of clinical symptoms or MRI lesions suspected of PML in Table 3H (Berger et al. Neurology 2013, 80, 1430 - 1438 and Kappos et al. Lancet Neurol. 2007, 6, 431 - 441).

[0576] If PML is suspected based on the imaging results, the local radiologist should notify the principal investigator directly, and intensive MRI review is not required. The principal investigator will obtain additional plasma, urine, and CSF samples for John Cunningham virus (JCV) analysis. Samples will be analyzed upon receipt, and the results will be provided directly to the trial site and the sponsor. Further management will be delegated to the principal investigator. However, the next step will include stopping the investigational treatment. Additional imaging will be at the discretion of the principal investigator based on post-diagnostic workup and treatment planning. · Detection of John Cunningham virus (JCV) DNA in the cerebrospinal fluid of patients with clinical and MRI features suggestive of PML establishes the diagnosis of PML. · If JCV DNA is not detected in the cerebrospinal fluid and the clinical suspicion of PML remains high, another lumbar puncture should be performed. · If the diagnosis remains uncertain and the suspicion of PML remains high, a brain biopsy can be considered to establish a definitive diagnosis.

[0577]

Table 139

[0578] Clinical or MRI features suggestive of PML should be recorded as AE / AESI / SAE according to the definitions and procedures in Appendix 3 (Section 10.3).

[0579] Examples of drugs that may alter the metabolism or absorption of SAR442168 The following drugs are strong / moderate inducers of CYP3A or strong and moderate inhibitors of the CYP2C8 hepatic enzyme and may alter the pharmacokinetics of SAR442168 by interaction with P450-mediated metabolism and should not be taken concomitantly with the IMP during the trial (according to the list in the University of Washington Drug Interaction Database program (www.druginteractioninfo.org)).

[0580] The list provided is not exhaustive, and it is important to note that product information of drugs for combined use should be referred to.

[0581]

Table 140

[0582] Abbreviations ADL: Activities of Daily Living AE: Adverse Event AESI: Adverse Event of Special Interest ALT: Alanine Transaminase aPTT: Activated Partial Thromboplastin Time BTK: Bruton 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 Study 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 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 Form ICH: International Council for Harmonisation IEC: Independent Ethics Committee IFNγ: Interferon γ IL: Interleukin IMP: Investigational Medicinal Product INR: International Normalized Ratio IRB: Institutional Review Board IRT: Interactive Response Technology IUD: Intrauterine Device IUS: Intrauterine System IV: Intravenous IWRS: Interactive Web Response System JCV: John Cunningham Virus LTS: Long-Term Safety 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: Magnetization Transfer Ratio 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: Non-Steroidal Anti-Inflammatory Drug PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive Multifocal Leukoencephalopathy PPMS: Primary Progressive Multiple Sclerosis pTreg: Peripheral regulatory T cells RMS: Relapsing-remitting multiple sclerosis RTE: Recent thymic emigrants SAP: Statistical analysis plan SEL: Slowly expanding lesion 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 Th17: 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 α Treg: Regulatory T cells tTreg: Thymus-derived Foxp3-positive regulatory T cells ULN: Upper limit of normal WBC: White blood cells WOCBP: Women of childbearing potential

[0583] Example 4 - Phase 3 randomized double-blind efficacy and safety trial comparing SAR442168 with placebo in participants with primary progressive multiple sclerosis (PERSEUS) The objective of this Phase 3 clinical trial was to demonstrate the efficacy and safety of SAR442168 compared with placebo in participants with PPMS. The primary endpoint was the time to onset of confirmed disability progression (CDP) over 6 months, as assessed via the Expanded Disability Status Scale (EDSS) score, which is shown in Figure 7.

[0584] The schematic diagram of the trial design is shown in Figure 1D. Abbreviations used in Figure 1D: CDP, confirmed disability progression; DMT, disease-modifying therapy; EOS, end of study; MRI, magnetic resonance imaging.

[0585] Tables 4A1, 4A2, and 4A3 shown below describe the activity schedule during the test. The following Table 4B describes the purpose and endpoints of the entire test.

[0586]

Table 141

[0587]

Table 142

[0588]

Table 143

[0589]

Table 144

[0590]

Table 145

[0591]

Table 146

[0592]

Table 147

[0593]

Table 148

[0594]

Table 149

[0595]

Table 150

[0596]

Table 151

[0597]

Table 152

[0598]

Table 153

[0599]

Table 154

[0600]

Table 155

[0601]

Table 156

[0602]

Table 157

[0603]

Table 158

[0604]

Table 159

[0605]

Table 160

[0606]

Table 161

[0607] The treatment objectives and endpoints are shown in Table 4B.

[0608]

Table 162

[0609]

Table 163

[0610]

Table 164

[0611] Dosing regimen: The selection of the 60 mg BTK inhibitor dose taken with food is based on the results of the Phase 2b dose ranging trial of tolebrutinib in participants with relapsing multiple sclerosis (DRI15928). See, for example, Reich, D.S., 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. 729-738.

[0612] Analysis of PK data and the effect of feeding status on tolebrutinib exposure is approximately a 2-fold increase in AUC 0-24showed a positive dietary effect associated with an increase. Furthermore, the correlation between treatment response and exposure to trebananib showed that higher exposure was associated with a small number of new gadolinium-enhanced T1 hyperintense lesions after 12 weeks of treatment. Collectively, these data support the recommendation to take trebananib with food.

[0613] There was no correlation between the dose of trebananib administered and the number of TEAEs. The most common events (preferred terms) observed in participants in the trebananib treatment group were headache, upper respiratory tract infection, and nasopharyngitis. The number of AESIs and PCSAs observed was low. Overall, no new risks were identified in this trial.

[0614] Overall design: This is a phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel-group, multi-site, event-driven (6-month CDP) trial in participants with PPMS using a variable treatment period in the range of approximately 24 to 48 months.

[0615] Disclosure statement: This is a parallel treatment trial using two blinded / masked arms for participants, treating physicians, facility staff, and trial sponsors.

[0616] Number of participants: Approximately 1320 participants were screened to achieve 990 who were randomly assigned to receive the study intervention.

[0617] Intervention group and duration: Participants are randomly assigned in a 2:1 ratio to receive either 60 mg of oral daily SAR442168 or matching daily placebo. Randomization is stratified by age at screening (over 40 years vs. 40 years and younger), geographic region (United States (US) vs. non-US), and PPMS McDonald diagnostic criteria (2005 [Polman et al. Ann Neurol. 2005, 58, 840] and 2017 version vs. 2017 version [Thompson et al. Lancet Neurol. 2018, 17, 162]).

[0618] Study Intervention Investigational Medicinal Product: · Formulation: SAR42168 film-coated tablets · Route of administration: Oral · Dosage regimen: 60 mg once daily

[0619] Investigational Medicinal Product: · Formulation: Placebo matching SAR442168 film-coated tablets · Route of administration: Oral · Dosage regimen: Once daily

[0620] Non-Investigational Medicinal Product · Formulation: MRI contrast agent · Route of administration: Intravenous (IV) · Dosage regimen: According to each label

[0621] Temporary IMP Interruption due to Surgery If surgery is required during the study, the benefit-risk of withholding IMP for at least 3 to 7 days before and after surgery is considered according to the type of surgery and the risk of bleeding.

[0622] The objective of this Phase 3 clinical trial is to demonstrate the efficacy and safety of SAR442168 compared to placebo in participants with PPMS. In this trial, 6-month CDP was selected as the primary endpoint. This is widely used in clinical trials and is considered to be clinically more meaningful than 3-month CDP. Confirmed disability improvement (CDI) over at least 6 months, measured by the EDSS score, is also used as a secondary endpoint due to its clinical importance.

[0623] Magnetic resonance imaging results include changes in brain volume, which are considered markers of CNS degeneration processes and are thus recommended for use in progressive MS trials (EMA Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. London, 26 March 2015. EMA / CHMP / 771815 / 2011, Rev. 2 [Cited 2020 Feb 13]).

[0624] To evaluate the PK of SAR442168 in the PPMS population, population pharmacokinetics (PK) is performed to obtain a larger and more diverse population, evaluate the causes of PK variability (ethnicity, special populations), and establish exposure correlations with clinical efficacy, biomarker, and safety endpoints. The analysis of population PK data can be performed as soon as all participants have completed their 12-month visit (using a separate non-blinded team to maintain blinding integrity).

[0625] In the ongoing Phase 3 trial and LTS trial, trebrutinib has generally been well tolerated to date. The risks identified for trebrutinib are identified as follows. - SAEs that manifested under treatment for drug-induced liver injury (DILI) were reported in the ongoing Phase 3 trial, but all cases occurred between the 2nd and 3rd months, appeared to be reversible after treatment discontinuation, and potential confounding factors were identified for some cases.

[0626] Definition of End of the Trial Regardless of whether the participant is continuing with the IMP, the trial is considered completed when all stages of the trial, including the EOS visit, are completed.

[0627] This trial ends when approximately 290 primary endpoint events of the 6 - month CDP are observed. If a recruitment period of approximately 24 months is planned, the trial duration is estimated to be approximately 48 months.

[0628] Event rates based on blinded data are regularly monitored to predict the event timeline and timely estimate possible trial end dates.

[0629] Trial Population Inclusion Criteria Participants are eligible to be included in the trial only if all of the following criteria are applied as shown in Table 4C.

[0630]

Table 165

[0631]

Table 166

[0632] Exclusion Criteria Participants are excluded from the trial if any of the following criteria are applied as shown in Table 4D.

[0633]

Table 167

[0634]

Table 168

[0635]

Table 169

[0636]

Table 170

[0637]

Table 171

[0638]

Table 172

[0639]

Table 173

[0640]

Table 174

[0641] Considerations Regarding Lifestyle Diet and Dietary Restrictions: Toremifene (IMP) should be taken with a normal diet. If possible, the meal at which IMP is taken (e.g., breakfast, lunch, or dinner) should be consistent throughout the entire study. A typical meal at which IMP is taken is collected at each visit. If it is necessary to change the meal time for IMP administration, a minimum 12-hour gap should be maintained between two administrations.

[0642] Caffeine, Alcohol, and Tobacco: For each visit with PK / PD evaluation, participants should refrain from consuming caffeine or xanthine-containing products (e.g., coffee, tea, cola beverages, and chocolate) from 2 hours before the start of treatment until late on the day after the collection of the final PK and / or PD samples.

[0643] For each visit with PK / PD assessment, participants should refrain from alcohol from 24 hours before treatment initiation until late on that day after collection of the final PK and / or PD samples.

[0644] Throughout the trial, participants should be warned not to consume a significant amount of alcohol defined as less than 14 grams per day (standard 1 drink) for female participants or less than 28 grams per day (standard 2 drinks) for male participants.

[0645] Study Intervention and Concomitant Therapy The study intervention was defined as any investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol.

[0646]

Table 175

[0647] Dose Modification A decrease in dose is not anticipated in this study. If it is considered necessary due to an AE, treatment may need to be interrupted or permanently discontinued.

[0648] Concomitant Therapy Any medications or vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) that participants are receiving at the time of enrollment or during the study must be recorded along with: · Reason for use. · Date of administration (including start and end dates). · Dose information including dose and frequency.

[0649] Live (attenuated) vaccines should not be administered during the intervention period. Treatments for MS described in exclusion criterion E06 are not permitted after randomization while participants are on study treatment. Short-term use (3 - 5 days) of glucocorticoids (e.g., for MS relapse treatment or acute illness) and topical corticosteroids (e.g., topical, nasal, eye, ear, intra-articular) is permitted.

[0650] If there are questions regarding combination therapy or previous therapy, it is necessary to contact the medical monitor.

[0651] Participants must refrain from taking prescription or non-prescription medications (including vitamins and dietary or herbal supplements) within 7 days before the start of the trial intervention (or 14 days if the drug is a potential enzyme inducer) or within 5 half-lives (whichever is longer) until the completion of the follow-up visit, in the opinion of the principal investigator and the sponsor of the clinical trial, unless the drug interferes with the trial. Medications for the treatment of MS symptoms (e.g., gait impairment, fatigue, spasticity, incontinence, pain) should be maintained at a stable dose during screening and the treatment period, if clinically feasible.

[0652] Anticoagulant / antiplatelet therapy is not permitted concomitantly with IMPs including: · Acetylsalicylic acid (aspirin) > 81 mg / day. · Antiplatelet agents (e.g., clopidogrel). · Warfarin (vitamin K antagonist). · Heparin (including low molecular weight heparin (antithrombin agent)). · Dabigatran (direct thrombin inhibitor). · Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors).

[0653] Paracetamol / acetaminophen at a dose of 3 grams / day or less is permitted for use at any time during the trial. If clinically necessary for the treatment of existing medical conditions or new events, non-steroidal anti-inflammatory drugs (NSAIDs) (other than acetylsalicylic acid), preferably selective cyclooxygenase-2 inhibitors at the lowest effective dose, may be administered for a short period (maximum 5 days) during the trial. The principal investigator must record the use of NSAIDs (and any other medications) in the eCRF.

[0654] CYP inhibitor / inducer: Potent and moderate inducers of CYP3A or potent inhibitors of the CYP2C8 hepatic enzyme are not permitted throughout the trial (see Appendix 8 (Section 10.8)). Based on non-clinical drug metabolism studies, SAR442168 is a substrate for the CYP3A4 and CYP2C8 isoenzymes. In healthy participants, a potent CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) increased SAR442168 area under the curve (AUC) exposure 1.8-fold (INT16385 study), and a potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased SAR442168 AUC exposure 8.4-fold (INT16726 study). Based on a satisfactory safety and tolerability profile and the observed exposures in healthy participants receiving SAR442168 once daily at a dose of up to 240 mg SAR442168 for 14 days under fed conditions (TDR16862 study), drugs that strongly inhibit CYP3A4 are permitted and drugs that strongly inhibit CYP2C8 are not permitted. In healthy participants, potent CYP3A4 and moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) decreased SAR442168 exposure 6-fold (INT16726 study). Therefore, potent and moderate (predicted) CYP3A inducers are not permitted as they may decrease SAR442168 exposure and efficacy. See Appendix 8 (Section 10.8) for a list of drugs to be avoided.

[0655] If there are questions regarding concomitant or previous therapies, it is necessary to contact the sponsor of the clinical trial.

[0656] Rescue medication If a participant achieves the primary endpoint (6-month CDP), the participant may choose to receive one of the following in collaboration with the treating investigator of the clinical trial. 1. Switch to open-label SAR442168 treatment; or 2. Switch to the non - investigational treatment approved for PPMS in each country. In this case, participants discontinue the IMP permanently and are encouraged to stay in the trial for the planned clinical visits until the end of the general trial.

[0657] If a participant switches to open - label SAR442168 treatment, the participant needs to be monitored for liver function tests at weeks 2, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and then monthly after the first open - label dose for 9 months. Thereafter, the scheduled visit times for each SoA (Tables 4A1 and 4A2) are resumed until the end of the general trial (i.e., every 3 months). Whenever a time point coincides with a scheduled visit as per the SoA (Section 1.3), not only the liver monitoring test but also the full scheduled visit assessment is performed.

[0658] If the participant and the principal investigator of the trial choose the provision of rescue medication, they remain blinded to the original treatment assignment.

[0659] To ensure data integrity for the primary evaluation, all individual blinded data are reviewed and all queries are resolved if possible before switching to the selected rescue approach. Before starting rescue treatment, the principal investigator of the trial must confirm that there has been no recurrence determined within 90 days before the onset or confirmation of 6 - month CDP. Based on the evaluation of individual symptoms and the further assessed risk of progression, the principal investigator of the trial and the participant may choose for the participant to continue the initial double - blinded treatment even after achieving 6 - month CDP.

[0660] Cessation of Trial Intervention and Participant Withdrawal / Discontinuation Cessation of Trial Intervention Final Cessation The trial intervention should be continued for as long as possible.

[0661] Permanent intervention discontinuation is any treatment interruption related to the final decision by the principal investigator or the participant not to re-expose the participant to the study intervention at any time. In rare cases, it may be necessary for the participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant is required to remain in the study for evaluation until the follow-up / EOS visit. For this group of participants (those who discontinued the IMP and / or switched to another DMT), PK or biomarker samples are not collected after the pEOT visit, and MRI evaluations are only performed annually starting from the next annual visit. This is important to continue to evaluate safety and efficacy. For data collected at the time of discontinuation of the study intervention, refer to the SoA (Tables 4A1 and 4A2). If the study intervention is permanently interrupted, the participant should be treated for MS according to the best judgment of the local clinical practice and the principal investigator of the treatment trial.

[0662] The legitimate reasons for the principal investigator or the sponsor of the study to discontinue the treatment of the participant may be as follows. · An adverse event that poses a risk to the safety of the participant, or when the principal investigator and / or the participant consider it desirable or necessary to discontinue the study intervention. · When the IMP discontinuation criteria are met according to the guidance for follow-up of test abnormalities (Table 4F). · In the opinion of the principal investigator, the participant is no longer deriving a therapeutic / clinical benefit. · When a female participant becomes pregnant during the study or wishes to become pregnant. · At the request of the participant, i.e., withdrawal of consent for treatment. · Severe opportunistic infections (e.g., PML (see Figure 6), HIV). · Continuing need for / chronic use of a prohibited concomitant medication (see Table 4I). · Use of the non-blind SAR442168 or non-study disease-modifying therapy approved for PPMS in each country (e.g., after 6 months of CDP). · Simple physical examinations should include at least an assessment of the skin, lungs, cardiovascular system, neurological examination, and abdomen (liver and spleen). ·The principal investigator of the clinical trial should pay special attention to the clinical symptoms related to previous serious diseases. ·Clinically significant new findings or deterioration of previous findings should be reported as AEs according to the judgment of the principal investigator of the clinical trial.

[0663] When a participant meets one of the conditions outlined in the algorithm (Table 4B), or when the principal investigator of the clinical trial deems it to be in the best interest of the participant, the principal investigator of the clinical trial should consider stopping the test intervention for abnormal liver function.

[0664] Clinical Examinations The tests detailed in Table 4F are to be performed by the central laboratory if feasible. Local test results are only required if the central test results are not in time for either test intervention administration and / or response assessment. Additionally, if local test results are used to make either a test intervention decision or a response assessment, the results must be entered into the eCRF.

[0665] Protocol-specific requirements for inclusion or exclusion of participants are detailed in Tables 4C and 4D of the protocol.

[0666] Additional tests can be conducted at any time during the trial if the principal investigator of the clinical trial determines it necessary or if required by local regulations. Additional serum or urine pregnancy tests can be performed to establish the absence of pregnancy at any point during a subject's participation in the trial if determined necessary by the principal investigator of the clinical trial or required by local regulations.

[0667]

Table 176

[0668]

Table 177

[0669] The principal investigator of the clinical trial must document the review of each laboratory safety report.

[0670] Test results / analysis results that may potentially unblind the trial are not reported to the trial site or other blinded staff until the trial is unblinded. This includes PK assessments and any post-baseline biomarker or PD assessments.

[0671] Liver and other safety: Behavioral and follow-up evaluations These behaviors described in Table 4G and Figures 2 - 8 are only required for ALT increases and thrombocytopenia events. For all other safety events described, these are suggested by the medical judgment of the principal investigator of the clinical trial.

[0672] Neutropenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0673] Thrombocytopenia is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0674] Abbreviations in Figure 3: aPTT: Activated partial thromboplastin time; EDTA: Ethylenediaminetetraacetic acid; INR: International normalized ratio; PK: Pharmacokinetics; PT: Prothrombin time.

[0675] Note: "Baseline" refers to ALT sampled at baseline visit, or if baseline values are not available, the most recent ALT sampled before the baseline visit. This algorithm does not apply to examples of ALT increases during screening.

[0676]

Table 178

[0677]

Table 179

[0678] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0679] An increase in CPK is recorded as an AE only if at least one of the criteria of the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0680] Abbreviations in Figure 5: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, pharmacokinetics.

[0681] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0682] Abbreviations in Figure 8: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0683] An increase in CPK is recorded as an AE only if at least one of the criteria of the general guidelines for AE reporting in Appendix 3 (Section 10.3) is met.

[0684] Suspected PML: If either the clinical symptoms or MRI features of the participant suggest PML, the diagnostic and action algorithm described in Figure 6 is recommended.

[0685] Abbreviations in Figure 6: Abbreviations: CSF, cerebrospinal fluid; GD, gadolinium; IMP, investigational drug; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy

[0686] Propose the characteristics of clinical symptoms or MRI lesions suspected of PML in Table 3H (based on Berger et al. Neurology 2013, 80, 1430 - 1438 and Kappos et al. Lancet Neurol. 2007, 6, 431 - 441).

[0687] If PML is suspected based on imaging results, the local radiologist should notify the principal investigator of the trial directly, and a focused review of the MRI is not required. The principal investigator of the trial 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 trial facility and the sponsor of the trial. Further management is delegated to the principal investigator of the trial. However, the next step includes discontinuation of the investigational treatment. Additional imaging is at the discretion of the principal investigator of the trial according to the post - diagnosis workup and treatment plan. · Detection of John Cunningham virus (JCV) DNA in the cerebrospinal fluid of patients with clinical and MRI features suggestive of PML establishes the diagnosis of PML. · If JCV DNA is not detected in the cerebrospinal fluid and the clinical suspicion of PML remains high, another lumbar puncture should be performed. · If the diagnosis remains uncertain and the suspicion of PML remains high, a brain biopsy can be considered to establish a definitive diagnosis.

[0688]

Table 180

[0689] Clinical or MRI features suggestive of PML should be recorded as AE / AESI / SAE according to the definitions and procedures in Appendix 3 (Section 10.3).

[0690] Examples of drugs that may change the metabolism or absorption of SAR442168 The following drugs are strong / moderate inducers of CYP3A or strong and moderate inhibitors of the CYP2C8 hepatic enzyme and may alter the pharmacokinetics of SAR442168 through interaction with P450-mediated metabolism and should not be taken concomitantly with the IMP during the trial (according to the list of the University of Washington's Drug Interaction Database Program (www.druginteractioninfo.org)).

[0691] Note that the list provided is not exhaustive and it is necessary to refer to the product information of the drugs intended for co-administration.

[0692]

Table 181

[0693] Abbreviations 9-HPT: 9-Hole Peg Test ADL: Activities of Daily Living AE: Adverse Event AESI: Adverse Event of Special Interest ALT: Alanine Aminotransferase aPTT: Activated Partial Thromboplastin Time ARR: Annual Recurrence Rate BTK: Bruton-Type Tyrosine Kinase BVL: Brain Volume Loss CD: Cluster of Differentiation CDI: Confirmed Disability Improvement CDP: Confirmed Disability Progression CFR: Code of Federal Regulations Chi3L1: Chitinase-3-Like Protein 1 CNS: Central Nervous System CPK: Creatine Phosphokinase CRF: Case Report Form CSF: Cerebrospinal Fluid CSR: Clinical Study 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: Expanded Disability Status Scale numbered embodiment eGFR: Estimated glomerular filtration rate EOS: End of study 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 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 Brochure ICF: Informed consent form ICH: International Council for Harmonisation 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: Intent 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: Mixed Effects Model for Repeated Measures MRI: Magnetic Resonance Imaging MS: Multiple Sclerosis MSFC-3: Multiple Sclerosis Functional Composite-3 MSQoL-54: Multiple Sclerosis Quality of Life-54 Questionnaire MTR: Magnetization Transfer Ratio NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NEDA: No Evidence of Disease Activity-3 NfL: Neurofilament Light Chain NIMP: Investigational Medicinal Product NSAID: Non-Steroidal 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 Cell QTcF: QTc Interval Corrected Using Fridericia's Formula RMS: Relapsing Remitting Multiple Sclerosis RTE: Recent Thymic Emigrant SAE: Serious Adverse Event SAP: Statistical Analysis Plan SDMT: Symbol Digit Modalities Test SEL: Slowly Expanding Lesion SoA: Schedule of Activities SPMS: Secondary progressive multiple sclerosis SUSAR: Suspected unexpected serious adverse reaction SWI: Susceptibility weighted imaging T25-FW: 25-foot walk time TB: Tuberculosis TEAE: Treatment-emergent adverse event Tfh: T follicular helper Th 17: T helper 17 cells Th 17: T helper 17 Th1: T helper 1 cells, T helper 1 Th2: T helper 2 cells Th2: T helper 2 TIGIT: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain TNFα: Tumor necrosis factor α Treg: Regulatory T cells tTreg: Thymus-derived Foxp3-positive regulatory T cells ULN: Upper limit of normal US: United States of America WOCBP: Women of childbearing potential

[0694] Embodiment #1: A method of treating MS in a patient in need of treatment for MS, the method comprising determining whether the patient has elevated transferrin levels or ferritin levels, and, if the patient is determined to not have elevated transferrin levels or ferritin levels, administering to the patient a therapeutically effective amount of BTK comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0695] Embodiment #2: A method for treating MG in a patient in need of MG treatment, comprising determining whether the patient has elevated transferrin levels or ferritin levels, and when it is determined that the patient does not have elevated transferrin levels or ferritin levels, administering to the patient a therapeutically effective amount of BTK comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0696] Embodiment #3: A method for treating MS in a patient in need of MS treatment, comprising determining the patient's iron panel, and when it is determined that the patient has an appropriate iron panel, 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.

[0697] Embodiment #4: A method for treating MG in a patient in need of MG treatment, comprising determining the patient's iron panel, and when it is determined that the patient has an appropriate iron panel, 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.

[0698] Embodiment #5: A method for treating MS in a patient in need of MS treatment, comprising determining the patient's alcohol consumption, and when it is determined that the patient has 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.

[0699] Embodiment #6: A method for treating MG in a patient in need of treatment for MG, comprising determining the patient's alcohol consumption, and 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 when it is determined that the patient has appropriate alcohol consumption.

[0700] Embodiment #7: A method for treating MS in a patient in need of treatment for MS, comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and 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 when it is determined that the patient does not have an inducer of CYP3A or an inhibitor of CYP3C8.

[0701] Embodiment #8: A method for treating MG in a patient in need of treatment for MG, comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and 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 when it is determined that the patient does not have an inducer of CYP3A or an inhibitor of CYP3C8.

[0702] Embodiment #9: A method for treating MS in a patient in need of treatment for MS, comprising determining whether the patient has elevated ALT enzyme, and administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one when it is determined that the patient does not have elevated ALT enzyme.

[0703] Embodiment #10: A method of treating MG in a patient in need of treatment for MG, comprising determining whether the patient has elevated ALT enzyme, and, if it is determined that the patient does not 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-phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0704] Embodiment #11: A method of treating MS in a patient in need of treatment for MS, comprising determining whether the patient has elevated transferrin level or ferritin level, and, if it is determined that the patient does not have elevated transferrin level or ferritin level, administering to the patient a therapeutically effective amount of a BTK comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0705] Embodiment #12: A method of treating MG in a patient in need of treatment for MG, comprising determining whether the patient has elevated transferrin level or ferritin level, and, if it is determined that the patient does not have elevated transferrin level or ferritin level, administering to the patient a therapeutically effective amount of a BTK comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0706] Embodiment #13: A method of treating multiple sclerosis (MS) in a patient in need thereof, comprising determining the iron panel of the patient, and discontinuing administration of a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor, which includes (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, to the patient if it is determined that the patient does not have an appropriate iron panel.

[0707] Embodiment #14: A method of treating myasthenia gravis (MG) in a patient in need thereof, comprising determining the iron panel of the patient, and discontinuing administration of a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor, which includes (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, to the patient if it is determined that the patient does not have an appropriate iron panel.

[0708] Embodiment #15: A method of treating multiple sclerosis (MS) in a patient in need thereof, comprising determining the alcohol consumption of the patient, and discontinuing administration of a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor, which includes (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, to the patient if it is determined that the patient does not have an appropriate alcohol consumption.

[0709] Embodiment #16: A method of treating myasthenia gravis (MG) in a patient in need thereof, comprising determining the alcohol consumption of the patient, and discontinuing administration of a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor, which includes (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, to the patient if it is determined that the patient does not have an appropriate alcohol consumption.

[0710] Embodiment #17: A method of treating multiple sclerosis (MS) in a patient in need thereof, comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and if it is determined that the patient has an inducer of CYP3A or an inhibitor of CYP3C8, discontinuing the administration of a therapeutically effective amount of a Bruton's tyrosine kinase (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.

[0711] Embodiment #18: A method of treating myasthenia gravis (MG) in a patient in need thereof, comprising determining whether the patient has an inducer of CYP3A or an inhibitor of CYP3C8 in the patient's system, and if it is determined that the patient has an inducer of CYP3A or an inhibitor of CYP3C8, discontinuing the administration of a therapeutically effective amount of a Bruton's tyrosine kinase (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.

[0712] Embodiment #19: A method of treating multiple sclerosis (MS) in a patient in need thereof, comprising determining whether the patient has elevated alanine transaminase (ALT) enzyme, and if it is determined that the patient has elevated ALT enzyme, discontinuing the administration of a therapeutically effective amount of a Bruton's tyrosine kinase (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.

[0713] Embodiment #20: A method for treating MG in a patient in need of treatment for MG, comprising determining whether the patient has elevated ALT enzyme, and if it is determined that the patient has elevated ALT enzyme, discontinuing administration of 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.

[0714] Embodiment #21: A method for treating MS in a patient in need of treatment for MS, comprising determining whether the patient has elevated ALT > 1.5×ULN or AST > 1.5×ULN or alkaline phosphatase > 2×ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5×ULN (except for Gilbert's syndrome or those due to non-liver-related disorders), and if it is determined that the patient has any of these conditions, discontinuing administration of 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.

[0715] Embodiment #22: A method for treating MG in a patient in need of treatment for MG, comprising determining whether the patient has elevated ALT > 1.5×ULN or AST > 1.5×ULN or alkaline phosphatase > 2×ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5×ULN (except for Gilbert's syndrome or those due to non-liver-related disorders), and if it is determined that the patient has any of these conditions, discontinuing administration of 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.

[0716] Embodiment #23: A method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining whether the patient has elevated ALT > 1.5×ULN or AST > 1.5×ULN or alkaline phosphatase > 2×ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5×ULN (except for Gilbert's syndrome or non-liver-related disorders), and, if the patient is found not to have any of these conditions, 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

[0717] Embodiment #24: A method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining whether the patient has elevated ALT > 1.5×ULN or AST > 1.5×ULN or alkaline phosphatase > 2×ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5×ULN (except for Gilbert's syndrome or non-liver-related disorders), and, if the patient is found not to have any of these conditions, 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

[0718] Embodiment #25: A method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining whether the patient has mild, moderate or severe liver impairment, and, if the patient is found not to have any of these conditions, 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.

[0719] Embodiment #26: A method of treating MG in a patient in need of treatment for MG, comprising determining whether the patient has mild, moderate or severe liver impairment, and if it is determined that the patient does not have any of these conditions, 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.

[0720] Embodiment #27: A method of treating MS in a patient in need of treatment for MS, comprising determining whether the patient has mild, moderate or severe liver impairment, and if it is determined that the patient has any of these conditions, discontinuing the administration to the patient of 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.

[0721] Embodiment #28: A method of treating MG in a patient in need of treatment for MG, comprising determining whether the patient has mild, moderate or severe liver impairment, and if it is determined that the patient has any of these conditions, discontinuing the administration to the patient of 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.

[0722] Embodiment #29: A method 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 transferrin levels or ferritin levels.

[0723] Embodiment #30: A method for 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 ferritin levels.

[0724] Embodiment #31: A method for 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 an appropriate iron panel.

[0725] Embodiment #32: A method for 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 an appropriate iron panel.

[0726] Embodiment #33: A method for 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 appropriate alcohol consumption.

[0727] Embodiment #34: A method for 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 appropriate alcohol consumption.

[0728] Embodiment #35: A method for 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 an inducer of CYP3A or an inhibitor of CYP3C8.

[0729] Embodiment #36: A method for 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.

[0730] Embodiment #37: A method for 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.

[0731] Embodiment #38: A method for 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.

[0732] Embodiment #39: A method 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 > 1.5 × ULN or AST > 1.5 × ULN or alkaline phosphatase > 2 × ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5 × ULN (except when due to Gilbert's syndrome or non-liver-related disorders).

[0733] Embodiment #40: A method 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 > 1.5 × ULN or AST > 1.5 × ULN or alkaline phosphatase > 2 × ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) or total bilirubin > 1.5 × ULN (except when due to Gilbert's syndrome or non-liver-related disorders).

[0734] Embodiment #41: A method 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)-1, wherein the patient does not have mild liver impairment, moderate liver impairment, or severe liver impairment.

[0735] Embodiment #42: A method for 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 mild liver impairment, moderate liver impairment, or severe liver impairment.

Claims

**Claim 1** A method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels; and, if it is determined that the patient does not 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. **Claim 2** A method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining whether the patient has elevated transferrin levels or elevated ferritin levels; and, if it is determined that the patient does not 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. **Claim 3** A method of treating multiple sclerosis (MS) in a patient in need thereof, the method comprising determining the iron panel of the patient; and, if it is determined that the patient has an appropriate iron panel, 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. **Claim 4** A method of treating myasthenia gravis (MG) in a patient in need thereof, the method comprising determining the iron panel of the patient; and, if it is determined that the patient has an appropriate iron panel, 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. **Claim 5** A method for 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 said patient does not have elevated transferrin levels or elevated ferritin levels.

6. A method for 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 said patient does not have elevated transferrin levels or elevated ferritin levels.

7. A method for 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 said patient has appropriate iron levels.

8. A method for 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 said patient has an appropriate iron panel.

9. A method for treating MS, comprising (a) performing an iron panel test on the patient's blood or serum; (b) detecting levels of the iron panel test within the normal range; (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; comprising The iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in a patient's blood or serum, and the normal range of the iron panel test includes one or more of (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240 to 450 μg / dL. Method. **Claim 10** A method of treating MS, comprising: (a) detecting the transferrin saturation level in the blood or serum of a patient within the 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 within the normal range in the blood or serum of male patients is a transferrin saturation of 50% or less, and the transferrin saturation level within the normal range in the blood or serum of female patients is a transferrin saturation of 40% or less. Method. **Claim 11** A method of treating MS, comprising: (a) detecting the level of ferritin in the blood or serum of a patient within the 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 ferritin level within the normal range in the blood or serum of the patient is 500 μg / L or less. Method. **Claim 12** A method of treating MS, comprising: (a) performing a liver function test on a patient; (b) detecting appropriate liver function in the 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 test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood, wherein the patient having appropriate liver function has one or more of an ALT of 1.5x or less of the upper limit of normal (ULN), an AST level of 1.5x or less of the ULN, an alkaline phosphatase of 2x or less of the ULN (except when caused by non-liver-related disorders or when explained by stable chronic liver disorders) and a total bilirubin of 1.5x or less of the ULN (except when due to Gilbert's syndrome or non-liver-related disorders), Method. **Claim 13** A method for treating MS, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 8x the upper limit of normal (ULN); (d) discontinuing the administration of the compound to the patient; and optionally, (e) monitoring the ALT level of the patient; (f) restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN. A method comprising the above steps. **Claim 14** A method for treating MS, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 5x the upper limit of normal (ULN) during a period of at least two weeks; (d) discontinuing the administration of the compound to the patient; and optionally, (e) monitoring the ALT level of the patient; (f) restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN. A method comprising

15. A method for treating MS, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in said patient; (c) detecting a level of ALT that is more than 3x the upper limit of normal (ULN); (d) measuring one or more of the total bilirubin and international normalized ratio (INR) of the patient; (e) detecting one or more of a total bilirubin that is more than 2x the ULN and an INR that is more than 1.5; (f) stopping the administration of said compound to said patient, and optionally, (g) monitoring the ALT level of said patient; (h) resuming the administration of a therapeutically effective amount of said compound to said patient when it is determined that the ALT level of said patient is less than 1.5x the ULN. A method comprising

16. A method for treating MS, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in said patient; (c) detecting a level of ALT that is more than 3x the upper limit of normal (ULN); (d) stopping the administration of said compound to said patient if said patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and an eosinophilia of more than 5%, and optionally, (e) monitoring the ALT level of said patient; (f) resuming the administration of a therapeutically effective amount of said compound to said patient when it is determined that the ALT level of said patient is less than 1.5x the ULN. A method comprising

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

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

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

20. A method of treating MS in a patient in need thereof, 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 has not received a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 liver enzyme.

21. A method of treating MS in a patient in need thereof, comprising: (a) advising the patient to limit alcohol consumption during treatment; (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; comprising wherein the patient is female and is advised to limit alcohol intake to 14 grams per day or less, or the patient is male and is advised to limit alcohol intake to 28 grams per day or less. method.

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 of treating MG, comprising: (a) performing an iron panel test on the patient's blood or serum; (b) detecting the level of the iron panel test within the normal range; (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; comprising The iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in a patient's blood or serum, and the normal range of the iron panel test includes one or more of (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240 to 450 μg / dL. Method.

24. A method for treating MG, comprising: (a) detecting the transferrin saturation level in the blood or serum of a patient within the normal range; (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; comprising: wherein the transferrin saturation level within the normal range in the blood or serum of male patients is a transferrin saturation of 50% or less, and the transferrin saturation level within the normal range in the blood or serum of female patients is a transferrin saturation of 40% or less. Method.

25. A method for treating MG, comprising: (a) detecting the level of ferritin in the blood or serum of a patient within the normal range; (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; comprising: wherein the ferritin level within the normal range in the blood or serum of the patient is 500 μg / L or less. Method.

26. A method for treating MG, comprising: (a) performing a liver function test on a patient; (b) detecting appropriate liver function in the patient; (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; comprising: The liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood, wherein the patient having appropriate liver function has one or more of ALT at 1.5x or less of the upper limit of normal (ULN), AST level at 1.5x or less of the ULN, alkaline phosphatase at 2x or less of the ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders) and total bilirubin at 1.5x or less of the ULN (except in the case of Gilbert's syndrome or non-liver-related disorders), method. **Claim 27** A method for treating MG, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 8x the upper limit of normal (ULN); (d) discontinuing the administration of the compound to the patient, and optionally, (e) monitoring the ALT level of the patient; (f) restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN. A method comprising the above steps. **Claim 28** A method for treating MG, comprising: (a) 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 (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 5x the upper limit of normal (ULN) during a period of at least two weeks; (d) discontinuing the administration of the compound to the patient, and optionally, (e) monitoring the ALT level of the patient; (f) restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN. A method comprising

29. A method 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 (Compound); measuring the level of alanine aminotransferase (ALT) in the patient; detecting a level of ALT that is more than 3x the upper limit of normal (ULN); measuring one or more of the patient's total bilirubin and international normalized ratio (INR); detecting one or more of a total bilirubin that is more than 2x the ULN and an INR that is more than 1.5; discontinuing administration of the compound to the patient, and optionally, monitoring the ALT level of the patient; resuming administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x the ULN. A method comprising

30. A method 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 (Compound); measuring the level of alanine aminotransferase (ALT) in the patient; detecting a level of ALT that is more than 3x the upper limit of normal (ULN); if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and an eosinophil increase of more than 5%, discontinuing administration of the compound to the patient, and optionally, monitoring the ALT level of the patient; resuming administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x the ULN. A method comprising

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

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

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

34. A method of treating MG in a patient in need thereof, 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 has not received a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 liver enzyme.

35. A method of treating MG in a patient in need thereof, comprising: (a) advising the patient to limit alcohol consumption during treatment; (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; comprising: wherein the patient is female and is advised to limit alcohol intake to 14 grams per day or less, or the patient is male and is advised to limit alcohol intake to 28 grams per day or less. Method.

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