Therapeutic tyrosine kinase inhibitors for myelin oligodendroglia glycoprotein antibody disease (MOGAD)

Abstract

The present invention relates to the field of therapeutic tyrosine kinase inhibitors, in particular Bruton's tyrosine kinase ("BTK") inhibitors, for use in the treatment of subjects suffering from oligodendromyelin glycoprotein antibody disease (MOGAD).

Description

Technical Field

[0001] The present invention relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase ("BTK") inhibitors, for use in the treatment of myelin oligodendrocyte glycoprotein antibody disease (MOGAD). Background Art

[0002] Myelin oligodendrocyte glycoprotein (MOG) is a highly conserved protein expressed only in oligodendrocytes in the central nervous system (CNS). MOG is located on the surface of myelin in the central nervous system (Fan et al. Mult Scler Relat Disord. 2018, 20, 144-152; Kezuka et al. Jpn J Ophthalmol. 2018, 62, 101-108). MOG has multiple subtypes with the same extracellular immunoglobulin (Ig) domain but with differentially spliced ​​intracellular C-terminals. The difference in C-terminal amino acids is the basis for distinguishing the α or β subtypes of MOG. Although the function of MOG is not fully understood, MOG is a target of the immune system in MOGAD (dos Passos et al. Front. Neurol. 2018, 9, 217). In the past two decades, MOG-IgG antibodies (MOG-IgG) have been widely studied in different acquired demyelinating syndromes (ADS). The development and use of highly specific cell-based assays has enabled the description of a variety of clinical disease manifestations, ranging from certain ADS (e.g., acute disseminated encephalomyelitis (ADEM) primarily in children or optic neuritis primarily in adults) to cases of encephalitis with seizures. This broad spectrum of clinical phenotypes associated with MOG-IgG has evolved into a new inflammatory CNS disease entity distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).

[0003] MOG antibody disease (MOGAD) is a recently characterized neuroinflammatory disorder that preferentially causes inflammation of the optic nerve, but can also cause inflammation in the spinal cord and brain. If MOG antibodies are found in the blood of patients with repeated episodes of central nervous system inflammation, the diagnosis can be confirmed (Weber et al. Ther Adv Neurol Disord. 2018, 11, 1-15). MOGAD patients may have previously been diagnosed with neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), or multiple sclerosis (MS) due to the pattern of inflammation caused by MOGAD, including brain, spinal cord, and optic nerve damage. Patients with persistently positive antibodies are at risk for recurrent events. MOGAD patients do not test positive for NMO antibodies called aquaporin 4 (AQP-4). MOGAD and AQP-4-positive NMOSD are thought to have different immunological mechanisms. In addition, MOGAD patients appear to be less likely to have other autoimmune conditions (such as rheumatoid arthritis, Hashimoto's thyroiditis, etc.) than AQP-4-positive NMOSD patients.

[0004] Currently, approximately 4,000 patients are diagnosed each year in the US and EU, but MOGAD is believed to be underdiagnosed in the US / EU by approximately 10%, i.e., MOGAD is estimated to be prevalent in approximately 40,000 patients each year.

[0005] MOGAD presents with symptoms including loss of color vision, loss or blurred vision, quadriplegia / paraparesis, and loss of bladder / bowel control. This condition presents many unmet needs, including that MOGAD patients are often misdiagnosed and difficult to treat; there are currently no treatments specifically approved or in development for MOGAD, and therefore, the current standard of care treatment is intravenous immunosuppressants such as methylprednisolone or oral prednisolone. Therefore, there is an unmet need for effective therapies for MOGAD.

[0006] The Bruton's tyrosine kinase (BTK) pathway is critical for signaling in B lymphocytes and myeloid cells including CNS microglia. Each of these cell types has been implicated in the pathophysiology of multiple sclerosis (MS). In addition, because BTK signaling is critical for the maturation of B cells into antibody-secreting plasma cells, BTK inhibition can modulate both cellular and humoral immunity. Therefore, compounds that inhibit BTK that are both able to inhibit antigen-induced B cell priming responsible for neuroinflammation and to modulate maladaptive microglia associated with neuroinflammation in the brain and spinal cord may be useful for treating MOGAD and offer superior benefits compared to the paucity of currently available therapies. BTK inhibitors may alter MOGAD disease progression through two distinct mechanisms: 1) modulating B cell-mediated autoinflammatory processes, and 2) inhibiting Fc receptor-mediated microglial inflammatory demyelination.

[0007] Drug-induced liver injury has been identified in an ongoing phase 3 trial of tolebrutinib. The reported events occurred between 2 and 3 months after initiation of tolebrutinib, and the elevations in liver enzymes appeared to be reversible after discontinuation of tolebrutinib. Therefore, there is a need to mitigate the risk of liver injury and provide safe treatments for patients with MOGAD. Summary of the invention

[0008] The present invention relates to a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which comprises administering to a subject 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 or a pharmaceutically acceptable salt thereof.

[0009] The present invention also relates to a method for reducing the frequency of MOGAD relapses in a subject suffering from MOGAD, the method comprising administering to a subject 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 or a pharmaceutically acceptable salt thereof.

[0010] The present invention further relates to a method for reducing MOG antibody titer in a subject suffering from MOGAD, the method comprising administering to a subject 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 or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the subject has at least one symptom of MOGAD prior to treatment.

[0012] In some embodiments, the at least one MOGAD symptom is selected from the group consisting of loss of color vision, loss or blurred vision, quadriplegia / paraplegia, and loss of bladder / bowel control.

[0013] In some embodiments, the treatment reduces or eliminates at least one symptom of MOGAD.

[0014] In some embodiments, the subject is relapse-free for about 1 year.

[0015] In some embodiments, the subject has at least one confirmed relapse within the past 12 months or 2 confirmed relapses within the past 24 months at the time of screening.

[0016] In some embodiments, a corticosteroid is administered to the subject who relapses.

[0017] In some embodiments, the corticosteroid is methylprednisone.

[0018] In some embodiments, a dose of about 5 mg to about 60 mg of the BTK inhibitor is administered.

[0019] In some embodiments, the dose is 5 mg.

[0020] In some embodiments, the dose is 15 mg.

[0021] In some embodiments, the dose is 30 mg.

[0022] In some embodiments, the dose is 60 mg.

[0023] In some embodiments, the dosage is once daily.

[0024] In some embodiments, the dose is administered once daily with food.

[0025] In some embodiments, the dose is 60 mg and is administered once daily with food.

[0026] In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0027] In some embodiments, the MOGAD is selected from acquired demyelinating syndrome (ADS).

[0028] In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0029] In some embodiments, the subject is a human.

[0030] In some embodiments, the subject is a human subject ranging in age from 12 to 55 years old.

[0031] The present invention 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 MOGAD in a subject in need thereof.

[0032] The present invention further 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 reducing the frequency of MOGAD relapses in a subject with MOGAD in need thereof.

[0033] The present invention further 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 reducing or eliminating MOG antibody titer in a subject with MOGAD in need thereof.

[0034] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (a) Performing an iron panel test in the patient's blood or serum; (b) detecting the level of said iron test panel within the normal range; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the iron panel test measures any one or more of iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum, and wherein the normal range for the iron panel test includes one or more of: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level ≤500 μg / L, (iii) a transferrin saturation level ≤50% for male patients or a transferrin saturation level ≤40% for female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0035] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (a) detecting a transferrin saturation level in the patient's blood or serum within a normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, Wherein the transferrin saturation level in the blood or serum of a male patient within the normal range is transferrin saturation ≤ 50%, and the transferrin saturation level in the blood or serum of a female patient within the normal range is transferrin saturation ≤ 40%.

[0036] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (a) detecting a ferritin level in the patient's blood or serum that is within a normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, The ferritin level in the patient's blood or serum is within the normal range and is ≤500 μg / L.

[0037] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (a) Perform liver function tests in patients; (b) testing the patient for appropriate liver function; 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 aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein in the patient's blood, and wherein the patient with adequate liver function has one or more of ALT ≤ 1.5 x upper limit of normal (ULN), AST level ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (except when caused by a non-liver related condition or explained by a stable chronic liver condition), and total bilirubin ≤ 1.5 x ULN (except when due to Gilbert's syndrome or a non-liver related condition).

[0038] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (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) ALT levels >8x upper limit of normal (ULN) were detected; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring the patient's ALT level; and (f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0039] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (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) detection of ALT levels >5x upper limit of normal (ULN) for a period of at least two weeks; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring the patient's ALT level; and (f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0040] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (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) ALT levels >3x upper limit of normal (ULN) were detected; (d) measuring one or more of the patient's total bilirubin and international normalized ratio (INR); (e) one or more of total bilirubin >2x ULN and INR >1.5 was detected; (f) ceasing administration of the compound to the patient; and optionally (g) monitoring the patient's ALT level; and (h) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0041] The present invention also relates to a method for treating MOGAD, the method comprising the steps of: (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) ALT levels >3x upper limit of normal (ULN) were detected; (d) stopping administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia>5%; and optionally (e) monitoring the patient's ALT level; and (f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0042] In some embodiments, the ALT level in step (b) is determined at least monthly.

[0043] In some embodiments, the ALT level in step (d) is monitored at least weekly.

[0044] In some embodiments, the ALT level in step (d) is monitored every 2 to 3 days.

[0045] The present invention also relates to a method of treating MOGAD 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 is not receiving strong and moderate inducers of cytochrome P450 3A (CYP3A) or strong inhibitors of the CYP2C8 liver enzyme.

[0046] The present invention also relates to a method of treating MOGAD in a patient in need thereof, the method comprising the steps of: (a) advising the patient to limit the amount of alcohol consumed during treatment; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, Wherein the patient is female and it is recommended to limit alcohol intake to 14 g / day or less, or the patient is male and it is recommended to limit alcohol intake to 28 g / day or less. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1A The study design for Example 1 is provided.

[0048] Figure 1B The study design for Example 2 is provided.

[0049] Figure 2 Suggested actions and follow-up assessments in the event of neutropenia are provided.

[0050] Figure 3 Suggested actions and follow-up assessments in the event of thrombocytopenia are provided.

[0051] Figure 4A Suggested actions and follow-up assessments in the event of an increase in alanine aminotransferase (ALT) algorithm are provided for Example 1.

[0052] Figure 4B For Example 2, suggested actions and follow-up assessments in the event of an increase in alanine aminotransferase (ALT) algorithm are provided.

[0053] Figure 5 Suggested actions and follow-up assessments in the event of an increase in serum creatinine are provided.

[0054] Figure 6 Suggested actions and follow-up evaluations when progressive multifocal leukoencephalopathy (PML) is suspected are provided.

[0055] Figure 7 A description of the Expanded Disability Status Scale score (EDSS) based on disability level is provided.

[0056] Figure 8 Recommended actions and follow-up assessments are provided in the event of CPK increases that are noncardiac in origin and not related to vigorous physical activity. DETAILED DESCRIPTION

[0057] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying drawings. Although the invention provides illustrative embodiments, it should be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included in the invention defined by the appended claims.

[0058] The section titles used herein are only for the purpose of organization and should not be interpreted as limiting the desired subject matter in any way. In the case where any document incorporated by reference conflicts with any term defined in this specification, this specification shall prevail. Although the teaching of the present invention is described in conjunction with each embodiment, it is not intended that the teaching of the present invention is limited to such embodiments. On the contrary, as will be appreciated by those skilled in the art, the teaching of the present invention encompasses various alternatives, modifications and equivalents. I. Definitions

[0059] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of the present invention and have the following meanings.

[0060] As used herein, "BTK inhibitor," "BTK inhibitor compound," and "compound" refers 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: It is also known as "tolebrutinib", and 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one having the following structure: or pharmaceutically acceptable salts thereof.

[0061] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes one and more than one such excipient.

[0062] “Treating” or “treatment” of a disease includes: (1) inhibiting the disease, such as preventing or reducing the development of the disease or its clinical symptoms; or (2) Alleviate a disease, such as causing regression of the disease or its clinical symptoms.

[0063] "Optional" or "optionally" means that the subsequently described event or circumstance can occur but does not have to occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0064] "Therapeutically effective amount" means the amount of the BTK inhibitor compound that, when administered to a mammal to treat a disease, is sufficient to achieve such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0065] A “MOGAD relapse” was defined as the acute or subacute onset of new neurological symptoms, or worsening of previous neurological symptoms, with objective changes on neurological examination.

[0066] The "Expanded Disability Status Scale (EDSS) score" is a method of quantifying disability in multiple sclerosis and monitoring changes in disability levels over time. The EDSS scale ranges from 0 to 10, with 0.5 unit increments indicating higher levels of disability. EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any instructions, and are based on measures of impairment in eight functional systems (FS): Pyramidal - muscle weakness or difficulty with limb movement; Cerebellar - ataxia, loss of balance, loss of coordination, or tremor; Brainstem - speech problems, swallowing problems, and nystagmus; Sensory - numbness or loss of sensation; Bowel and bladder function; Visual function - vision problems; Cerebral function - thinking and memory problems. EDSS steps 5.0 to 9.5 are defined as walking impairment. See, e.g. Figure 7 Information on this score can be found in Kurtzke et al. Neurology 1983, 33, 1444-1452.

[0067] "Serum aquaporin 4 antibody titer negative" means a subject who tests negative for aquaporin 4 receptor antibodies in the subject's serum, which is used to diagnose and evaluate neuromyelitis optica, acute myelitis, spinal cord injury, autoimmune encephalitis, or neuromyelitis optica spectrum (NMO) disorders. "Aquaporin 4 receptor antibodies" are highly specific serum markers for neuromyelitis optica that can facilitate differential diagnosis of the above diseases. If a patient's serum tests positive for aquaporin 4 receptor antibodies, the patient has NMO and not MOGAD.

[0068] Before the present teachings are described in detail, it is to be understood that this invention is not limited to specific compositions or method steps as these may vary.

[0069] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a conjugate" includes a plurality of conjugates and reference to "a cell" includes a plurality of cells, and so forth.

[0070] Numerical ranges include the numbers that define the ranges. Taking into account significant figures and errors associated with the measurements, measured values ​​and measurable values ​​should be understood as approximate values. In addition, the use of "comprise, comprises, comprising", "contain, contains, containing", "include, includes and including" is not intended to be limiting. It should be understood that the foregoing summary of the invention and the specific embodiments are only exemplary and explanatory, and are not limitations on the teachings of the present invention.

[0071] Unless otherwise specified in the above description, embodiments in this specification that list "comprising" various components are also contemplated as "consisting of the listed components" or "consisting essentially of the listed components"; embodiments in this specification that list "consisting of various components" are also contemplated as "comprising the listed components" or "consisting essentially of the listed components"; and embodiments in this specification that list "consisting essentially of various components" are also contemplated as "consisting of the listed components" or "comprising the listed components" (this interchangeability does not apply to the use of these terms in the claims).

[0072] As used herein, the term "or a combination thereof and or combinations thereof" refers to any and all permutations and combinations of the terms listed before the term. For example, "A, B, C, or a combination thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and if the order is important in a particular context, BA, CA, CB, ACB, CBA, BCA, BAC, or CAB. Continuing with this example, explicitly included are combinations containing repetitions of one or more items, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. It will be appreciated by those skilled in the art that, unless otherwise apparent from the context, there is typically no limit to the number of items or terms in any combination.

[0073] Unless the context requires otherwise, "or" is used in its inclusive sense (ie, equivalent to "or").

[0074] "Ceasing" or "cessation" when used with respect to the administration of a BTK inhibitor compound means that the BTK inhibitor compound is no longer administered to a patient, either temporarily or permanently.

[0075] "Monitoring" with respect to assessing a patient's ALT level means checking and / or detecting a 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 weekly; in some embodiments, every 5 days; in some embodiments, every 3 days; in some embodiments, every 2 to 3 days; in some embodiments, every 2 days; in some embodiments, every day. II. BTK Inhibitor Compounds Administered

[0076] 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 for use in treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) in a subject in need thereof. In some embodiments, the BTK inhibitor compound is a pharmaceutically acceptable salt of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, a therapeutically effective amount of the BTK inhibitor compound is administered. In some embodiments, a 5 to 60 mg dose of the BTK inhibitor compound is administered. In some embodiments, a 60 mg dose of the BTK inhibitor compound is administered. In some embodiments, a 60 mg dose of the BTK inhibitor compound is administered once daily.

[0077] 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 MOGAD in a subject in need thereof.

[0078] 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 MOGAD relapses in a subject with MOGAD in need thereof.

[0079] 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 reducing MOG antibody titer in a subject with MOGAD in need thereof.

[0080] BTK inhibitor compounds can be prepared according to the methods and protocols described, for example, in U.S. Pat. No. 9,688,676 B2, particularly at Column 62, line 8 to Column 65, line 32 and Column 67, line 28 to Column 69, which are incorporated herein by reference.

[0081] The following preparation of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one compounds is provided to enable one skilled in the art to prepare BTK inhibitor compounds. The synthetic routes should not be considered to limit the scope of the invention, but are merely illustrative and representative.

[0082] Exemplary Synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one: Into a 100 mL round-bottom flask was placed (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), DCM-CH3OH (6 mL), TEA (113 mg, 1.12 mmol, 3.00 equiv). Propyl-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv) was then added dropwise and stirred at 0°C for 5 min. The resulting solution was stirred at 0°C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (30:1). The crude product (100 mg) was purified by preparative HPLC using the following conditions (column, XBridge Prep C 18 OBD column, 5 μm, 19*150 mm; mobile phase, water (containing 0.05% TFA) and ACN (25.0% ACN up to 45.0% in 8 min)) purification. 54.5 mg of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m / z: 465.2 (M+1). III. Treatment Methods

[0083] Provided herein is a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising administering to a subject in need thereof a therapeutically effective amount of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof, wherein the BTK inhibitor comprises (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0084] In some embodiments, the subject has at least one MOGAD symptom before or during treatment. In some embodiments, the at least one MOGAD symptom is selected from color vision loss, loss or blurred vision, quadriplegia / paraplegia, and loss of bladder / bowel control. In some embodiments, treatment reduces or eliminates the at least one symptom. In some embodiments, the reduction or elimination of at least one symptom occurs after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks of daily treatment, or after 6 months, 1 year, 1.5 years, or 2 years.

[0085] In some embodiments, the subject has no recurrence for about 1 year. In some embodiments, the subject has at least one confirmed recurrence in the past 12 months or 2 confirmed recurrences in the past 24 months at the time of screening. In some embodiments, a corticosteroid is administered to the subject of the recurrence. In some embodiments, the corticosteroid is methylprednisone.

[0086] In some embodiments, after about one year of treatment, the rate of increase of the expanded disability status scale score (EDSS) is reduced. In some embodiments, after about one year of treatment, the EDSS score is the same as the baseline or is reduced from the baseline. In some embodiments, the subject's EDSS score before treatment is greater than 7.0. In some embodiments, the subject has a negative serum aquaporin 4 antibody titer according to a cell-based assay. In some embodiments, the subject has a history of at least two confirmed MOGAD attacks.

[0087] In some embodiments, the therapeutically effective amount is about 5 to about 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.

[0088] In some embodiments, the dosage is once a day. In some embodiments, the dosage is administered once a day with food. In some embodiments, the dosage is 60 mg and is administered once a day with food. In some embodiments, the BTK inhibitor compound is administered as a monotherapy.

[0089] In some embodiments, MOGAD is selected from acquired demyelinating syndrome (ADS). In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0090] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is a human subject in the range of 12 to 55 years of age.

[0091] Also provided herein is a method of reducing the frequency of MOGAD relapses in a subject suffering from MOGAD, the method comprising administering to a subject 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 or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the subject has at least one MOGAD symptom prior to treatment. In some embodiments, the at least one MOGAD symptom is selected from color vision loss, loss or blurred vision, quadriplegia / paraplegia, and loss of bladder / bowel control. In some embodiments, the subject has at least one MOGAD symptom prior to treatment, wherein the treatment reduces or eliminates the one or more symptoms.

[0093] In some embodiments, the subject has no relapse for about 1 year. In some embodiments, the subject has at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at the time of screening. In some embodiments, the subject relapses and is administered a corticosteroid. In some embodiments, the corticosteroid is methylprednisone.

[0094] In some embodiments, after about one year of treatment, the rate of increase of the Expanded Disability Status Scale score (EDSS) is reduced. In some embodiments, after about one year of treatment, the EDSS score is the same as the baseline or reduced from the baseline. In some embodiments, the subject's EDSS score before treatment is greater than 7.0. In some embodiments, the subject's EDSS score after treatment remains flat and no longer increases. In some embodiments, the subject's EDSS score after treatment is reduced to less than 9.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 9.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 8.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 8.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 7.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 7.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 6.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 6.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 5.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 5.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 4.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 4.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 3.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 3.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 2.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 2.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 1.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 1.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 0.5. In some embodiments, the subject has a negative serum aquaporin 4 antibody titer according to a cell-based assay. In some embodiments, the subject has a history of at least two confirmed MOG antibody disease attacks. In some embodiments, the BTK inhibitor compound is administered as a monotherapy.

[0095] In some embodiments, MOGAD is selected from acquired demyelinating syndrome (ADS). In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0096] In some embodiments, the therapeutically effective amount is about 5 to about 60 mg. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is a human subject in the range of 12 to 55 years of age.

[0097] Still further provided herein is a method of reducing or eliminating MOG antibody titer in a subject suffering from MOGAD, the method comprising administering to a subject 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 or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the subject has at least one MOGAD symptom prior to treatment. In some embodiments, the at least one MOGAD symptom is selected from color vision loss, vision loss or blurring, quadriplegia / paraplegia, and bladder / bowel control loss. In some embodiments, the subject has at least one MOGAD symptom prior to treatment, wherein the treatment reduces or eliminates the one or more symptoms.

[0099] In some embodiments, the subject has no recurrence for about 1 year. In some embodiments, the subject has at least one confirmed recurrence in the past 12 months or 2 confirmed recurrences in the past 24 months when screened. In some embodiments, the subject relapses and is administered a corticosteroid. In some embodiments, the corticosteroid is methylprednisone.

[0100] In some embodiments, after about one year of treatment, the rate of increase of the Expanded Disability Status Scale score (EDSS) is reduced. In some embodiments, after about one year of treatment, the EDSS score is the same as the baseline or reduced from the baseline. In some embodiments, the subject's EDSS score before treatment is greater than 7.0. In some embodiments, the subject's EDSS score after treatment remains flat and no longer increases. In some embodiments, the subject's EDSS score after treatment is reduced to less than 9.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 9.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 8.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 8.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 7.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 7.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 6.5. In some embodiments, the subject's EDSS score after treatment is reduced to less than 6.0. In some embodiments, the subject's EDSS score after treatment is reduced to less than 5.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 5.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 4.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 4.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 3.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 3.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 2.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 2.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 1.5. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 1.0. In some embodiments, the EDSS score of the subject after treatment is reduced to less than 0.5. In some embodiments, the subject has a negative serum aquaporin 4 antibody titer according to a cell-based assay. In some embodiments, the subject has a history of at least two confirmed MOG antibody disease attacks. In some embodiments, the BTK inhibitor compound is administered as a monotherapy.

[0101] In some embodiments, MOGAD is selected from acquired demyelinating syndrome (ADS). In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0102] In some embodiments, the therapeutically effective amount is about 5 to about 60 mg. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is a human subject in the range of 12 to 55 years of age. In some embodiments, the subject is a human patient. In some embodiments, the subject is a human patient in the range of 12 to 55 years of age.

[0103] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in a subject having one or more MOGAD symptoms prior to treatment. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses, and the treatment reduces or eliminates one or more symptoms. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in subjects suffering from MOGAD-induced color vision loss, vision loss or blurring, quadriplegia / paraplegia, and bladder / bowel control loss. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in subjects who have been relapse-free for about 1 year. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in subjects who have at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at screening. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in subjects who are administered corticosteroids. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in a subject administered methylprednisone. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses, wherein the rate of increase in the Expanded Disability Status Scale score (EDSS) is reduced after about one year of treatment.In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses, wherein after about one year of treatment, the EDSS score is the same as or decreased from baseline. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) is reduced in subjects with a pre-treatment EDSS score greater than 7.0. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses, wherein after about one year of treatment, the EDSS score of a subject with a pre-treatment EDSS score greater than 7.0 is the same as or decreased from baseline. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in a subject with a negative serum aquaporin 4 antibody titer according to a cell-based assay. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce the frequency of MOGAD relapses in a subject with a history of at least two confirmed MOG antibody disease episodes.

[0104] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce MOG antibody titers. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in a subject having one or more symptoms of MOGAD prior to treatment. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers and the treatment reduces or eliminates one or more symptoms. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in subjects suffering from color vision loss, vision loss or blurring, quadriplegia / paraplegia, and bladder / bowel control loss caused by MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in subjects who have been relapse-free for about 1 year. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in subjects who have at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at screening. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in a subject administered corticosteroids. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in a subject administered methylprednisone.In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) is reduced. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers, wherein after about one year of treatment, the EDSS score is the same as or decreased from baseline. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) is reduced in subjects with a pre-treatment EDSS score greater than 7.0. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers, wherein after about one year of treatment, the EDSS score of subjects with a pre-treatment EDSS score greater than 7.0 is the same as or decreased from baseline. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in subjects with negative serum aquaporin 4 antibody titers according to a cell-based assay. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to reduce or eliminate MOG antibody titers in subjects with a history of at least two confirmed MOG antibody disease episodes.

[0105] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a mammalian subject with MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject with MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject with MOGAD whose age ranges from 12 to 55. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and has one or more symptoms of MOGAD prior to treatment. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and suffers from loss of color vision, loss or blurred vision, quadriplegia / paraparesis, and loss of bladder / bowel control caused by MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and an EDSS score greater than 7.0 prior to treatment. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and a negative serum aquaporin 4 antibody titer according to a cell-based assay. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and a history of at least two confirmed MOG antibody disease episodes.

[0106] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a subject having MOGAD and being relapse-free for about 1 year. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 having MOGAD and being relapse-free for about 1 year. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and has been relapse-free for about 1 year prior to treatment and has one or more symptoms of MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and has been relapse-free for about 1 year and suffers from color vision loss, vision loss or blurring, quadriplegia / paraparesis, and bladder / bowel control loss caused by MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and has been relapse-free for about 1 year prior to treatment and has an EDSS score greater than 7.0. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and has been relapse-free for about 1 year prior to treatment and has a negative serum aquaporin 4 antibody titer according to a cell-based assay. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD and is relapse-free for about 1 year and has a history of at least two confirmed MOG antibody disease episodes.

[0107] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a subject having MOGAD and having at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at the time of screening. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 having MOGAD and having at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at the time of screening. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject ranging in age from 12 to 55 who has MOGAD prior to treatment and who has at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months and one or more symptoms of MOGAD at screening. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to human subjects aged 12 to 55 who have MOGAD and who have at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at screening and who suffer from color vision loss, visual loss or blurred vision, quadriplegia / paraparesis, and loss of bladder / bowel control due to MOGAD. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to human subjects aged 12 to 55 who have MOGAD prior to treatment and who have at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months and an EDSS score greater than 7.0 at screening. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to human subjects ranging in age from 12 to 55 who have MOGAD and who have at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months at screening and a negative serum aquaporin 4 antibody titer according to a cell-based assay.In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to a human subject aged 12 to 55 who has MOGAD and has at least one confirmed relapse in the past 12 months or 2 confirmed relapses in the past 24 months and a history of at least two confirmed MOG antibody disease episodes at screening.

[0108] In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as a monotherapy. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered at a dose of 60 mg as a monotherapy. In some embodiments, a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered once daily at a dose of 60 mg as a monotherapy. In some embodiments, a BTK inhibitor including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered once daily as a monotherapy at a dose of 60 mg with food.

[0109] In some embodiments, a dose of about 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, or 55-60 mg is administered. In some embodiments, the dose is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg. In some embodiments, the dose is 5 mg. In some embodiments, the dose is 15 mg. In some embodiments, the dose is 30 mg. In some embodiments, the dose is 60 mg.

[0110] In some embodiments, the dosage is administered every day. The daily dosage can be delivered as a single dose or divided into multiple parts. For example, in some embodiments, the dosage is administered once a day (e.g., approximately every 24 hours). In some embodiments, the dosage is administered twice a day by subdividing the dosage into two parts to be administered twice a day (e.g., approximately every 12 hours). In some embodiments, the dosage is subdivided into three parts to be administered three times a day (e.g., approximately every 8 hours). In some embodiments, the dosage is subdivided into four parts to be administered four times a day (e.g., approximately every 6 hours).

[0111] In some embodiments, the dose is administered orally. In some embodiments, the dose is administered in the form of a tablet. In some embodiments, the dose is administered in the form of a pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0112] In some embodiments, the BTK inhibitor compound is administered to the subject for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or for life. In some embodiments, the BTK inhibitor compound is administered to the subject for a period of about 12 months. In some embodiments, the dosage is once a day. In one embodiment, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising administering 60 mg of a BTK inhibitor including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one to a subject in need.

[0113] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising administering to a subject in need thereof 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 BTK inhibitor compound is administered for a period of at least about 12 months. In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising administering to a subject in need thereof 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 BTK inhibitor compound is administered once a day for at least about 12 months. In some embodiments, a method for myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising administering to a subject in need thereof a daily dose of about 5 to about 60 mg 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, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising administering to a subject in need thereof a dose of about 5 to about 60 mg 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 BTK inhibitor compound is administered daily for a period of at least about 12 months.

[0114] In some embodiments, the BTK inhibitor compound is administered as a monotherapy. In some embodiments, the method comprises administering a BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent can be administered concurrently or sequentially with the BTK inhibitor compound.

[0115] The determination of the dosing frequency can be made by a person skilled in the art (e.g., an attending physician) based on considerations of 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 treating RMS. The therapeutically effective amount typically depends on the weight of the subject being treated, his or her physical or health condition, the extensiveness of the condition to be treated or the age of the subject being treated, the drug formulation method, or the method of administration (e.g., administration time and route of administration).

[0116] In some embodiments, a method of treating MOGAD is provided, comprising administering to a subject in need thereof a dose of about 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, or 55-60 mg 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 or a pharmaceutically acceptable salt thereof. IV. Methods of treating liver damage risk

[0117] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of performing an iron panel test using the patient's blood or serum, and administering to the patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one if the patient has a suitable iron panel test. In some embodiments, the iron panel test measures any one or more of iron levels, ferritin levels, transferrin saturation levels, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, a suitable iron testing panel includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level ≤500 μg / L, (iii) a transferrin saturation level ≤50% for male patients or ≤40% for female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0118] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of performing an iron panel test in the patient's blood or serum, detecting a level of the iron panel test within a normal range, and administering to the patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the iron panel test measures any one or more of the iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range for the iron panel test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level ≤500 μg / L, (iii) a transferrin saturation level ≤50% for male patients or ≤40% for female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0119] In some embodiments, the present invention 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), the BTK inhibitor being used in a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the steps of performing an iron panel test in the patient's blood or serum, detecting a level of the iron panel test within a normal range, and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the iron panel test measures any one or more of the iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range for the iron panel test includes one or more of the following: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level ≤500 μg / L, (iii) a transferrin saturation level ≤50% for male patients or ≤40% for female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0120] In some embodiments, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of determining the transferrin saturation level in the patient's blood or serum, and if the transferrin saturation level is appropriate, 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. In some embodiments, the appropriate transferrin saturation level in the blood or serum of a male patient is a transferrin saturation of ≤50%. In some embodiments, the appropriate transferrin saturation level in the blood or serum of a female patient is a transferrin saturation of ≤40%.

[0121] In some embodiments, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of detecting a transferrin saturation level within a normal range in the patient's blood or serum, 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. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a male patient is transferrin saturation ≤50%. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a female patient is transferrin saturation ≤40%.

[0122] In some embodiments, the present invention 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), the BTK inhibitor being used in a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the steps of detecting a transferrin saturation level within a normal range in the patient's blood or serum, and administering a therapeutically effective amount of the compound to the patient. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a male patient is a transferrin saturation of ≤50%. In some embodiments, the transferrin saturation level within a normal range in the blood or serum of a female patient is a transferrin saturation of ≤40%.

[0123] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of determining the ferritin level in the patient's blood or serum, and if the ferritin level is appropriate, administering to the patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the appropriate ferritin level in the patient's blood or serum is ≤500 μg / L.

[0124] In some embodiments, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of detecting a ferritin level in the patient's blood or serum within a normal range, and administering to the patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the ferritin level in the patient's blood or serum within a normal range is ≤500 μg / L.

[0125] In some embodiments, the present invention 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), the BTK inhibitor being used in a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the steps of detecting a ferritin level within a normal range in the patient's blood or serum, and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the ferritin level within a normal range in the patient's blood or serum is ≤500 μg / L.

[0126] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of performing a liver function test in a patient and, if the patient has suitable liver function, administering to the patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the liver function test measures one or more of the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein in the patient's blood. In some embodiments, patients with adequate liver function have one or more of ALT levels ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (except when caused by a non-liver related condition or explained by a stable chronic liver condition), and total bilirubin ≤ 1.5 x ULN (except when due to Gilbert's syndrome or a non-liver related condition).

[0127] In some embodiments, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, 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 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 aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein in the patient's blood. In some embodiments, patients with adequate liver function have one or more of ALT levels ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, alkaline phosphatase ≤ 2 x ULN (except when caused by a non-liver related condition or explained by a stable chronic liver condition), and total bilirubin ≤ 1.5 x ULN (except when due to Gilbert's syndrome or a non-liver related condition).

[0128] In some embodiments, the present invention 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), the BTK inhibitor being used in a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the steps of performing a liver function test in a patient, detecting appropriate liver function, and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the liver function test measures one or more of the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein in the patient's blood. In some embodiments, patients with adequate liver function have one or more of ALT levels ≤ 1.5 x upper limit of normal (ULN), AST levels ≤ 1.5 x ULN, and alkaline phosphatase ≤ 2 x ULN (except when caused by a non-liver related condition or explained by a stable chronic liver condition), and total bilirubin ≤ 1.5 x ULN (except when due to Gilbert's syndrome or a non-liver related condition).

[0129] In some embodiments, liver function tests are performed at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about every month. In some embodiments, liver function tests are performed at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about every week.

[0130] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of: 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) ALT level >8x upper limit of normal (ULN) detected; d) ceasing administration of said compound to said patient; and optionally e) monitoring the patient's ALT level; and f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0131] In some embodiments, the present invention 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 myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) ALT level >8x upper limit of normal (ULN) detected; d) ceasing administration of said compound to said patient; and optionally e) monitoring the patient's ALT level; and f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0132] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of: 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) ALT levels >5x upper limit of normal (ULN) detected over a period of at least two weeks; d) ceasing administration of said compound to said patient; and optionally e) monitoring the patient's ALT level; and f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0133] In some embodiments, the present invention 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 myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) ALT levels >5x upper limit of normal (ULN) detected over a period of at least two weeks; d) ceasing administration of said compound to said patient; and optionally e) monitoring the patient's ALT level; and f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0134] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of: 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) ALT level >3x upper limit of normal (ULN) detected; d) measuring one or more of the patient's total bilirubin and international normalized ratio (INR); e) One or more of total bilirubin >2x ULN and INR>1.5 was detected; f) ceasing administration of said compound to said patient; and optionally g) monitoring the patient's ALT level; and h) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0135] In some embodiments, the present invention 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 myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) ALT level >3x upper limit of normal (ULN) detected; d) measuring one or more of the patient's total bilirubin and international normalized ratio (INR); e) One or more of total bilirubin >2x ULN and INR>1.5 was detected; f) ceasing administration of said compound to said patient; and optionally g) monitoring the patient's ALT level; and h) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0136] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of: 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) ALT level >3x upper limit of normal (ULN) detected; d) if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%, discontinuing administration of the compound to the patient; and optionally e) monitoring the patient's ALT level; and f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0137] In some embodiments, the present invention 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 myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the following steps: a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) ALT level >3x upper limit of normal (ULN) detected; d) if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%, discontinuing administration of the compound to the patient; and optionally e) monitoring the patient's ALT level; and f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

[0138] 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 every month. 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 every week.

[0139] In some embodiments, the patient's ALT levels are monitored about every 2 to 3 days, about every 3 days, about every 2 days, or about every day after cessation of administration of the compound.

[0140] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising administering to a patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not receiving a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 liver enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampicin, carbamazepine, phenobarbital, St. John's wort extract, avasimib, lumacato, rifapentine, rifabutin, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semacid, anaprevir, belabuvir, dakartasvir, cenobamate, nafcillin, lesinade, modafinil, bosentan, terostat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0141] In some embodiments, the present invention 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 myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising administering a therapeutically acceptable amount of the compound to a patient, wherein the patient is not receiving a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 liver enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampicin, carbamazepine, phenobarbital, St. John's wort extract, avasimibe, lumacato, rifapentine, rifabutin and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semacid, anaprevir, belabuvir, dakartasvir, cenobamate, nafcillin, lesinade, modafinil, bosentan, terostat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0142] In some embodiments, a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising the steps of advising the patient to limit alcohol consumption during treatment, and administering to the patient a therapeutically acceptable amount of a BTK inhibitor including (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 it is recommended to limit alcohol consumption to 1 drink or less per day. In some embodiments, 1 drink is approximately 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 it is recommended to limit alcohol consumption to 2 drinks or less per day. In some embodiments, 2 drinks are approximately 28 grams of alcohol.

[0143] In some embodiments, the present invention 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), the BTK inhibitor being used in a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising the steps of advising the patient to limit alcohol consumption during treatment, and administering to the patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the patient is female and is advised to limit alcohol consumption to 1 drink or less per day. In some embodiments, 1 drink is approximately 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of liquor). In some embodiments, the patient is male and is advised to limit alcohol consumption to 2 drinks or less per day. In some embodiments, 2 drinks are approximately 28 grams of alcohol.

[0144] The selection of preparation depends on various factors, such as the mode of drug administration (for example, for oral administration, the preparation in the form of tablets, pills or capsules is preferred) and the bioavailability of the drug substance. Recently, based on the principle that bioavailability can be increased by increasing the surface area (that is, reducing the particle size), a pharmaceutical preparation specifically for drugs showing poor bioavailability has been developed. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical preparation, the size of which is within the range of 10 to 1,000 nm, wherein the active material is loaded on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical preparation, wherein in the presence of a surface modifier, the drug substance is crushed into nanoparticles (average particle size of 400 nm), which are then dispersed in a liquid medium to obtain a pharmaceutical preparation showing very high bioavailability. The bioavailability of a drug decomposed at gastric pH can be increased by administering such a drug with a preparation that releases the drug in the duodenum.

[0145] The composition is generally composed of a BTK inhibitor compound and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient (e.g., a binder, a surfactant, a diluent, a buffer, an anti-adhesive agent, a glidant, a hydrophilic or hydrophobic polymer, a retardant, a stabilizer (stabilizing agent or stabilizer), a disintegrant or super disintegrant, an antioxidant, an antifoaming agent, a filler, a flavoring agent, a coloring agent, a lubricant, an adsorbent, a preservative, a plasticizer or a sweetener or a mixture thereof), wherein the excipient helps to process the BTK inhibitor compound and / or a pharmaceutically acceptable salt thereof into a preparation that can be used pharmaceutically. Any of the well-known techniques and excipients may be used as appropriate and understood in the art, see, for example, Remington: The Science and Practice of Pharmacy, Twenty-first Edition (Pharmaceutical Press, 2005); Liberman, HA, Lachman, L. and Schwartz, JB, eds., Pharmaceutical Dosage Forms, Vols. 1-2 Taylor and Francis 1990; and RI Mahato, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Second Edition (Taylor and Francis, 2012).

[0146] In certain embodiments, the formulation may include one or more pH adjusters or buffers, such as acids such as acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethylaminomethane); and buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride, and the like. Such buffers used as bases may have other counterions other than sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases, and buffers are included in amounts required to maintain the pH of the composition within an acceptable range.

[0147] In certain embodiments, the formulation may also include one or more salts in an amount required to bring the 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; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0148] In certain embodiments, the formulation may also include one or more defoamers to reduce foaming during processing which may cause coagulation of the aqueous dispersion, the appearance of bubbles in the finished film, or generally impair processing. Exemplary defoamers include silicone emulsions or sorbitan sesquioleate.

[0149] In certain embodiments, the formulation may also include one or more antioxidants, such as non-thiol antioxidants, for example butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivatives and tocopherol or its derivatives. In certain embodiments, antioxidants enhance chemical stability when necessary. Other agents such as citric acid or citrate or EDTA may also be added to slow down oxidation.

[0150] In certain embodiments, the formulation may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0151] In certain embodiments, the formulation may also include one or more binders. Binders impart viscosity and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ) and microcrystalline cellulose (e.g., ); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acid; bentonite; gelatin; polyvinyl pyrrolidone / vinyl acetate copolymer; cross-linked polyvinylpyrrolidone; povidone; starch; pregelatinized starch; tragacanth; dextrin; sugars, such as sucrose (e.g., ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., ) and lactose; natural or synthetic gums, such as gum arabic, tragacanth, and the mucilage of the bark of the isapol tree; polyvinylpyrrolidone (e.g., CL, CL, XL-10); larch arabinogalactan; Polyethylene glycol; polyethylene oxide; wax; sodium alginate, etc.

[0152] In certain embodiments, the formulation may also include a dispersant or viscosity modifier. Dispersants or viscosity modifiers include materials that control the diffusion and uniformity of the drug through the liquid medium or granulation method or blending method. In some embodiments, these agents also contribute to the effectiveness of the coating or dissolution matrix. Exemplary diffusion enhancers / dispersants include, for example, hydrophilic polymers, electrolytes, or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as ), and carbohydrate-based dispersants (e.g., 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, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate stearate (HPMCAS), non-crystalline cellulose), polyethylene oxide, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronic and which is a block copolymer of ethylene oxide and propylene oxide), and poloxamines (e.g., Tetronic Also known as Poloxamine which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate 8 0, sodium alginate, gums (such as, for example, gum tragacanth and gum arabic), guar gum, xanthan (including xanthangum), sugars, cellulose (such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan and combinations thereof. Plasticizers such as cellulose or triethylcellulose may also be used as dispersants. Dispersants particularly useful for liposomal dispersions and self-emulsifying dispersions are dimyristoylphosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate. Typically, a binder level of about 10% to about 70% is used in powder-filled gelatin capsule formulations. Whether direct compression, wet granulation, roller compaction or the use of other excipients (such as fillers, which themselves can act as moderate binders), the level of binder used in tablet formulations varies. Formulators skilled in the art can determine the binder level of the formulation, but levels of binder use of up to 90%, more typically up to 70%, in tablet formulations are common.

[0153] In certain embodiments, the formulation may also include one or more diluents, which refers to chemical compounds used to dilute the target compound prior to delivery. Diluents can also be used to stabilize the compound because the diluent can provide a more stable environment. Salts dissolved in buffered solutions (which can also provide pH control or maintenance) are used as diluents in the art, including but not limited to phosphate buffered saline solutions. In certain embodiments, the diluent increases the volume of the composition to aid in compression or to create enough uniform blend volume for capsule filling. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose, such as Dicalcium phosphate; Dicalcium phosphate dihydrate; Tricalcium phosphate; Calcium phosphate; Anhydrous lactose; Spray-dried lactose; Pregelatinized starch; Compressible sugars, such as (Amstar); hydroxypropyl methylcellulose; hydroxypropyl methylcellulose acetate stearate; sucrose-based diluents; confectioners sugar; calcium dihydrogen sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; mannitol; sodium chloride; inositol; bentonite, etc.

[0154] In certain embodiments, the formulation may also include one or more disintegrants, which include both dissolution and dispersion of the dosage form when it comes into contact with gastrointestinal fluids. Disintegrants (disintegration agents or disintegrants) aid in the decomposition or disintegration of a substance. Examples of disintegrants include starches, such as natural starches (such as corn starch or potato starch), pregelatinized starches (such as National 1551), or sodium starch glycolate (such as or ); cellulose, such as wood products, methyl crystalline cellulose (e.g., PH101, PH 102, PH105, P100, and ), methylcellulose, cross-linked carboxymethylcellulose or cross-linked cellulose (such as cross-linked carboxymethylcellulose sodium cross-linked carboxymethyl cellulose or cross-linked cross-linked carboxymethyl cellulose); cross-linked starch (such as sodium starch glycolate); cross-linked polymers such as cross-linked povidone and cross-linked polyvinyl pyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as HV (magnesium aluminum silicate); gums such as agar, guar gum, locust bean gum, karaya gum, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponge; surfactant; resin, such as cation exchange resin; citrus pulp; sodium lauryl sulfate; a combination of sodium lauryl sulfate and starch, etc.

[0155] In certain embodiments, the formulation may also include an erosion promoter. Erosion promoters include materials that control the erosion of specific materials in gastrointestinal fluids. Erosion promoters are generally known to those of ordinary skill in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0156] In certain embodiments, the formulations may also include one or more fillers, including compounds such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0157] In certain embodiments, the formulations may also include one or more flavoring agents or sweeteners, such as acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, sodium cyclamate, sodium cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizate, glycyrrhiza / licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, mint cream, cream), mixed 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, saccharin sodium, saccharin, aspartame, acesulfame potassium The invention can include flavoring ingredients such as menthol, mannitol, talin, xylitol, sucralose, sorbitol, Swiss cream, tagatose, orange, thaumatin, tuttifrutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0158] In certain embodiments, the formulation may also include one or more lubricants and glidants, which are compounds that prevent, reduce or inhibit material adhesion or friction. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons (such as mineral oil), or hydrogenated vegetable oils (such as hydrogenated soybean oil), higher fatty acids and alkali metal and alkaline earth metal salts thereof (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 methoxy polyethylene glycol (e.g., ), sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silicon dioxide (such as ), starch (such as corn starch), silicone oil, surfactants, etc.

[0159] In certain embodiments, the preparation can also include one or more plasticizers, which are used to soften enteric or delayed release coatings to make them non-brittle compounds. Suitable plasticizers include, for example, polyethylene glycol (such as PEG300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800), stearic acid, propylene glycol, oleic acid, triethyl citrate, dibutyl sebacate, triethylcellulose and triacetin. In some embodiments, plasticizers can also act as dispersants or wetting agents.

[0160] In certain embodiments, the formulation may further include one or more solubilizing agents, such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, docusate sodium, vitamin ETPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin (e.g. ), ethanol, n-butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-600, tetrahydrofuran glycol ether, diethylene glycol monoethyl ether, propylene glycol and isosorbide dimethyl ether and the like. In one embodiment, the solubilizing agent is vitamin E TPGS or or β-hydroxypropyl cyclodextrin.

[0161] In certain embodiments, the formulation may also include one or more suspending agents, including polyvinyl pyrrolidone (e.g., polyvinyl pyrrolidone K112, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30), vinyl pyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (e.g., the polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose acetate stearate, polysorbate 80, hydroxyethyl cellulose, sodium alginate, gums (e.g., such as tragacanth and gum arabic), guar gum, xanthan gum (including xanthan gum (xanthan gum) gum), sugars, cellulose (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose), polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, povidone and the like.

[0162] In certain embodiments, the formulation may also include 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, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil) and polyoxyethylene alkyl ethers and alkyl phenyl ethers (e.g., octylphenol ether 10, octylphenol ether 40). In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0163] In certain embodiments, the formulation may also include one or more viscosity enhancers including, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol alginate, gum arabic, chitosan, and combinations thereof.

[0164] In certain embodiments, the formulation may also include one or more wetting agents, including compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, docusate sodium, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and the like.

[0165] The pharmaceutical preparations disclosed herein can be obtained by mixing one or more solid excipients (such as carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof) with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granule mixture after adding suitable excipients (if necessary) to obtain tablets.

[0166] Pharmaceutical preparations disclosed herein also include capsules made of gelatin and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Capsules can also be made of polymers (such as hypromellose). Capsules can contain a mixture of active ingredients and fillers (such as lactose), adhesives (such as starch) or lubricants (such as talc or magnesium stearate) and optional stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin, lipid, solubilizer or liquid polyethylene glycol). In addition, stabilizers can be added. The dosage of all preparations for oral administration should be suitable for such administration.

[0167] These preparations can be manufactured by conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, (6) melting, or (7) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd edition (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, extrusion / spheronization, etc.

[0168] It should be understood that there is considerable overlap between the excipients used in the solid dosage forms described herein. Therefore, the additives listed above should be considered as merely exemplary and non-limiting types of excipients that can be included in the solid dosage forms described herein. The type and amount of such excipients can be easily determined by those skilled in the art based on the specific properties desired.

[0169] In some embodiments, the solid dosage form described herein is an enteric coated oral dosage form, i.e., an oral dosage form as a pharmaceutical composition as described herein, which utilizes an enteric coating to achieve the release of a compound in the intestine of the gastrointestinal tract. An "enteric coated" drug or tablet refers to a drug or tablet coated with a material that remains intact in the stomach but dissolves and releases the drug once it reaches the intestine (in one embodiment, the small intestine). As used herein, an "enteric coating" is a material, such as one or more polymeric materials, that is used as a dosage form or as a particle to encapsulate a core of a therapeutically active agent. Typically, a large amount or all of the enteric coating material is dissolved before the therapeutically active agent is released from the dosage form, thereby achieving delayed dissolution of the core or particles of the therapeutically active agent in the small intestine or large intestine. Enteric coatings are discussed, for example Loyd, V.Allen, Remington: The Science and Practice of Pharmacy, 21st edition, Pharmaceutical Press, 2005; and PJ Tarcha, Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991. Methods for applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, US Patent Publication No. 2006 / 0045822.

[0170] Enteric coated dosage forms can be compressed or molded or extruded tablets (coated or uncoated), containing granules, powders, pellets, beads or granules of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof or other excipients, which themselves are coated or uncoated, provided that at least the tablet or the BTK inhibitor compound is coated. Enteric coated oral dosage forms can also be capsules (coated or uncoated), containing pellets, beads or granules of a BTK inhibitor compound or a pharmaceutically acceptable salt thereof or other excipients, which themselves are coated or uncoated, provided that at least one of them is coated. Some examples of coatings originally used as enteric coatings are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, frankincense and shellac and shellac and stearic acid (U.S. Pat. No. 2,809,918); polyvinyl acetate and ethylcellulose (U.S. Pat. No. 3,835,221). Recently, the coatings used are neutral copolymers of polymethacrylates (Eudragit L30D). (FW Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymers of methacrylic acid and methyl methacrylate (Eudragit S), or neutral copolymers of polymethacrylates containing metal stearates (U.S. Pat. Nos. 4,728,512 and 4,794,001 to Mehta et al.); cellulose acetate succinate and hypromellose phthalate.

[0171] In the methods and compositions described herein, any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating to achieve delivery to the intestine. In one embodiment, delivery can be to the small intestine. In another embodiment, delivery can be to the duodenum. In some embodiments, the polymer described herein is an anionic carboxylic acid polymer. In other embodiments, polymers and compatible mixtures thereof and some of their characteristics include, but are not limited to, the following.

[0172] Shellac: Also known as purified lac, it is a refined product obtained from the resin secretions of insects. This coating dissolves in a medium with a pH>7.

[0173] Acrylic polymers: The properties of acrylic polymers (primarily their solubility in biological fluids) can vary depending on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series L, S and RS (manufactured by Rohm Pharma and known as ) are soluble in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract, but permeable and are primarily used for colon targeting. Eudragit series L, L-30D and S are insoluble in the stomach and soluble in the intestine and can be selected and formulated to dissolve at pH values ​​greater than 5.5 or as low as greater than 5 or as high as greater than 7.

[0174] Cellulose derivatives: Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of cellulose acetate esters with phthalic anhydride. The properties may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water-based system and is a spray-dried CAP pseudolatex with particles <1 μm. Other components in Aquateric may include pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (HPMCAS, such as AQOAT (Shin Etsu)). The properties may vary depending on the degree and type of substitution. For example, HPMCP such as HP-50, HP-55, HP-55S, HP-55F grades are suitable. The properties may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF) which dissolves at pH 5, AS-MG (MF) which dissolves at pH 5.5, and AS-HG (HF) which dissolves at higher pH. These polymers are provided as granules or as fine powders for aqueous dispersions.

[0175] Polyvinyl acetate phthalate (PVAP): PVAP dissolves at pH > 5 and is much less permeable to water vapor and gastric fluid. A detailed description of the above polymers and their pH-dependent solubility can be found in the article by Professors Karl Thoma and Karoline Bechtold entitled "Enteric coated hard gelatin capsules" at http: / / pop.www.capsugel.com / media / library / enteric-coated-hard-gelatin-capsules.pdf. In some embodiments, the coating can and usually does contain a plasticizer and possibly other coating excipients, such as colorants, talc or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (triacetin), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers usually contain 10%-25% by weight of plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques such as fluid bed or Wurster coaters, or spray coating or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired topical delivery site in the intestinal tract.

[0176] In addition to plasticizers, colorants, surfactants, anti-adherents, defoamers, lubricants (eg, carnauba wax or PEG) and other additives may be added to the coating to dissolve or disperse the coating material and to improve coating properties and the coated product.

[0177] To accelerate the dissolution of the enteric coating, a half-thick double layer of enteric polymer can be applied (e.g., Eudragit L30 D-55), and the inner enteric coating can have a buffer up to pH 6.0 in the presence of 10% citric acid, followed by a final layer of standard Eudragit L 30 D-55. Liu and Basit applied two layers of enteric coating (each layer half the thickness of a typical enteric coating), which was able to accelerate the dissolution of the enteric coating compared to a similar coating system applied as a single layer without buffer (Liu, F. and Basit, A. Journal of Controlled Release. 147 (2010) 242-245).

[0178] The integrity of the enteric coating can be measured, for example, by the degradation of the drug within the pellets. As described in the USP, enteric coated dosage forms or pellets can be tested in dissolution tests first in gastric fluid and separately in intestinal fluid to determine their functionality.

[0179] Enteric coated tablets and capsules containing the disclosed compounds can be prepared by methods well known in the art. For example, tablets containing the compounds disclosed herein can be coated using a Freund Hi-Coater with a coating containing Enteric coating is performed with a coating solution of diethyl phthalate, isopropyl alcohol, talc and water.

[0180] Alternatively, multiple unit dosage forms comprising enteric coated pellets which may be incorporated into tablets or capsules may be prepared as follows.

[0181] Core material: The core material of the enteric coated layered pellets can be composed according to different principles. The seeds (seed) layered with active agents (i.e., BTK inhibitor compounds or pharmaceutically acceptable salts thereof) optionally mixed with alkaline substances or buffers can be used as core materials for further processing. The seeds to be layered with active agents can be water-insoluble seeds containing different oxides, cellulose, organic polymers and other materials alone or in a mixture, or water-soluble seeds containing different inorganic salts, sugars, sucrose pellets (non-pareil) and other materials alone or in a mixture. In addition, the seeds may contain active agents in the form of crystals, agglomerates, briquettes, etc. The size of the seeds is not necessary for the present invention, but the size can range from about 0.1 to 2 mm. Seeds layered with active agents are produced by layering powders or solutions / suspensions using, for example, granulation or spraying layering equipment.

[0182] Before seed layering, activating agent can be mixed with other components.Such components can be binding agent, surfactant, filler, disintegrant, alkaline additive or other or pharmaceutically acceptable composition separately or in mixture form.Binder is for example polymer such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, polyvinyl pyrrolidone (PVP), or sugar, starch or other pharmaceutically acceptable substances with cohesive properties.Suitable surfactant can be found in lower group: pharmaceutically acceptable nonionic or ionic surfactant, for example as sodium lauryl sulfate.

[0183] Alternatively, the activating agent optionally mixed with the appropriate ingredients can be formulated into a core material. The core material can utilize conventional processing equipment to produce by extrusion / spheronization, spheronization or compression. The size of the core material prepared is approximately 0.1 to 4mm, and for example, 0.1 to 2mm. The core material manufactured can further be layered with the other composition comprising the activating agent or be used for further processing.

[0184] The active agent is mixed with the pharmaceutical ingredients to obtain the preferred handling and processing characteristics and the appropriate concentration of the active agent in the final formulation. Pharmaceutical ingredients such as fillers, binders, lubricants, disintegrants, surfactants and other pharmaceutically acceptable additives may be used.

[0185] Alternatively, the aforementioned core material may be prepared by using spray drying or spray congealing techniques.

[0186] One or more enteric coating layers: Before the one or more enteric coating layers are applied to the core material in the form of individual pellets, the pellets may optionally be covered with one or more separating layers comprising pharmaceutical excipients, which optionally include alkaline compounds, such as pH buffering compounds. This / these separating layers separate the core material from the outer layer which is one or more enteric coating layers. This / these separating layers protecting the active agent core material should be water soluble or rapidly disintegrate in water.

[0187] Can be in suitable equipment (such as coating pan, coating granulator) or in the fluidized bed instrument that uses water or organic solvent for coating process, optionally by coating or layering procedure one or more separating layers are applied to core material.As an alternative, can by using powder coating technology, described one or more separating layers are applied to core material.The material used for separating layer is pharmaceutically acceptable compound used separately or in mixture form, for example as water-soluble salt of sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, enteric coating polymer etc.Additive (such as plasticizer, coloring agent, pigment, filler, antiadherent and antistatic agent, for example as magnesium stearate, titanium dioxide, talcum and other additives) also can be included in described one or more separating layers.

[0188] When an optional separating layer is applied to the core material, it can constitute a variable thickness. The maximum thickness of the one or more separating layers is usually limited only by processing conditions. The separating layer can be used as a diffusion barrier and can be used as a pH buffer. The one or more separating layers optionally applied are not critical for embodiments of the present invention. However, the one or more separating layers can improve the chemical stability of the active substance or the physical properties of the novel multiple unit tablet dosage form.

[0189] Alternatively, the separating layer can be formed in situ by a reaction between an enteric coating polymer layer applied on the core material and an alkaline reacting compound in the core material. Thus, the separating layer formed comprises a water-soluble salt formed between the one or more enteric coating layer polymers and an alkaline reacting compound in a position to form a salt.

[0190] By using suitable coating technology, one or more enteric coating layers are applied on the core material or are covered with one or more separating layers on the core material. The enteric coating layer material can be dispersed or dissolved in water or in a suitable organic solvent. As the enteric coating layer polymer, one or more of the following can be used alone or in combination, for example solution or dispersion of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, shellac or one or more other suitable enteric coating polymers.

[0191] The enteric coating layer contains a pharmaceutically acceptable plasticizer to obtain desired mechanical properties, such as flexibility and hardness of the enteric coating layer. Such plasticizers are, for example, but not limited to, triacetin, citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate or other plasticizers.

[0192] About the application amount of one or more enteric coating layer polymers selected, one or more plasticizers selected and the one or more polymers, the amount of plasticizer is optimized for each enteric coating layer formulation, and the mechanical properties are adjusted in such a way that the flexibility and hardness of the one or more enteric coating layers are adjusted, for example, with Vickers hardness as an example, so that if tablets are needed, the acid resistance of the pellets covered with one or more enteric coating layers will not be significantly reduced in the process of compressing the pellets into tablets. By the weight of the one or more enteric coating layer polymers, the amount of plasticizer is usually higher than 5%, such as 15%-50%, and further such as 20%-50%. Additives (such as dispersants, colorants, pigment polymers such as poly (ethyl acrylate, methyl methacrylate), anti-adhesive agents and defoamers) can also be included in the one or more enteric coating layers. Other compounds can be added to increase film thickness and reduce the diffusion of acidic gastric juice into acid-sensitive materials. The maximum thickness of the enteric coating applied is usually only limited by processing conditions and desired dissolution curves.

[0193] Outer coating layer: The pellets covered with one or more enteric coating layers may be optionally further covered with one or more outer coating layers. The one or more outer coating layers should be water-soluble or rapidly disintegrate in water. The one or more outer coating layers may be applied to the enteric coated layered pellets by coating or layering procedures in suitable equipment (such as coating pans, coating granulators) or in fluidized bed apparatus using water or organic solvents for coating or layering processes. The materials used for the outer coating layer are selected from pharmaceutically acceptable compounds used alone or in the form of a mixture, such as sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. Additives (such as plasticizers, colorants, pigments, fillers, anti-adhesives and antistatic agents, such as magnesium stearate, titanium dioxide, talc and other additives) may also be included in the one or more outer coating layers. The outer coating layer can further prevent the potential agglomeration of the enteric coated layered pellets, it can also protect the enteric coating layer from rupture during the compression process, and enhance the tableting process. The maximum thickness of the applied one or more outer coating layers is usually limited only by processing conditions and the desired dissolution profile. The outer coating layer can also be used as a tablet film coating layer.

[0194] Enteric coatings for soft gelatin capsules can contain emulsions, oils, microemulsions, self-emulsifying systems, lipids, triglycerides, polyethylene glycols, surfactants, other solubilizing agents, etc. and combinations thereof, to dissolve active agents. The flexibility of soft gelatin capsules is maintained by residual water and plasticizers. In addition, for gelatin capsules, gelatin can be dissolved in water so that spraying must be completed at a rate with relatively low relative humidity, such as can be completed in a fluidized bed or Wurster. In addition, drying should be completed without removing residual water or plasticizers to cause capsule shell rupture. Commercially available blends optimized for enteric coatings for soft gelatin capsules, such as Instamodel EPD (enteric polymer dispersions), can be purchased from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a laboratory scale, enteric coated capsules can be prepared by a) swirling the capsules in a flask of mildly heated enteric coating material and plasticizer at the lowest possible temperature or dipping the capsules into a solution of mildly heated enteric coating material and plasticizer, or b) in a laboratory scale sprayer / fluidized bed followed by drying.

[0195] For aqueous active agents, it may be particularly desirable to incorporate the drug into the aqueous phase of the emulsion. Such "water-in-oil" emulsions provide a suitable biophysical environment for the drug and can provide an oil-water interface that can protect the drug from the adverse effects of pH or enzymes that may degrade the drug. In addition, such water-in-oil formulations can provide a lipid layer that can interact favorably with lipids in body cells and can increase the distribution of the formulation on the cell membrane. This distribution can increase the absorption of the drug in such formulations in the circulation, and therefore can increase the bioavailability of the drug.

[0196] In some embodiments, the water-in-oil emulsion contains an oil phase composed of a medium-chain or long-chain carboxylic acid or its ester or alcohol, a surfactant (surfactant or surface-active agent), and an aqueous phase mainly containing water and an active agent.

[0197] Medium-chain and long-chain carboxylic acids are those ranging from C8 to C22, with up to three unsaturated bonds (also branched). Examples of saturated straight-chain acids are dodecanoic acid, tetradecanoic acid, 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. Examples of these carboxylic acids are oleic acid, gadoleic acid and erucic acid. Unsaturated (polyolefin) straight-chain monocarboxylic acids are also useful. Examples of these carboxylic acids are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid and behenic acid. Useful branched-chain acids include, for example, diacetyltartaric acid. Unsaturated olefin chains can also be hydroxylated or ethoxylated to prevent oxidation or to alter surface properties.

[0198] Examples of long chain carboxylic acid esters include, but are not limited to, those from the group consisting of glyceryl monostearate; glyceryl monopalmitate; a mixture of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoleate; glyceryl monooleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, and glyceryl monolinoleate; glyceryl monolinolenate; glyceryl monocodoleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monocodoleate, and glyceryl monocodoleate; acetylated glycerides, such as distilled acetylated monoglycerides; propylene glycol monoesters, distilled monoglycerides, sodium steroyl lactylate, lactylate) and silica; d-alpha tocopheryl polyethylene glycol 1000 succinate; mixtures of mono- and diglycerides such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and diglycerides; lactic acid mono- and diglycerides; lactylic acid carboxylic acid esters of glycerol and propylene glycol; lactylic acid esters of long chain carboxylic acids; polyglycerol esters of long chain carboxylic acids; propylene glycol mono- and di-esters of long chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearoyl monocitrate; stearoyl heptanoate; cetyl esters of waxes; stearoyl caprylate; C8-C30 cholesterol / lanosterol esters; and sucrose long chain carboxylic acid esters. The example of self-emulsifying long chain carboxylic acid esters comprises those self-emulsifying long chain carboxylic acid esters from the following group: stearate, palmitate, ricinoleate, oleate, behenate, ricinolenate, myristate, laurate, caprylate and caproate.In some embodiments, the oil phase can comprise a combination of 2 or more long chain carboxylic acids or their esters or alcohols.In some embodiments, a medium chain surfactant can be used, and the oil phase can comprise a mixture of caprylic / capric triglyceride and caprylic C8 / C10 monoglyceride / diglyceride, caprylic glyceride or propylene glycol monocaprylate or a mixture thereof.

[0199] Alcohols that can be used are exemplified by the hydroxyl forms of the above-exemplified carboxylic acids and stearyl alcohol.

[0200] Surfactants (surface active agents or surfactants) are long chain molecules that can accumulate at hydrophilic / hydrophobic (water / oil) interfaces and reduce the surface tension at the interface. Therefore, they can stabilize emulsions. In some embodiments, surfactants can include: (polyoxyethylene sorbate) family of surfactants, (Sorbitan long-chain carboxylate) family of surfactants, (ethylene oxide or propylene oxide block copolymer) family of surfactants, and (each a polyglycolyzed glyceride) family surfactants, sorbitan esters of oleic acid, stearic acid, lauric acid or other long-chain carboxylic acids, poloxamers (polyethylene glycol-polypropylene glycol block copolymers or ), other sorbitan or sucrose long chain carboxylates, mono- and di-glycerides, PEG derivatives of caprylic / capric triglycerides, and mixtures thereof, or mixtures of two or more of the foregoing. In some embodiments, the surfactant phase may include polyoxyethylene (20) sorbitan monooleate (Tween ) and sorbitan monooleate (Span ).

[0201] The aqueous phase may optionally contain the active agent and a buffering agent suspended in water.

[0202] In some embodiments, such emulsions are macroemulsions, microemulsions, and liquid crystal emulsions. In other embodiments, such emulsions may optionally contain a penetration enhancer. In other embodiments, spray-dried dispersions or microparticles or nanoparticles containing encapsulated microemulsions, macroemulsions, or liquid crystals may be used.

[0203] In some embodiments, the solid dosage form described herein is a non-enteric delayed release dosage form. As used herein, the term "non-enteric delayed release" refers to a delivery that allows the release of the drug to be completed at a generally predictable location in the intestine, which is farther away than where it would be completed without the delayed release change. In some embodiments, the method for delayed release is a coating that becomes permeable, dissolved, ruptured or no longer intact after a designed duration. The coating in the delayed release dosage form can have a fixed dissolution time, after which the drug is released (suitable coatings include polymer coatings such as HPMC, PEO, etc.), or have a core composed of one or more super disintegrants or one or more osmotic agents or water attractants (such as salts, hydrophilic polymers (typically polyethylene oxide or alkyl cellulose), salts (such as sodium chloride, magnesium chloride, sodium acetate, sodium citrate), sugars (such as glucose, lactose or sucrose), etc., the water attractant passes through a semipermeable membrane or a gas generator (such as citric acid and sodium bicarbonate), with or without In the presence of an acid (such as citric acid or any of the foregoing acids incorporated into the dosage form), the water is drawn out. The semipermeable membrane, while mostly impermeable to the drug and osmotic agent, is permeable to water, which penetrates into the dosage form at a near constant rate to increase the pressure, and ruptures after the swelling pressure exceeds a certain threshold for a desired delay time. The permeability of the drug through this membrane should be less than 1 / 10 of that of water, and in one embodiment, less than 1 / 100 of the permeability of water. Alternatively, the membrane can be made porous by leaching an extractable aqueous solution for a desired delay time.

[0204] Osmotic dosage forms have been described in U.S. Pat. No. 3,760,984 of Theeuwes, and osmotic burst dosage forms are described in U.S. Pat. No. 3,952,741 of Baker. If different devices with different timings are used, this osmotic burst dosage form can provide a single release pulse or multiple pulses. The timing of osmotic burst can be controlled by selecting the thickness or area of ​​the semipermeable membrane around the core containing both the polymer and the drug and the osmotic agent or the attractant. As the pressure in the dosage form increases with additional osmotic water, the membrane stretches until its breaking point, and then the drug is released. Alternatively, by having a thinner, weaker area in the membrane, or by adding a weaker material to the area of ​​the coating membrane, a specific rupture area can be produced in the membrane. Some preferred polymers with high water permeability that can be used as semipermeable membranes are cellulose acetate, cellulose acetate butyrate, nitrocellulose, cross-linked polyvinyl alcohol, polyurethane, nylon 6, nylon 6.6 and aromatic nylon. Cellulose acetate is a particularly preferred polymer.

[0205] In another embodiment, the delayed release coating that begins to delay the release of the drug after the enteric coating is at least partially dissolved is composed of a hydrophilic, erodible polymer that begins to gradually dissolve over time when in contact with water. Examples of such polymers include cellulosic polymers and their derivatives, including but not limited to hydroxyalkyl cellulose, hydroxymethyl 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, especially high molecular weight polyethylene glycol; chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly(vinyl pyrrolidone); starch and starch-based polymers; maltodextrin; poly(2-ethyl-2-oxazoline); poly(ethyleneimine); polyurethanes; hydrogels; cross-linked polyacrylic acid; and combinations or blends of any of the foregoing.

[0206] Some preferred erodible hydrophilic polymers suitable for forming erodible coatings are poly(ethylene oxide), hydroxypropyl methylcellulose, and combinations of poly(ethylene oxide) and hydroxypropyl methylcellulose. Poly(ethylene oxide) is used herein to refer to linear polymers of unsubstituted ethylene oxide. The molecular weight of the poly(ethylene oxide) polymer can range from about 105 Daltons to about 107 Daltons. The preferred molecular weight range of the poly(ethylene oxide) polymer is about 2x105 to 2x106 Daltons and is commercially available from Dow Chemical Company (Midland, Michigan) as SENTRYR POLYOX TM Water-soluble resin, NF (National Pharmacopoeia) grade. When a higher molecular weight polyethylene oxide is used, other hydrophilic agents such as salts or sugars (such as glucose, sucrose or lactose) that promote erosion or disintegration of the coating are also included.

[0207] Delayed dosage forms can be mechanical boluses (such as capsules or pH-sensitive capsules) that can release the drug after a pre-programmed time or when it receives a signal that can be transmitted or once it leaves the stomach.

[0208] The amount of the compound of the present invention in the formulation can vary within the full range used by those skilled in the art. Typically, based on the weight percentage (wt%) of the total formulation, the formulation will contain about 0.01-99.99wt% of the BTK inhibitor compound, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80wt%.

[0209] For the purpose of clarity and understanding, the aforementioned disclosure has been described in some detail by way of illustration and example. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive. Therefore, the scope of the present invention should not be determined with reference to the above description, but should be determined with reference to the full scope of the equivalents described in the following claims and these claims. Example

[0210] The following examples are provided to illustrate certain disclosed embodiments, and should not be construed as limiting the scope of the invention in any way.In the examples discussed below, BTK inhibitors as defined above may also be referred to interchangeably as "compounds" or "drugs." Example 1 - Study of BTK Inhibitor Tolebutinib in MOG Antibody Disease (MOGAD) Example 1.1 - Introduction and study rationale

[0211] Tolebrutinib is a brain-penetrant inhibitor of Bruton's tyrosine kinase (BTK). This compound is being developed for the treatment of MOG antibody disease (MOGAD). This study aims to collect evidence on the efficacy and safety of this compound in the active relapsing MOGAG population.

[0212] MOGAD is a relapsing, immune-mediated disease of the central nervous system that causes vision loss, weakness, sensory loss, bowel / bladder dysfunction, and cognitive dysfunction (Narayan et al. Mult Scler Relat Disord 2018, 25, 66-72). In the spectrum of CNS autoimmune diseases, MOG antibody disease overlaps with multiple sclerosis (MS). Pathologically, anti-MOG appears similar to MS, with demyelination and macrophage infiltration as well as intact axons and limited fluid deposits (Hoftberger et al. Acta Neuropathol 2020, 139, 875-892). Clinically, MOGAD attacks show a tendency to the optic nerve (66% of attacks), and unlike MS, there is no known MOG disease progression process. That is, if relapses can be prevented, the disease can be effectively alleviated.

[0213] Graphical scheme of research design such as Figure 1A Table 1 below describes the timeline of activities during the study process. Table 2 below describes the objectives and endpoints of the entire study. Table 1: Schedule of Activities (SOA) Abbreviations: AE: adverse event; AST: aspartate aminotransferase; ALT: alanine aminotransferase; C-SSRS: Columbia-Suicide Severity Rating Scale; D: day; ECG: electrocardiogram; EDSS: expanded disability status scale; GCIPL: ganglion cell-inner plexiform layer; HIV: human immunodeficiency virus; Ig: immunoglobulin; IMP: clinical trial medication; INR: international normalized ratio; M: month (28 days); MRI: magnetic resonance imaging; MOG: myelin oligodendrocyte glycoprotein; OCT: optical coherence tomography; RNFL: retinal nerve fiber layer; SAE: serious adverse event. Participants should return for a follow-up visit 2 to 4 weeks after premature termination of treatment. * Screening and D1 labs: Pregnancy test (serum), complete blood count with differential, coagulation (at screening only), metabolic profile (blood urea nitrogen [BUN], creatinine, glucose [nonfasting], potassium, sodium, chloride, sodium bicarbonate, calcium, liver function tests [AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein; creatine phosphokinase], lipase (at screening only). IgG and IgM levels (at D1 and M12 only), blood tests (e.g., TB Gold test) is preferred for tuberculosis (only at screening), hepatitis B / C serology (only at screening), HIV serology (if locally permitted, only at screening), urinalysis (only at screening, M3 and M12); follicle-stimulating hormone (FSH) (if required, only in female participants, to confirm postmenopausal status at screening); serum anti-aquaporin 4 antibodies (only at screening). **Safety Monitoring Laboratories: Complete blood count with differential, liver function tests, and metabolic profile. Urinalysis (M3 and M12). Any type of pregnancy test determined necessary by the PI or local regulations may be requested at any time during the study. ***Urine Pregnancy Test: Completed at Home - M3 through M12 (quarterly) and Safety F / U Visits - allows for communication with site via phone regarding results of the pregnancy test performed at home. **** Biomarkers (blood / serum): Neurofilament light chain, glial fibrillary acidic protein levels, tau protein, S100B, and B / T cell profiling (possibly in future analyses). Optional for participants who have relapsed during the trial.

[0214] The goals and end points of treatment are shown in Table 2 . Table 2 - Objectives and End Points Appropriateness of measurement

[0215] MOG antibody disease appears to accumulate symptoms in a stepwise progression driven by relapses, which occasionally leads to persistent loss of neurological function (Jurynczyk et al. Brain 2017, 140, 3128-3138). Therefore, reducing the frequency of relapses is a clinically relevant outcome and is the goal of any potential disease-modifying therapy.

[0216] Monophasic patients never relapse. These monophasic patients may not be part of the study (because the inclusion criteria require at least 2 episodes). About half of the patients will experience a second episode and / or additional relapses. See, for example, Akaishi et al. J Neurol 2021; Kornberg et al. Neurology, 2021. Reducing the frequency of relapses is the goal; the patient's residual disability worsens after an episode. The goal of treatment is to administer therapy to prevent and / or reduce the likelihood of additional episodes in patients. For more information, see Alessandro Dinoto et al. "Serum and Cerebrospinal Fluid Biomarkers in Neuromyelitis Optica Spectrum Disorder and Myelin Oligodendrocyte Glycoprotein Associated Disease" Frontiers in Neurology, March 2022, Volume 13, Article No. 866824.

[0217] MOG antibody titers that persist for more than 6 months are associated with a higher risk of a relapsing phenotype, which may be present in almost 88% of patients with MOG antibody disease (Lopez-Chiriboga et al. JAMA Neurol 2018.75, 1355-1363). There is also preliminary evidence that high MOG antibody titers may be associated with more aggressive disease (Tea et al. Acta Neuropathol Commun 2019,7,145). Therefore, reducing or eliminating MOG antibody titers may be a positive outcome of treatment with potential disease-modifying therapies.

[0218] Using transfected MOG expressing cells, the presence of MOG antibodies was analyzed by extracellular live cell staining immunofluorescence technique. Antibody titer was assessed by measuring the fluorescence intensity signal of serial dilutions by flow cytometry.

[0219] A reduction in MOG antibody titer is being observed. Whether this biomarker can be reliably used to monitor disease status has yet to be determined. If the antibody titer is reduced or eliminated (converted from positive to negative) - then this would constitute a reduction in MOG titer. In technical terms, if the MOG antibody titer level forms a negative slope after 1 year of treatment with tolebrutinib, then this would constitute a reduction in MOG antibody titer. Likewise, in technical terms, elimination of MOG antibody titer means that after 1 year of treatment with tolebrutinib, the fluorescence intensity signal from flow cytometry shows the same level as the untransfected negative control cells.

[0220] The measurement of the accumulation of neurological symptoms is an important clinical endpoint in demyelinating diseases of the central nervous system. The EDSS is widely used to measure neurological symptoms in clinical trials and routine settings. Given the short duration of this preliminary study, the change from baseline in the Expanded Disability Status Scale score (EDSS) was measured as a secondary endpoint 1 year after starting treatment with tolebrutinib.

[0221] In addition to the above assessments, this study will analyze MRI and OCT findings and serum / blood biomarker measurements as exploratory supportive efficacy data. Example 1.2 - Study Design Example 1.2A - Overall Design

[0222] This is a Phase 2, open-label, single-arm, single-center trial designed to evaluate the efficacy and safety of 1 year of tolebrutinib treatment in participants with MOG antibody disease. Participants will be screened based on study inclusion and exclusion criteria to assess participant eligibility. After screening, eligible participants will be recruited to receive 60 mg of tolebrutinib orally per day. The primary endpoint will be the proportion of participants who are relapse-free 1 year after recruitment.

[0223] The study will be conducted entirely remotely, with no in-person site visits required. After recruitment, virtual visits will be conducted every 3 months to assess limited neurologic function, MOG antibody titers, and safety measures. In addition to routine virtual evaluations, based on clinical presentation and relevant neurologic signs and symptoms, if a participant reports new neurologic symptoms consistent with MOG antibody disease relapse, a relapse evaluation will be triggered and include an MRI of the optic nerve or spinal cord or brain. Participants who meet relapse criteria will receive relapse treatment from the participant's local physician (according to local standards of care) and a remote follow-up relapse visit 4 weeks after the onset of relapse symptoms; discontinuation of study medication will then be recommended. Participants will be encouraged to continue participating in the trial even if study medication is discontinued. Example 1.2B - Number of Participants

[0224] Approximately 30 participants will be screened to obtain 25 recruited participants to receive the study intervention. Example 1.2C - Intervention Groups and Duration

[0225] All participants will be screened within 4 weeks to review consent, wean off background immunotherapy, and confirm eligibility for the trial. Participants will take 20 mg of prednisone daily during the 4-week screening period while weaning off background immunotherapy. Then, at the start of the 1-year treatment period, prednisone will be reduced by 5 mg per day weekly with concurrent use of 60 mg of tolebrutinib daily. During the 1-year trial period, no additional prednisone or background immunotherapy will be allowed except as treatment for confirmed relapse. Example 1.2D-Basic Principle

[0226] This is a Phase 2 study, and an open-label design has been selected to avoid unnecessary exposure of participants to placebo and to preliminarily explore the efficacy and safety of tolebrutinib in an undertreated population. This study will select male and female participants diagnosed with MOGAD ranging in age from 12 to 55 years. The age range is limited to participants ≤55 years old to reduce confounding neurological conditions (e.g., spinal degenerative pathology, vascular conditions, other neurodegenerative processes) that are prevalent in older individuals. The dose for participants aged 12 to 17 years will be informed by the results of PK extrapolation modeling. The expected duration of the treatment period is 12 months and is fixed for all individual participants. In the event that a participant stops the study intervention early, the participant will be encouraged to remain in the study and comply with all study visits until the M12 visit. Given the average recurrence rate of 1 attack per year, 12 months is a sufficient period of time to evaluate the efficacy of tolebrutinib in preventing attacks. Example 1.2E - Dosage Regimen

[0227] The choice of a 60 mg dose of BTK inhibitor taken with food was based on the results of a phase 2b dose-finding trial of tolebrutinib in participants with relapsing multiple sclerosis (DRI15928). See, for example, Reich, DS et al., Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol, 2021.20(9): pp. 729-738.

[0228] Analysis of the PK data and the effect of dosing status on tolebrutinib exposure showed a positive food effect, with an approximately 2-fold increase in AUC0-24. In addition, the correlation between treatment response and exposure to tolebrutinib showed that higher exposure was associated with a lower number of new gadolinium-enhancing T1 hyperintense lesions after 12 weeks of treatment. Taken together, these data support the recommendation to take tolebrutinib with food.

[0229] There was no correlation between the dose of tolebrutinib administered and the number of TEAEs. The most common events (preferred terms) observed in participants in the tolebrutinib-treated group were headache, upper respiratory tract infection, and nasopharyngitis. The number of AESI and PCSA observed was low. Overall, no new risks were identified in this trial. Example 1.2F—Study End Definition

[0230] Participants are considered to have completed the study if they have completed all phases of the study, including M12. Participants who relapse during the trial will be considered completers if they discontinue study medication and complete an early end of treatment visit. The study will end when approximately 25 participants complete the M12 visit. Given the planned recruitment period of approximately 12 months and the study duration of approximately 12 months per participant, the estimated study duration is approximately 24 months. Example 1.3 - Study Population Example 1.3A - Inclusion Criteria

[0231] Participants were eligible for inclusion in the study only if all criteria listed in Table 3 below were met. Table 3 - Inclusion criteria Example 1.3B - Exclusion criteria

[0232] Participants were excluded from this study if any of the following criteria as shown in Table 4 applied. Table 4 - Exclusion criteria Example 1.3C - Lifestyle Considerations

[0233] Meals and Dietary Restrictions: Tolebrutinib (IMP) should be taken with a full meal. Where possible, meals taken with IMP (e.g., breakfast, lunch, or dinner) should remain consistent throughout the study. Typical meals taken with IMP will be collected at each visit. In the event that a change in meal timing is required to administer IMP, an interval of at least 12 hours should be maintained between doses. Example 1.4 - One or more study interventions and concomitant therapy

[0234] Study interventions were defined as any one or more study interventions, one or more marketed products, placebo, or one or more medical devices designed to be administered to study participants according to the study protocol. Example 1.4A - Administration of One or More Study Interventions and Concomitant Therapies

[0235] The study intervention included IMP and non-clinical trial medication (NIMP). To maintain blinding, participants received 4 tablets of BTK inhibitor or placebo once daily in a blinded manner. Details of the intervention are provided in Table 5. Table 5 - Summary of Study Interventions for Administration *IMP: drugs used in clinical trials; NIMP: drugs used outside clinical trials

[0236] Detailed information on nonclinical trial drugs is provided in Table 6. Table 6 - Overview of drugs used in non-clinical trials Example 1.4B - Measures to Minimize Bias: Randomization and Blinding

[0237] This is an open-label study; potential bias will be reduced by the following steps: Objective measures will be used to determine the primary outcome of relapse. Relapse is clinically defined, but MRI-confirmed episodes that explain clinical symptoms are also required. Example 1.4C - Dosage Changes

[0238] Dose changes are not foreseen for this study. Interruption or permanent discontinuation of treatment may be necessary if deemed necessary due to AEs. Example 1.4D - Continuous access to intervention after study completion

[0239] If required by local regulations, post-trial acquisition may be considered. Example 1.4E - Concomitant Therapy

[0240] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, or herbal supplements) that the participant is receiving at the time of enrollment or during the study must be recorded along with the following: reason for use, dates of administration (including start date and end date); and dosage information (including dose and frequency).

[0241] Live (attenuated) vaccines should not be administered during the intervention period.

[0242] While participants were receiving study treatment, treatment for MOG antibody disease mentioned in the exclusion criteria in Example 1.3B was not allowed after randomization. Short-term (3 to 7 days) use of glucocorticoids (e.g., for relapse treatment or acute illness) and topical glucocorticoids (e.g., topical, nasal, ophthalmic, otic, intra-articular) were allowed.

[0243] The Medical Monitor should be contacted if there are any questions regarding concomitant treatment or prior therapy.

[0244] Participants abstain from taking prescription or over-the-counter medications (including vitamins and dietary or herbal supplements) for 7 days (or 14 days if the medication is a potential enzyme inducer) or 5 half-lives, whichever is longer, before the start of the study intervention and until completion of the follow-up visit unless the investigator and sponsor determine that the medication will not interfere with the study.

[0245] If clinically feasible, medications to treat symptoms of MOG antibody disease (e.g., walking disorders, spasticity, incontinence, pain) should be maintained at a stable dose prior to screening and for the duration of the treatment period.

[0246] Concomitant use of anticoagulant / antiplatelet therapy with IMP is not permitted, including: acetylsalicylic acid (aspirin) > 81 mg / day; antiplatelet agents (e.g., clopidogrel); warfarin (vitamin K antagonist); heparins including low molecular weight heparin (antithioclobin agents); dabigatran (direct thrombin inhibitor); apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors).

[0247] Acetaminophen / paracetamol at a dose of ≤ 3 g / day was permitted at any time during the study. During the study, a short course (up to 5 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) (except acetylsalicylic acid), preferably a selective cyclooxygenase-2 inhibitor such as the lowest effective dose of an NSAID, may be administered if clinically necessary for treatment of an existing medical condition or a new event. The investigator must record the use of NSAIDs (and any other concomitant medication) in the eCRF.

[0248] CYP Inhibitors / Inducers: Strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes were not permitted throughout the study. Example 1.5 - Cessation of Study Intervention and Participant Discontinuation / Withdrawal Example 1.5A - Cessation of Study Intervention Example 1.5A1 - Permanently Stop

[0249] The study intervention should be continued whenever possible. Permanent intervention discontinuation is any treatment discontinuation associated with a final decision made by the investigator or participant at any time not to re-expose the participant to the study intervention. In rare cases, it may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant should be asked to remain in the study for evaluation until the follow-up visit. For this group of participants (participants who discontinue the IMP or switch to another immunomodulatory / immunosuppressive drug), biomarker samples will not be collected after the treatment visit ends prematurely. This is very important for continued evaluation of safety. See SoA (Example 1.1) for information to be collected when discontinuing a study intervention. In the event of permanent discontinuation of the study intervention, the participant's MOGAD should be treated according to local clinical practice and the best judgment of the treating investigator.

[0250] The following may be valid reasons for the researcher to stop the study treatment of a participant: Adverse events that jeopardize the safety of participants, or if the investigators or participants wish or believe it is necessary to stop the study intervention. If the criteria for discontinuation of IMP are met according to the laboratory abnormality follow-up guidelines (Example 1.8A). The investigator believes that the participant is no longer receiving therapeutic / clinical benefit. · Withdraw consent for treatment at the request of the participant. If the female participant becomes pregnant or wishes to become pregnant during the study. • Any serious opportunistic infection (eg, PML (Example 1.8C), HIV). ·Continued need for long-term use of prohibited concomitant medications.

[0251] The Investigator should consider discontinuing the study intervention for abnormal liver function when a participant meets one of the conditions outlined in the algorithm (Example 1.8C) or if the Investigator deems it to be in the best interest of the participant.

[0252] Any clinically significant abnormal laboratory values ​​or ECG parameters will be confirmed by immediate re-examination after 24 hours before a decision is made to definitively stop the IMP for the relevant participant.

[0253] If a clinically significant finding is found in the post-enrollment ECG (including but not limited to a change from baseline in the QT interval [QTcF] corrected using the Fridericia formula), the investigator or qualified designee will determine whether the participant can continue to participate in the study and whether changes in participant management are needed. Review of the ECG findings by a cardiologist may be considered for the decision to ultimately stop the study intervention due to ECG changes. A review of the printed ECG at the time of collection must be documented. Any new clinically relevant findings should be reported as an AE. See SoA (Example 1.1) for data to be collected at intervention stop and follow-up, and any further evaluations that need to be completed.

[0254] Treatment of Participants after Permanent Intervention Discontinuation: Participants will be followed up according to the study procedures specified in this protocol: Until the scheduled study completion date, or Until recovery or stabilization of any AE required for follow-up as specified in the protocol, whichever comes last.

[0255] Participants should be treated for MOG antibody disease according to local clinical practice and the best judgment of the treating investigator.

[0256] When possible, and after final discontinuation of study medication, participants will be assessed using the planned procedures for early termination of visits.

[0257] Participants will be asked to remain in the study and attend all scheduled visits as per the SoA (Example 1.1), if possible until the end of the study. If a participant does not agree to the full visit schedule after deciding to permanently end treatment, a reduced visit schedule may be agreed with the participant. Every effort should be made to collect endpoint information and vital status as frequently as possible.

[0258] Participants who ultimately discontinue IMP and do not agree to remain in the study after an early termination of the treatment visit should have an additional visit with assessments normally planned for a follow-up visit if the early termination of the treatment visit is less than 3 weeks after the last dose of study drug.

[0259] Patients treated with non-study medication who decide to prematurely and permanently discontinue study participation should be evaluated as soon as possible prior to their study end date using procedures normally planned for an Early End of Treatment Visit. Participants who prematurely and permanently discontinue study medication who do not agree to remain in the study after a visit similar to the Early End of Treatment Visit should have an additional visit and assessments normally planned for a Follow-up Visit if the last study visit is less than 3 weeks after the last dose of an open-label IMP.

[0260] When considered confirmed, all final study drug discontinuations must be documented by the treating investigator on the appropriate page of the eCRF. Example 1.5A2 - Liver Chemistry Stopping Criteria

[0261] When a participant meets one of the conditions outlined in Example 1.8C or in the presence of abnormal liver chemistries that do not meet the protocol-specified stopping rules, the Investigator requires discontinuation of study intervention for abnormal liver tests if the Investigator deems it to be in the best interest of the participant. Example 1.5A3-QTc Stopping Criteria

[0262] If a clinically significant finding is detected after enrollment (including but not limited to a change from baseline in the QT interval corrected using the Fridericia formula [QTcF]), the investigator or a qualified designee (e.g., local physician) will determine whether the participant can continue to participate in the study and whether a change in participant management is necessary. A review of the printed ECG at the time of collection must be documented. Any new clinically relevant finding should be reported as an AE. Example 1.5A4 - Temporary Suspension

[0263] Temporary intervention stops that interrupt the clinical trial due to suspected AEs or regional or national emergencies declared by governmental agencies: The treating investigator may consider contingency measures for regional or national emergencies declared by governmental agencies. For all temporary intervention stops, the investigator should record the duration in the appropriate pages of the eCRF.

[0264] If surgery is required during the study period, the benefit-risk of retaining the IMP for at least 3 to 7 days before and after surgery will be considered, depending on the type of surgery and the risk of bleeding.

[0265] The following will result in temporary treatment cessation: • Cytopenias: According to Example 1.8C, the Sanofi algorithm is used for neutropenia and thrombocytopenia. • Increases in serum creatinine, creatine phosphokinase (CPK), and liver enzymes: follow the corresponding Sanofi algorithm according to Example 1.8C. • Arrhythmia (atrial fibrillation): Any Grade 3 event (symptomatic urgent intervention indicated; device [eg, pacemaker]; ablation; new onset). Suicide risk based on the C-SSRS: if the participant scored “yes” on items 4 or 5 of the suicidal ideation section or “yes” on any item of the suicidal behavior section.

[0266] If necessary, investigators or participants may consider temporary treatment cessation for any other reason, including any safety concerns arising from a regional or national emergency declared by a government agency (e.g., COVID-19 or other illnesses) or if a concomitant medication is required that prohibits the use of a clinical trial. Treatment may be continued later when it is deemed safe and appropriate. Example 1.5A5 - Re-stimulation

[0267] Once the investigator determines, in his or her best medical judgment, that responsibility for one or more of the IMPs in the occurrence of the relevant events is unlikely, there are no safety concerns, and that the criteria for permanent treatment cessation have not been met, reinitiation of the IMP will occur under close and appropriate clinical and / or laboratory monitoring. Example 1.5A6 - Study Intervention Restart or Rechallenge After Hepatic Stop Criteria Are Met

[0268] No participant in this study was permitted to restart or re-challenge the study intervention after meeting liver chemistry discontinuation criteria. Example 1.6 - Study Evaluation and Procedures

[0269] The study procedures and their timing are summarized in the SoA (Example 1.1).No waivers or exemptions from the protocol were permitted.

[0270] Compliance with the study design requirements, including those specified in the SoA (Example 1.1), is necessary and required for the conduct of the study.

[0271] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. Research staff will maintain a screening log to record details of all participants screened and confirm eligibility or record reasons for screening failure, if applicable.

[0272] Procedures performed as part of the participant's routine clinical management (e.g., blood counts) and obtained prior to signing the ICF may be used for screening or baseline purposes, provided that the procedure meets the protocol-specified criteria and is performed within the timeframe defined in the SoA (Example 1.1). Such assessments should be recorded in the designated fields on the CRF.

[0273] Details of blood sampling, including volume for all laboratory assessments, will be provided in the informed consent form. Sampling may be repeated or unscheduled for safety reasons or technical issues with the samples. Example 1.6A - Efficacy Evaluation

[0274] All planned time points for efficacy assessments are provided in the SoA (Example 1.1).

[0275] Key efficacy assessments (eg, EDSS) will be scored by the study team.

[0276] Confirmation of relapse will be the responsibility of the investigators. In these cases, MRI findings during the acute episode and local neurologist evaluation will be required.

[0277] MRI scans for efficacy analysis (relapse assessment and follow-up relapse visits) will be analyzed by the investigators.

[0278] The basic MRI scan will be performed locally and will consist of the following sequences: T2 and T1 weighted sequences before and after administration of Gd contrast agent (if there are no contraindications). Example 1.6 Definition of disease relapse with A1-MOG antibody

[0279] For the purposes of this study, MOG antibody disease relapse was defined as a monophasic, acute, or subacute onset of new neurologic symptoms, or worsening of previous neurologic symptoms with objective changes on neurologic examination. Symptoms must: · Disease attributable to MOG antibodies, · Lasts ≥ 24 hours, with or without recovery, Presents with normothermia (ie, without infection, excessive exercise, or elevated ambient temperature), has had ≥30 days of previous clinical stability (including no previous relapses), and • One or more new or enhancing MRI lesions attributed to the brain or spinal cord or optic nerves. NOTE: Worsening or recurrence of signs and symptoms in participants with MOG antibody disease that can reasonably be attributed to transient impairment of conduction through previously demyelinated pathways caused by an increase in core body temperature will not be considered a relapse.

[0280] Researchers will confirm MOG antibody disease relapse based on the following definitions: A confirmed MOG antibody disease relapse was a relapse that was accompanied by a clinically relevant change in EDSS score as assessed by a local neurologist, i.e., an increase in EDSS score of at least 0.5 points, an increase in 2 function scores of 1 point, or an increase in 1 function score of 2 points, excluding changes in scores involving bowel / bladder and brain function compared to the previous available assessment (the last EDSS assessment that did not occur during the relapse period). An MRI (brain or spinal cord or optic nerve) must be performed as soon as possible to support confirmation of recurrence. Example 1.6A2 - Relapse Assessment and Follow-up Relapse Visits

[0281] Participants must be instructed to report new neurological symptoms and recurrence or worsening of previous symptoms to the investigator immediately. Any reported symptoms will be collected. If a participant reports symptoms that may be consistent with a relapse, a relapse evaluation visit with the investigator must be scheduled as soon as possible (within 7 days of symptom onset if possible). MOG antibody disease relapse will be assessed and reported by the investigator. Management of relapses will be accomplished locally by the treating neurologist according to local standards of care. Recommendations for treatment of relapses are detailed in Table 6 and are not mandatory.

[0282] Diagnosis of MOG Antibody Disease Relapse During the Study: The local neurologist will assess whether the reported episode is consistent with the definition of relapse, including MRI findings. If consistent with the definition of MOG Antibody Disease Relapse or if there is any doubt and the possibility of relapse cannot be excluded, a standard neurological examination (for EDSS scoring) will be performed by the local neurologist and the situation will be discussed with the investigator. If an EDSS assessment is not performed for the participant, this will be recorded and the reason stated. The local neurologist should perform an EDSS assessment whenever possible and request at least an MRI before the investigator's relapse evaluation visit.

[0283] All MOG antibody disease relapses must be reported on the Relapse eCRF page. Unless the investigator considers a MOG antibody disease relapse to be unusually severe or medically unexpected, or matches the definition of an SAE, it should not be reported as an AE.

[0284] If no concurrent illness is suspected, safety laboratory testing is optional for this recurrence evaluation visit. If any concurrent illness is diagnosed, it will be reported as an AE in accordance with the safety reporting rules.

[0285] Participants will be proactively asked about possible relapse symptoms at each study visit. If a relapse is suspected, the decision-making and reporting rules described above will apply.

[0286] The investigator will conduct a follow-up relapse visit 4 weeks after confirmation of relapse according to the SoA (Example 1.1). Example 1.6B - Safety Assessment

[0287] All planned time points for safety assessments are provided in the SoA (Example 1.1). Example 1.6B1 - Electrocardiogram

[0288] A 12-lead ECG will be obtained as outlined in SoA (Example 1.1) using an ECG machine that automatically calculates heart rate and measures PR, QRS, QT, and QTcF intervals. If the ECG machine cannot automatically calculate QTcF, it can be calculated manually using a nomogram or an automated website calculator (e.g., https: / / reference.medscape.com / calculator / 48 / ecg-corrected-qt).

[0289] An ECG and 30-second heart rate graph will be obtained locally. Example 1.6B2-Vital Signs

[0290] Temperature, heart rate, and blood pressure will be assessed.

[0291] Blood pressure and heart rate measurements will be assessed in the supine or sitting position using fully automated equipment. Manual techniques will be used only if automated equipment is not available.

[0292] Participants should rest for at least 5 minutes in a quiet environment without distractions (e.g., television, cell phones) before blood pressure and heart rate measurements.

[0293] Heart rate and blood pressure measurements will be taken before blood is collected for laboratory testing and will include 1 heart rate and 3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at least 1 minute apart). Example 1.6B3 - Clinical Safety Laboratory Evaluation

[0294] See Example 1.8A for a list of clinical laboratory tests to be performed. According to the SoA (Example 1.1), serological testing for hepatitis B and C will be performed during screening; testing for other infectious diseases should be performed during screening if locally required.

[0295] In the event of an urgent safety event, the investigator may request local urgent laboratory data to make appropriate treatment decisions. All clinically relevant local urgent laboratory data requested will be recorded in the eCRF.

[0296] The investigator must review the laboratory reports, document this review, and record any clinically relevant changes that occur during the study in the AE section of the eCRF. Laboratory reports must be archived with the source documents. Clinically significant abnormal laboratory results are those that are not related to the underlying disease unless the investigator believes that the participant's condition is more severe than expected.

[0297] All laboratory tests with values ​​considered clinically significant abnormal should be repeated during study participation or within 28 days after the last dose of study intervention until such values ​​return to normal or baseline or are no longer clinically significant in the opinion of the investigator.

[0298] If abnormal laboratory test values ​​do not return to normal or baseline within a time that is reasonable in the investigator's judgment, the cause should be identified and the sponsor notified.

[0299] All protocol-required laboratory evaluations as defined in Example 1.8A must be performed per the SoA. If the laboratory evaluations in Example 1.8C indicate discontinuation of the IMP, a temporary discontinuation should be considered unless otherwise indicated.

[0300] If a laboratory value for a non-protocol-mandated laboratory assessment performed at the institution's local laboratory requires a change in participant management or is considered clinically significant by the investigator (e.g., a SAE or AE or dose modification), the result must be documented in the eCRF. Example 1.6C - Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reports Example 1.6C1-MOG disease recurrence report

[0301] MOG disease recurrences determined by the evaluations described in Example 1.5A1 will be exempted from reporting as AEs unless they meet the definition of an SAE or are unusually severe or medically unexpected. Hospitalization for recurrence will not be considered a severity criterion for this study if routinely accomplished on-site (e.g., high-dose IV methylprednisolone).

[0302] Data on MOG disease relapse will be collected on the eCRF and analyzed as part of the efficacy analysis. Other worsening of neurological symptoms that do not meet the definition of MS relapse will be reported as AEs according to general safety reporting rules. Example 1.6C2-Reporting of Safety Examination Results of Magnetic Resonance Imaging

[0303] Magnetic resonance imaging scans will need to be reviewed locally for any pathology. If there are clinically relevant findings, the relevant information will need to be provided to the investigator for appropriate safety reporting and to ensure appropriate management of the participant's identified safety findings. If any, the diagnosis of the pathology or the findings themselves as the cause of such MRI findings will be reported as an AE, with guidance that the diagnosis is clear. Example 1.6C3 - Adverse Events of Special Interest

[0304] AEs of special interest (AESIs) are scientifically and medically relevant AEs (serious or non-serious) that are unique to the sponsor's product or procedure and require ongoing monitoring by the investigator and timely notification to the sponsor. Such events may require further investigation to characterize and understand them. Adverse events of special interest may be added, modified, or deleted by protocol amendments during a study.

[0305] Pregnancies in female participants taking part in the study and in female partners of male participants taking part in the IMP / NIMP study. • It will be classified as a SAE only if it meets one of the severity criteria (see Example 1.8B). If a female participant becomes pregnant, IMP should be discontinued. Female participants or female partners of male participants must be followed up for pregnancy before results can be confirmed.

[0306] Symptomatic overdose (serious or non-serious) of IMP. An IMP overdose (accidental or intentional) was an event suspected by the investigator or spontaneously notified by the participant (not based on systematic pill counting) and was defined as at least twice the intended dose within the intended treatment interval (e.g., >2 IMP tablets in a 12-hour interval).

[0307] Alanine aminotransferase (ALT) increased >3×ULN. ALT increase >3×ULN confirmed by retesting within 72 hours or no retesting within 72 hours.

[0308] The project-specific AESI or AESIs are: ECG observation of atrial fibrillation or atrial flutter Serious infections (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade 3 or higher) that may or may not meet the severity criteria (e.g., grade 3 opportunistic infections). Moderate or severe bleeding events (NCI CTCAE Grade 2 or above), including but not limited to symptomatic bleeding in critical areas or organs (e.g., CNS) or intraocular hemorrhage. Thrombocytopenia, platelet count <75,000 / mm 3 (See Example 1.8C for a management flow chart).

[0309] The definition of AE or SAE can be found in Example 1.8B.

[0310] Adverse events will be reported by the participant (or, when appropriate, by a caregiver, substitute, or the participant's legally authorized representative).

[0311] The Investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and for ongoing follow-up of AEs that are serious, considered related to the study intervention or study procedures, or that lead to a participant discontinuing a study intervention. Example 1.6D - Biomarkers

[0312] Blood samples for biomarker studies will be collected from all participants in this study as specified in the SoA (Example 1.1). Participants who have relapsed during the trial may elect to have blood samples collected for biomarkers from that time onwards.

[0313] Collection of plasma and serum samples for biomarker studies is also part of this study.

[0314] Samples will be tested to evaluate biomarkers and their association with observed clinical response to tolebrutinib.

[0315] Additionally, samples will be stored and biomarker variants believed to play a role in MOG antibody disease, including but not limited to serum analytes, may be analyzed to assess their association with observed clinical responses to tolebrutinib (depending on local regulations).

[0316] Samples may be stored for up to 2 years after the last participant's final study visit at a facility of the investigator's choice (or as per local regulations) for further analysis of biomarker responses to tolebrutinib. Example 1.7 - Statistical considerations Example 1.7A - Sample size determination

[0317] Approximately 25 participants will be recruited for the study intervention. This is a pilot, single-group, exploratory study, and there are few existing data on patients with MOG antibody disease on which to base a sample size calculation. Clinically, patients with MOG antibody disease are estimated to have an average of one relapse per year. If it is assumed that 60% of patients will have at least one relapse within 1 year (i.e., 40% will be relapse-free), 25 patients provide 80% power to detect the difference between the null hypothesis and the alternative hypothesis, H0:π=0.4 and H1:π≥0.66, where π represents the proportion of patients who are relapse-free at the end of the 1-year treatment period; based on an exact binomial distribution test with a nominal 5% one-sided significance level. If at least 14 of the 25 patients recruited and treated in this study are relapse-free within 1 year, the null hypothesis that tolebrutinib is not effective in preventing relapses of MOG antibody disease will be rejected. Example 1.7B - Populations for analysis

[0318] The definitions of the following groups used for analysis are shown in Table 7. Table 7 - Populations used for analysis

[0319] Participants who were exposed to the study intervention prior to recruitment or who were not recruited will not be considered recruited and will not be included in any analysis population. The safety experience of these participants will be reported separately.

[0320] For any participant who was recruited more than once, only data related to the first recruitment were used in any analysis population. Safety experiences related to any subsequent recruitment will be reported separately. Example 1.7C - Statistical Analysis

[0321] The Statistical Analysis Plan (SAP) will include a more technical and detailed description of the statistical analyses described in this chapter. This chapter is a summary of the planned statistical analyses of the most important endpoints, including the primary and key secondary endpoints. Given that this is a single-arm efficacy trial, most of the data will be presented as descriptive statistics. Example 1.7C1 - General Notes

[0322] The baseline value is defined as the last available value before the first dose of IMP. For enrolled but untreated participants, the baseline value is defined as the last available value before enrollment. Baseline EDSS will be calculated as the average of the screening and Day 1 assessment values.

[0323] The observation period will be divided into 3 stages: The pre-treatment period was defined as the period from signing of the ICF to the first IMP administration. The treatment-emergent (TE) period was defined as the period from the first IMP dose to the last IMP dose + 10 days. The post-treatment period was defined as the period from the end of the treatment-emergent period to the last study assessment of the participant. Example 1.7C2 - One or more primary endpoints

[0324] Point estimates and exact 95% confidence intervals for the proportion of participants in the PP population who are relapse-free at 1 year will be provided. The observed success rate will help inform decisions about whether to continue developing tolebrutinib for the treatment of MOG antibody disease.

[0325] Time to relapse after recruitment will be calculated and Kaplan-Meier (KM) plots of cumulative incidence will be provided to depict the occurrence of relapse over time in the PP population. The proportion of participants who relapse at 3, 6, 9, and 12 months will be calculated using KM estimates. Participants who complete treatment without relapse will be censored at the end of treatment date.

[0326] Sensitivity analyses including participants who discontinued study treatment early for reasons other than relapse will be provided in the following circumstances: All of these participants were censored on the date of early treatment cessation. Participants who experienced a relapse within 10 days of premature discontinuation of tolebrutinib (if any) were classified as having an event, and other participants were censored at the date of premature treatment cessation + 10 days.

[0327] Although prior treatment is variable, the time to relapse in participants who received tolebrutinib will be explored compared to the time to relapse in the same group of participants one year after starting first treatment for MOG antibody disease. In addition, the time to relapse in participants who received tolebrutinib will be explored compared to a propensity score-matched external control group one year after starting first treatment for MOG antibody disease. Crude KM curves and estimates will be provided. Various statistical methods will be explored to provide estimates of the reduction in the probability of relapse with tolebrutinib compared with "other treatments". Details will be provided in the SAP. Example 1.7C3 - One or more secondary endpoints

[0328] Changes from baseline in EDSS and MOG antibody titers after 1 year of tolebrutinib treatment will be summarized as secondary efficacy endpoints in the relapse-free PP population. Example 1.7C4 - One or more tertiary / exploratory endpoints

[0329] Details of any tertiary / exploratory endpoints will be included in the SAP. Example 1.7C5-Safety Analysis

[0330] All safety analyses will be performed on the safety population. Example 1.7C6 - Adverse Events

[0331] General common rules for adverse events: A summary of AEs will be provided based on the number of events. If the number is small, a list of events will be provided.

[0332] AEs will be analyzed in the following 3 categories: Pre-treatment AEs: AEs that developed, worsened, or became severe during the pre-treatment period. TEAE: An AE that develops, worsens, or becomes serious during treatment emergencies. Post-treatment AEs: AEs that developed, worsened, or became severe during the post-treatment period.

[0333] Information on any deaths will be listed.

[0334] Analysis of all adverse events: Adverse event incidence tables will be provided for all types of TEAEs: all TEAEs, all treatment-emergent AESI (defined by PT or pre-specified group), all treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation.

[0335] An AE summary will be generated along with the number (%) of participants who experienced at least one event.

[0336] The number of deaths will also be analyzed. Example 1.7C7 - Laboratory variables, vital signs and electrocardiogram (ECG)

[0337] Quantitative Analyses: For laboratory variables, vital signs, and ECG variables, descriptive statistics of outcomes and changes from baseline will be provided for each planned visit during treatment. These analyses will be performed using central measurements of MOG antibody titers and other laboratory variables and local measurements of vital signs and ECG variables.

[0338] Analysis of Laboratory, ECG, and Vital Sign Abnormalities: Potentially clinically significant laboratory, ECG, and vital sign abnormalities will be summarized. Example 1.7C8 - Other safety

[0339] A summary of participants with C-SSRS classification for suicidal ideation or suicidal behavior will be provided. Example 1.7C9 - Other Analysis

[0340] Exploratory analyses of biomarkers that will be included in the study report will be described in SAP. Example 1.7C10-Interim Analysis

[0341] No interim analysis is planned for this study. Example 1.8 - Support records and operational considerations Example 1.8A - Clinical Laboratory Testing

[0342] When feasible, the tests detailed in Table 8 below will be performed by the central laboratory. Local laboratory results are required only if central laboratory results are not available in a timely manner for study intervention dosing and / or response assessment. In addition, if local laboratory results are used to make study intervention decisions or response assessments, the results must be entered into the eCRF.

[0343] Tables 3 and 4 detail the protocol-specific requirements for inclusion or exclusion of participants.

[0344] Additional testing as determined necessary by the Investigator or required by local regulations may be performed at any time during the study. Additional serum or urine pregnancy testing as determined necessary by the Investigator or required by local regulations may be performed to determine the absence of pregnancy at any time during the subject's participation in the study. Table 8 - Laboratory Assessments Required by the Protocol ALT: alanine aminotransferase; anti-HBc: antibody against hepatitis B core antigen; anti-HBs: hepatitis B surface antibody; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BUN: blood urea nitrogen; β-hCG: human chorionic gonadotropin; FSH: follicle-stimulating hormone; IEC: independent ethics committee; INR: international normalized ratio; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; IRB: institutional review board; MCH: mean corpuscular hemoglobin; MCV: mean corpuscular volume; PT: prothrombin time; RBC: red blood cell; SGOT: serum glutamate-oxaloacetate transaminase; SGPT: serum glutamate-pyruvate transaminase; TB: tuberculosis; ULN: upper limit of normal; WBC: white blood cell a Details of liver chemistry stopping criteria and required actions and follow-up assessments after ALT > 3 x ULN is observed are provided in Example 1.8C. If INR is measured, clinical laboratory test results of ALT > 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin) or ALT > 3 x ULN and international normalized ratio (INR) > 1.5 may indicate severe liver injury and must be reported as a SAE. bUnless serum testing is required by local regulations or the IRB / IEC, a local urine test for pregnancy will be standard of care for this protocol (except at the Screening Visit, when a serum pregnancy test is requested). c Further details are provided in E 01 of Table 4

[0345] Biomarkers (blood / serum): Neurofilament light chain, glial fibrillary acid protein levels, tau protein, S100B, and B / T cell profiling (possibly in future analyses). Optional for participants who have relapsed during the trial.

[0346] Researchers must document their review of each laboratory safety report. Example 1.8 B-AEs and SAEs: Definitions and Procedures for Recording, Evaluation, Follow-up, and Reporting Example 1.8 Definition of B1-AE Example 1.8B1a-AE Definition

[0347] An AE is any unfavorable medical event in a patient or clinical study participant that is temporally associated with the use of an investigational intervention, whether or not considered related to the investigational intervention.

[0348] NOTE: An AE may therefore be any unfavorable and unplanned sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally related to the use of the study intervention. Example 1.8B1b - Events meeting the definition of AE

[0349] Any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) or other safety assessment (e.g., ECG, radiology scan, vital sign measurement) that is considered clinically significant (i.e., not related to progression of underlying disease) based on the medical and scientific judgment of the investigator, including any result or assessment that is worse from baseline, such as: Lead to discontinuation or dose change of IMP, or meets the severity criteria, or Defined as AESI.

[0350] Aggravation of a chronic or intermittent pre-existing condition, including an increase in the frequency or intensity of the condition.

[0351] New conditions are detected or diagnosed after the study intervention is administered, even though they may have existed before the study began.

[0352] Signs, symptoms, or clinical sequelae of suspected drug interactions.

[0353] Suspected signs, symptoms, or clinical sequelae of overdose of the study intervention or concurrent medication.

[0354] "Lack of efficacy" or "failure of intended pharmacological action" per se will not be reported as an AE or SAE. These conditions will be reflected in the efficacy evaluation. However, signs, symptoms, or clinical sequelae resulting from the lack of efficacy will be reported as an AE or SAE if they meet the definition of an AE or SAE. Example 1.8B1c - Events that do not meet the AE definition

[0355] Any clinically significant abnormal laboratory test result or other abnormal safety assessment related to the underlying disease, unless the investigator believes that the participant's illness is more severe than expected.

[0356] The disease / condition being studied or the expected progression, signs, or symptoms of the disease / condition being studied, unless the participant's condition is more severe than expected.

[0357] Medical or surgical (eg, endoscopy, appendectomy): Conditions leading to surgery are AEs.

[0358] There were no adverse medical events (social or convenience hospitalizations).

[0359] Expected day-to-day fluctuations in one or more pre-existing diseases or one or more conditions that were present or detected at the start of the study without worsening. Example 1.8 Definition of B2-SAE

[0360] SAEs were defined as any adverse event at any dose that resulted in the following:

[0361] Leading to death.

[0362] Life-threatening: The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of death at the time of the event. The term does not refer to an event that could hypothetically have caused death if it were more serious.

[0363] Requirement of hospitalization or prolongation of an existing hospitalization: In general, a hospitalization means that a participant has been admitted to a hospital or emergency department for observation or treatment (usually involving at least an overnight stay) that would not be appropriate in a physician's office or outpatient setting. Complications that occurred during a hospitalization are AEs. An event is serious if the complication prolongs the hospitalization or meets any other criteria for severity. An AE should be considered serious when there is doubt as to whether a hospitalization occurred or was necessary. Hospitalizations for elective treatment of a pre-existing condition that did not worsen from baseline are not considered AEs.

[0364] Resulting in persistent or significant disability / incapacity. The term disability means a significant impairment in a person's ability to carry out normal life functions. This definition is not intended to include relatively minor medically significant experiences, such as simple headaches, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., a sprained ankle) that may interfere with or prevent daily functioning but do not constitute a serious disruption.

[0365] Congenital anomalies / birth defects.

[0366] Other situations. It should be determined by the investigator using medical or scientific judgment whether SAE reporting is appropriate in other circumstances, such as for medically significant events that could endanger a participant or that might require medical or surgical intervention to prevent one of the other outcomes listed in the definition above. These events should generally be considered serious. Note: The following list of medically significant events is intended as a guide to determine which conditions must be considered medically significant events. This list is not exhaustive. Intensive treatment in the emergency room or at home: - Allergic bronchospasm. - Blood disorders (i.e. agranulocytosis, aplastic anemia, bone marrow aplasia, bone marrow dysplasia, pancytopenia, etc.). - Convulsions (epilepsy, epilepsy, seizures, absences, etc.). Development of drug dependence or drug abuse. ALT > 3 × ULN + total bilirubin > 2 × ULN or asymptomatic ALT increase > 10 × ULN. Suicide attempt or any event suggestive of suicide. Syncope, loss of consciousness (unless recorded as due to blood sampling). Bullous rash. Cancer diagnosed during the study period or worsening during the study period. Example 1.8 Evaluation and Follow-up of B3-AEs and / or SAEs Example 1.8B3a-Severity Assessment

[0367] Investigators will assess the severity of each AE and SAE using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, published on November 27, 2017. The list of MedDRA terms in the NCI CTCAE should be consulted first to find the severity level description for a specific AE. For AEs not listed in the NCI CTCAE, investigators will be asked to assess the severity of the AE using general guidelines: Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; no intervention indicated. · Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limitations to age-appropriate instrumental ADL*. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limiting self-care ADL**. Level 4: Life-threatening consequences; urgent intervention indicated. Grade 5 death related to AEs. Note: Activities of daily living (ADL) *Instrumental ADLs include preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. **Self-care ADL refers to bathing, dressing and undressing, self-feeding, toileting, taking medications, and being bedridden. Example 1.8B3b-Causality Assessment

[0368] The investigators were obligated to evaluate the relationship between the study intervention and the occurrence of each AE / SAE.

[0369] A “reasonable possibility” of a relationship indicates that there are facts, evidence, or arguments to suggest a causal relationship, not that a relationship cannot be ruled out.

[0370] The researcher will use clinical judgment to determine this relationship.

[0371] Other causes, such as underlying disease or diseases, concomitant treatments, and other risk factors, as well as the temporal relationship of the event to the administration of the study intervention, will be considered and investigated.

[0372] Researchers will also consult the Investigator Brochure (IB) or product information used to sell the product in their evaluation.

[0373] For each AE / SAE, the investigator must document in the medical note that they have reviewed the AE / SAE and provided an assessment of causality.

[0374] Investigators can change their opinion on causality based on follow-up information and send SAE follow-up reports with the updated causality assessment.

[0375] Causality assessment is one of the criteria used when determining regulatory reporting requirements. Example 1.8 Follow-up of B3c-AE and SAE

[0376] The investigator is obligated to perform or arrange for additional measurements or assessments, as medically indicated, to elucidate the nature or causality of the AE or SAE as fully as possible. This may include additional laboratory tests or studies, histopathology, or consultation with other health care providers. Example 1.8C—Hepatic and Other Safety: Recommended Actions and Follow-up Assessments

[0377] The following Table 10 and Figure 2 , Figure 3 , Figure 4A , Figure 5 and Figure 6 These actions are described only for events of ALT increase and thrombocytopenia. For all other safety events described, these are recommended based on the medical judgment of the investigator.

[0378] Only those who meet the general guidance for reporting adverse events in Example 1.8B ( Figure 3 ) was recorded as an AE only if at least 1 of the criteria listed in .

[0379] Neutropenia was recorded as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting Adverse Events in Example 1.8B was met.

[0380] Figure 4A Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CMV: cytomegalovirus; CPK: creatine phosphokinase; CRF: case report form; EBV: Epstein-Barr virus; HAV: hepatitis A virus; HBV: hepatitis B virus; HCV: hepatitis C virus; IgM: immunoglobulin M; IMP: clinical trial drug; INR: international normalized ratio; LFT: liver function test; LKM: liver-kidney microsomal antibodies; PT: prothrombin time; ULN: upper limit of normal.

[0381] Note: Figure 4A In the , “baseline” refers to the ALT sampled at the baseline visit: or if a baseline value is not available, to the most recent ALT sampled before the baseline visit. This algorithm is not applicable to instances where ALT increases during the screening period.

[0382] exist Figure 4A In the , if the baseline value is >ULN, normalization is defined as ≤ULN or baseline value.

[0383] Only those who meet the general guidance for reporting adverse events in Example 1.8B ( Figure 5 ) was recorded as an AE only if at least 1 of the criteria listed in .

[0384] An increase in CPK was recorded as an AE only if at least 1 criterion in the General Guidelines for Reporting Adverse Events in Example 1.8B was met.

[0385] If a participant has clinical presentation or MRI features suggestive of PML, the following diagnostic and action algorithm is suggested ( Figure 6 ).

[0386] Figure 6 Abbreviations: CSF: cerebrospinal fluid; Gd: gadolinium; IMP: clinical trial drug; JCV: JC virus; MRI: magnetic resonance imaging; PCR: polymerase chain reaction; PML: progressive multifocal leukoencephalopathy.

[0387] Table 9 presents the clinical presentation or MRI features of lesions suspected of PML. Table 9 - Clinical and MRI features suggestive of PML

[0388] If PML is suspected based on imaging results, the local radiologist will inform the investigator directly and no centralized review of the MRI will be requested. The investigator will obtain additional plasma, urine, and CSF samples for JC virus (JCV) analysis. The samples will be analyzed upon receipt and the results will be provided directly to the study site and the sponsor. Further management will be deferred to the treating investigator. However, the next steps will include discontinuation of study treatment. Additional imaging will be performed at the investigator's discretion based on the diagnostic workup and treatment plan.

[0389] Detection of JCV DNA in the CSF of patients with clinical and MRI features suggestive of PML can confirm the diagnosis of PML.

[0390] If JCV DNA is not detected in the CSF and if the clinical suspicion of PML remains high, another lumbar puncture should be performed.

[0391] If the diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may be considered to confirm the final diagnosis.

[0392] Clinical or MRI features suggestive of PML should be recorded as AEs / AESIs / SAEs according to the definitions and procedures in Example 1.8B. Example 1.8 Diagnostic criteria for D-MOG antibody disease

[0393] A definitive diagnosis of MOG antibody disease must meet all of the following criteria (Jarius et al. J Neuroinflammation 2018, 15, 134): Monophasic or recurrent acute ON, myelitis, brainstem encephalitis or encephalitis, or any combination of these syndromes. MRI or electrophysiologic (visual evoked potentials in patients with isolated ON) findings compatible with CNS demyelination. • Seropositivity for MOG-IgG detected by a cell-based assay using full-length human MOG as target antigen. Example 1.8E-Abbreviations ADL: Activities of Daily Living AE: Adverse event AESI: Adverse events of special interest ALT: Alanine aminotransferase aPTT: activated partial thromboplastin time ARF: Acute renal failure ARR: Annualized relapse rate BTK: Bruton's tyrosine kinase CDP: Confirmation of Disability Progression CK-MB: Creatine kinase (heart) CK-MM: Creatine kinase (skeletal muscle) CNS: Central nervous system CPK: Creatine phosphokinase CRF: Case Report Form CSF: cerebrospinal fluid CSR: Clinical Research Report C-SSRS: Columbia-Suicide Severity Rating Scale CYP: Cytochrome P450 DMC: Data Monitoring Committee DMT: disease modifying therapy DNA: deoxyribonucleic acid DTP: Direct to Patient ECG: electrocardiogram, electrocardiography eCRF: Electronic Case Report Form EDSS: Expanded Disability Status Scale EDTA: Ethylenediaminetetraacetic acid eGFR: estimated glomerular filtration rate EOS: Research completed EOT: End of Treatment FSH: Follicle-stimulating hormone GCIPL: Ganglion cell-inner plexiform layer GCP: Good Clinical Practice Gd: Gadolinium HIV: Human Immunodeficiency Virus HR: Hazard ratio HRT: Hormone Replacement Therapy IB: Handbook for Researchers ICF: Informed Consent ICH: International Council for Harmonization IEC: Independent Ethics Committee Ig: immunoglobulin IL: interleukin IMP: Drugs for clinical trials INR: International Normalized Ratio IRB: Institutional Review Board ITT: intention to treat IUD: intrauterine device IUS: intrauterine hormone-releasing system IV: Intravenous IVIg: intravenous immunoglobulin JCV: JC (John Cunningham) virus KM: Kaplan-Meyer LFT: Liver function test LLN: Lower limit of normal MedDRA: Medical Dictionary for Regulatory Activities MOG: Myelin oligodendrocyte glycoprotein MRI: Magnetic resonance imaging MS: Multiple Sclerosis NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NfL: neurofilament light chain NIMP: Non-clinical medicine NMO: Neuromyelitis optica NSAID: Nonsteroidal anti-inflammatory drugs NYHA: New York Heart Association OCT: Optical computed tomography ON: Optic neuritis PD: Pharmacodynamics PK: Pharmacokinetics (various) PML: Progressive multifocal leukoencephalopathy PP: Follow the protocol PT: prothrombin time QTcF: QT interval corrected using Fridericia's formula RMS: Relapsing multiple sclerosis RNFL: Retinal nerve fiber layer SAE: Serious Adverse Event SAP: Statistical Analysis Program SoA: Schedule of Activities SUSAR: Suspected unexpected serious adverse reaction TB: Tuberculosis TEAE: Treatment-emergent adverse event US:United States WOCBP: Women of childbearing potential Example 2 - Study of BTK Inhibitor Tolebutinib in MOG Antibody Disease (MOGAD) Example 2.1 - Introduction and Study Rationale

[0394] Tolebrutinib is a brain-penetrant inhibitor of Bruton's tyrosine kinase (BTK). This compound is being developed for the treatment of MOG antibody disease (MOGAD). This study aims to collect evidence on the efficacy and safety of this compound in the active relapsing MOGAG population.

[0395] MOGAD is a relapsing, immune-mediated central nervous system disease that causes vision loss, weakness, sensory loss, bowel / bladder function disorders, and cognitive function disorders (Narayan et al. Mult Scler Relat Disord 2018, 25, 66-72). In the spectrum of CNS autoimmune diseases, MOG antibody disease overlaps with multiple sclerosis (MS). Pathologically, anti-MOG appears similar to MS, with demyelination and macrophage infiltration as well as intact axons and limited fluid deposits (Hoftberger et al. Acta Neuropathol 2020, 139, 875-892). Clinically, MOGAD attacks show a tendency to the optic nerve (66% of attacks), and unlike MS, there is no known MOG disease progression process. That is, if relapses can be prevented, the disease can be effectively alleviated.

[0396] Graphical scheme of research design such as Figure 1B Table 11 below describes the timeline of activities during the study. Table 12 below describes the objectives and endpoints of the entire study. Table 11: Schedule of Activities (SOA) EOT = end of treatment; EOS = end of study; FSH = follicle-stimulating hormone; TIBC = total iron-binding capacity 1 A blood pressure cuff and a remote ECG device that can measure heart rate will be sent to each study participant. These parameters will be measured at all remote visits. In addition, participants will be asked to measure their blood pressure, heart rate, and record an ECG monthly and report the results to the study coordinator monthly. If there are any abnormalities in these measurements, the investigators may refer the patient to a local hospital for a personal medical evaluation. 2 MRI of the brain, optic nerves, and spinal cord at baseline. MRI is used for relapse confirmation and follow-up to include relevant areas based on clinical presentation and associated neurological signs and symptoms; optical coherence tomography (OCT) may also be performed according to local practice if confirmation of relapse is required. 3 Tuberculosis (TB) blood test is preferred (eg, TB Gold test); repeat TB testing based on clinical judgment, borderline results, or clinical suspicion of TB infection; HIV serology (if local restrictions allow); FSH: if indicated, only in female participants to confirm postmenopausal status at Screening; lipase, iron, ferritin, transferrin, and calculated transferrin saturation at the Screening visit only. 4 Complete blood count with differential, absolute lymphocyte count (CD19 count), metabolic profile (blood urea nitrogen [BUN], creatinine, glucose [nonfasting], potassium, sodium, chloride, bicarbonate, calcium) X Liver function tests: [aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, total protein; creatine phosphokinase. 5 Urine pregnancy test: (at home) Report results to the investigator at the virtual visit. Any type of pregnancy test determined necessary by the PI or local regulations may be requested at any time during the study. 6 The investigator may conduct unscheduled visits at any time (e.g., to evaluate adverse events). Assessments may be completed based on the needs of the participant as assessed according to the investigator's best judgment and in accordance with the study protocol. 7 Biomarkers (blood / serum): Neurofilament light chain, glial fibrillary acid protein levels, tau protein, complement initiation marker panel (for classical and alternative pathways) and B / T / NK cell lineage (possibly in future analyses). End-of-study (EOS) biomarker samples are optional for participants who have relapsed during the trial. 8 All clinical assessments are subject to a ±14-day visit window 9 Universal End: Participants may continue treatment after Month 12 until the last participant reaches Month 12 (or data collection for the primary endpoint is completed).

[0397] The goals and endpoints of treatment are shown in Table 12. Table 12 - Objectives and End Points Appropriateness of measurement

[0398] Patients with MOG antibody disease appear to accumulate disease in a stepwise progression driven by relapses, which occasionally leads to persistent loss of neurological function (Jurynczyk et al. Brain 2017, 140, 3128-3138). Therefore, preventing relapses is a clinically relevant outcome and is the goal of any potential disease-modifying therapy.

[0399] The measurement of the accumulation of neurological disorders is an important clinical endpoint for demyelinating diseases of the central nervous system. EDSS is widely used to measure neurological disorders in clinical trials and routine settings. In this study, EDSS will be assessed by limited neurological examinations performed via remote video (Bove et al. Mult Scler 2019, 25, 1526-1534). Given the number and duration of participants in this preliminary study, the change in EDSS from baseline after one year of tolerbutinib treatment will be measured as an exploratory endpoint.

[0400] MOG antibody levels may be transient in a monophasic course over time, with persistence associated with a relapsing course or patients who have poor recovery or are most likely to relapse (Reindl and Waters Nat Rev Neurol. 2019, 15, 89-102). MOG Ab antibody titers that persist for more than 6 months are associated with a higher risk of a relapsing phenotype, which may be present in almost 88% of MOGAD patients (Lopez-Chiriboga et al. JAMA Neurol 2018, 75, 1355-1363). There is also preliminary evidence that high MOG antibody titers may be associated with more aggressive disease (Tea et al. Acta Neuropathol Commun. 2019, 7, 145). Therefore, reducing or eliminating MOG antibody titers may be a positive outcome of treatment with potential disease-modifying therapies.

[0401] MRI imaging of the brain, optic nerve, and spinal cord plays an important role in the diagnosis of MOGAD and in the recurrence management of severe attacks with large T2 lesions in the brain or spinal cord. In MOG antibody disease, lesions are more likely to regress completely than in other demyelinating conditions (such as MS and NMO) (Sechi et al. Neurology 2021, 97, e1097-e1109). Optic neuritis is the most common clinical manifestation of MOG antibody disease, and therefore optical coherence tomography (OCT) can be used to confirm acute attacks and evaluate optic nerve damage (Chen et al. Mult Scler Relat Disorder. 2022, 58, 103525).

[0402] The BDI-II is a widely used 21-item self-report inventory that measures the severity of depression in adolescents and adults (Beck and Steer 1993 Beck Anxiety Inventory Manual. San Antonio, Texas: Psychological Corporation). The BDI-II can be administered verbally and is suitable for use in a virtual visit setting.

[0403] In addition to the above assessments, this study will analyze serum / blood biomarker measurements as exploratory supportive efficacy data. Example 2.2 - Study Design Example 2.2A - Overall Design

[0404] This is a Phase 2, open-label, single-arm, single-center trial designed to evaluate the efficacy and safety of 1 year of 60 mg daily tolebrutinib treatment in participants with MOG antibody disease. During the screening period, participants will stop any ongoing immunosuppressive therapy and continue to receive prednisone daily for 4 weeks during this washout period. After screening, eligible participants will be recruited to receive 60 mg of tolebrutinib oral daily dose and complete a steroid taper during the first four weeks of the study. The primary endpoint will be the proportion of participants who are on treatment and relapse-free 1 year after recruitment. Participants can choose to continue study treatment after 1 year of recruitment in consultation with the investigator and remain in the study until the last data collection for the primary analysis. The universal end of study (EOS) for all participants will occur when the last participant completes one year of treatment. Therefore, the total duration of treatment will vary from individual to individual based on the time of recruitment, with the longest possible duration of treatment being 24 months (e.g., for the first subject recruited).

[0405] The study will be conducted entirely remotely, with no in-person site visits required. All participants will attend virtual visits every 3 months that include limited neurological examinations (Bove et al. Mult Scler 2019, 25, 1526-1534), relapse and adverse event monitoring via remote video. Participants will receive sample kits at home and access remote central laboratory services to collect samples for MOG antibody titers and other laboratory monitoring. In addition to routine virtual visits, based on clinical presentation and relevant neurological signs and symptoms, if a participant reports new neurological symptoms consistent with MOG antibody disease relapse, a relapse evaluation will be triggered and include MRI of the optic nerves and / or spinal cord and / or brain. Optical coherence tomography (OCT) may also be performed if confirmation of relapse is needed.

[0406] Participants who meet relapse criteria will receive relapse care from the participant's local physician (according to local standard of care) and a remote follow-up relapse visit 4 weeks after the onset of relapse symptoms. Based on individual symptoms and assessed risk of further disease activity, investigators and participants may choose to continue tolerabine until the end of the study.

[0407] The investigator should document the discussion with the participant and the decision on relapse treatment in the source document. If the decision is to discontinue study medication, the participant will complete a study visit within 4-8 weeks of the last dose of study medication. Example 2.2B - Number of Participants

[0408] Approximately 30 participants will be screened to achieve the recruitment of 25 participants. Example 2.2C - Intervention Groups and Duration

[0409] All participants will be screened within 4 weeks to review the consent form and confirm eligibility for the trial. Participants must complete the washout of any background immunotherapy, and because the duration of washout depends on the half-life of each treatment, this period may need to start before the 4-week screening period (see Table 14 Exclusion Criteria E07). Participants will receive 20 mg of prednisone per day during the 4-week screening period while completing the washout of any background immunotherapy. Then, at the beginning of the treatment period, prednisone will be gradually reduced by 5 mg per day per week by reducing the dose by 5 mg per week until it is completely stopped, with 60 mg of tolebrutinib used concurrently per day.

[0410] During the 1-year trial period, no additional prednisone or immunotherapy was allowed except as treatment for confirmed relapse. Example 2.2D-Basic Principle

[0411] The purpose of this open-label, single-arm Phase 2 study is to evaluate the efficacy and safety of tolebrutinib 60 mg daily in the MOGAD patient population. Efficacy evaluation will focus primarily on assessing the proportion of patients who remain in remission at one year of treatment. Relapse will be confirmed by objective evidence of brain or spinal cord MRI lesions corresponding to acute symptoms. This study will initially evaluate evidence of the compound's potential efficacy in the MOGAD population. Example 2.2E - Dosage Regimen

[0412] The option to take 60 mg of tolebrutinib with food was based on results from a phase 2b dose-finding trial of tolebrutinib in adult participants with relapsing multiple sclerosis (DRI15928).

[0413] Analysis of the PK data and the effect of dosing status on tolebrutinib exposure showed a positive food effect, with an approximately 2-fold increase in AUC0-24. In addition, the correlation between treatment response and exposure to tolebrutinib showed that higher exposure was associated with a lower number of new gadolinium-enhancing T1 hyperintense lesions after 12 weeks of treatment. Taken together, these data support the recommendation to take tolebrutinib with food.

[0414] There was no correlation between the dose of tolebrutinib administered and the number of TEAEs. The most common events (preferred terms) observed in participants in the tolebrutinib-treated group were headache, upper respiratory tract infection, and nasopharyngitis. The number of AESI and PCSA observed was low. Overall, no new risks were identified in this trial. Example 2.2F—Study End Definition

[0415] Participants were considered to have completed the study by completing all phases of the study, including the Month 12 visit. However, participants who relapsed during the trial and discontinued study treatment would be considered to have completed the study if they attended the Early End of Treatment Visit.

[0416] The study will generally close for all participants after the last data collection for the primary endpoint. The last data collection for the primary endpoint will occur when the last participant without relapse completes the Month 12 visit. With a planned recruitment period of approximately 12 months, a core study treatment period of one year, and a follow-up visit 4-8 weeks after the last dose, the total estimated duration of the study is approximately 28-32 months.

[0417] Individual study durations will vary depending on the occurrence of relapse and the timing of recruitment. For individual participants who do not relapse, the minimum and maximum durations of treatment are 12 and 24 months, respectively, with a follow-up visit 4-8 weeks after the last dose. Example 2.3 - Study Population Example 2.3A - Inclusion Criteria

[0418] Participants were eligible for inclusion in the study only if all criteria listed in Table 13 below were met. Table 13 - Inclusion criteria Example 2.3B - Exclusion criteria

[0419] Participants were excluded from this study if any of the following criteria as shown in Table 14 applied: Table 14 - Exclusion criteria Example 2.3C - Lifestyle Considerations

[0420] Meals and Dietary Restrictions: Tolebrutinib (IMP) should be taken with a full meal. Where possible, meals taken with IMP (e.g., breakfast, lunch, or dinner) should remain consistent throughout the study. Typical meals taken with IMP will be collected at each visit. In the event that a change in meal timing is required to administer IMP, an interval of at least 12 hours should be maintained between doses.

[0421] Caffeine, Alcohol, and Tobacco: IMP should be used with caution in participants who are cautioned not to consume large amounts of alcohol throughout the study, defined as regularly >20 g per day for female participants (2 cups of 14 g (1 standard drink) and >30 g per day for male participants (3 cups of 28 g (2 standard drinks)); or occasionally >40 g per day (4 cups). Example 2.4 - One or more study interventions and concomitant therapies

[0422] Study interventions were defined as any one or more study interventions, one or more marketed products, placebo, or one or more medical devices designed to be administered to study participants according to the study protocol. Example 2.4A - Administration of One or More Study Interventions and Concomitant Therapies

[0423] The study intervention included IMP and non-clinical trial medication (NIMP). To maintain blinding, participants received 4 tablets of BTK inhibitor or placebo once daily in a blinded manner. The details of the intervention are provided in Table 15. Table 15 - Summary of Study Interventions for Administration *IMP: drugs used in clinical trials; NIMP: drugs used outside clinical trials

[0424] Detailed information on the drugs used in non-clinical trials is provided in Table 16. Table 16 - Overview of Drugs Used in Non-clinical Trials Example 2.4B - Measures to Minimize Bias: Randomization and Blinding

[0425] This is an open-label study; potential bias will be reduced by the following steps: Objective measures will be used to determine the primary outcome of relapse. Relapse is clinically defined, but MRI-confirmed episodes that explain clinical symptoms are also required. Example 2.4C - Dosage Changes

[0426] Dose changes are not foreseen for this study. Interruption or permanent discontinuation of treatment may be necessary if deemed necessary due to AEs or recurrence. Example 2.4D - Continued access to intervention after study completion

[0427] There are currently no plans for study interventions with tolebrutinib after the study is completed. Example 2.4E - Concomitant Therapy

[0428] Any medications or vaccines (including over-the-counter or prescription medications, vitamins, or herbal supplements) that the participant is receiving at the time of enrollment or during the study must be recorded along with the following: reason for use, dates of administration (including start date and end date); and dosage information (including dose and frequency).

[0429] Live (attenuated) vaccines should not be administered during the intervention period.

[0430] No treatment for MOG antibody disease mentioned in Exclusion Criterion E07 is permitted after enrollment or during the core study intervention period. Short-term (3 to 7 days) use of glucocorticoids (e.g., for acute illness) and topical glucocorticoids (e.g., topical, nasal, ocular, aural, intra-articular) are permitted. In the event of a relapse, acute treatment as recommended in the Relapse Treatment Recommendations in Table 16 may be considered. In addition, participants should consult with the investigator and treating neurologist to assess the benefits and risks of continuing study treatment.

[0431] Participants abstained from taking prescription or over-the-counter medications (including vitamins and dietary or herbal supplements) for 7 days (or 14 days if the medication was a potential enzyme inducer) or 5 half-lives, whichever was longer, before the start of the study intervention and until completion of the follow-up visit unless the investigator and sponsor determined that the medication would not interfere with the study.

[0432] If clinically feasible, medications to treat symptoms of MOG antibody disease (e.g., walking disorders, spasticity, incontinence, pain) should be maintained at a stable dose prior to screening and for the duration of the treatment period.

[0433] Concomitant use of anticoagulant / antiplatelet therapy with IMP is not permitted, including: acetylsalicylic acid (aspirin) > 81 mg / day; antiplatelet agents (e.g., clopidogrel); warfarin (vitamin K antagonist); heparins including low molecular weight heparin (antithioclobin agents); dabigatran (direct thrombin inhibitor); apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors).

[0434] Acetaminophen / paracetamol at a dose of ≤ 3 g / day was permitted at any time during the study. During the study, a short course (up to 5 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) (except acetylsalicylic acid), preferably a selective cyclooxygenase-2 inhibitor such as the lowest effective dose of an NSAID, may be administered if clinically necessary for treatment of an existing medical condition or a new event. The investigator must record the use of NSAIDs (and any other concomitant medication) in the eCRF.

[0435] CYP Inhibitors / Inducers: Strong and moderate inducers of CYP3A or strong inhibitors of CYP2C8 hepatic enzymes were not permitted throughout the study. Example 2.5 - Cessation of Study Intervention and Participant Discontinuation / Withdrawal Example 2.5A - Cessation of Study Intervention Example 2.5A1 - Permanently Stop

[0436] Unless there is a possibility of MOG antibody disease relapse, the study intervention should be continued whenever possible. In the event of a relapse, the participant should consult with the investigator and treating neurologist to assess the benefits and risks of continuing the study treatment or may choose to switch to another immunomodulatory / immunosuppressive therapy. Permanent intervention discontinuation is any treatment discontinuation associated with a final decision made by the investigator or participant at any time not to re-expose the participant to the study intervention.

[0437] The following may be valid reasons for the researcher to stop the study treatment of a participant: Adverse events that jeopardize the safety of participants, or if the investigators and / or participants wish or deem it necessary to stop the study intervention. If the criteria for discontinuation of IMP are met according to the laboratory abnormality follow-up guidelines (Example 2.8A). The investigator believes that the participant is no longer receiving therapeutic / clinical benefit. · Withdraw consent for treatment at the request of the participant. If the female participant becomes pregnant or wishes to become pregnant during the study. Any serious opportunistic infection. ·Continued need for long-term use of prohibited concomitant medications.

[0438] The Investigator should consider discontinuing the study intervention for abnormal liver function when the participant meets one of the conditions outlined in the algorithm (Example 2.8C) or if the Investigator deems it to be in the best interest of the participant.

[0439] Any clinically significant abnormal laboratory values ​​or ECG parameters will be confirmed by immediate re-examination after 24 hours before a decision is made to definitively stop the IMP for the relevant participant.

[0440] If a clinically significant finding is found in the post-enrollment ECG (including but not limited to a change from baseline in the QT interval [QTcF] corrected using the Fridericia formula), the investigator or qualified designee will determine whether the participant can continue to participate in the study and whether changes in participant management are needed. Review of the ECG findings by a cardiologist may be considered for the decision to ultimately stop the study intervention due to ECG changes. A review of the printed ECG at the time of collection must be documented. Any new clinically relevant findings should be reported as an AE. See SoA (Example 2.1) for data to be collected at intervention stop and follow-up, and any further evaluations that need to be completed.

[0441] If the study intervention is permanently discontinued, the participant should be asked to complete an Early End of Treatment Visit. See SoA (Example 2.1) for data to be collected at visits and follow-up, and any further evaluations to be completed. All final study drug discontinuations must be recorded on the appropriate pages of the eCRF when considered confirmed. Example 2.5A2-Temporary Stop

[0442] Temporary intervention stops that interrupt the clinical trial due to suspected AEs or regional or national emergencies declared by governmental agencies: The treating investigator may consider contingency measures for regional or national emergencies declared by governmental agencies. For all temporary intervention stops, the investigator should record the duration in the appropriate pages of the eCRF.

[0443] If surgery is required during the study period, the benefit-risk of retaining the IMP for at least 3 to 7 days before and after surgery will be considered, depending on the type of surgery and the risk of bleeding.

[0444] The following will result in temporary treatment cessation: • Cytopenias: According to Example 2.8C, the Sanofi algorithm was used for neutropenia and thrombocytopenia. • Increases in serum creatinine, creatine phosphokinase (CPK), and liver enzymes: follow the corresponding Sanofi algorithm according to Example 2.8C. • Cardiac arrhythmia (atrial fibrillation): any Grade 3 event (symptomatic urgent intervention indicated; device [eg, pacemaker]; ablation; new onset). Suicide risk according to the BDI: if the participant scored 1 or higher.

[0445] If necessary, temporary treatment stops may be considered by the investigator or participant for any other reason, including any safety concerns arising from a regional or national emergency declared by a governmental agency (e.g., COVID-19 or other illnesses) or if a concomitant medication is prohibited and therefore clinical trial interruption is required. Treatment may be resumed at a later time if it is deemed safe and appropriate and taking into account the duration of the entire study. Example 2.5A3 - Re-stimulation

[0446] Once the investigator determines, in his or her best medical judgment, that responsibility for one or more of the IMPs in the occurrence of the relevant events is unlikely, there are no safety concerns, and that the criteria for permanent treatment cessation have not been met, reinitiation of the IMP will occur under close and appropriate clinical and / or laboratory monitoring. Example 2.6 - Study Evaluation and Procedures

[0447] The study procedures and their timing are summarized in the SoA (Example 2.1). No waivers or exemptions from the protocol were permitted.

[0448] Compliance with the study design requirements, including those specified in the SoA (Example 2.1), is necessary and required for the conduct of the study.

[0449] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. Research staff will maintain a screening log to record details of all participants screened and confirm eligibility or record reasons for screening failure, if applicable.

[0450] Procedures performed as part of the participant's routine clinical management (e.g., blood counts) and obtained prior to signing the ICF may be used for screening or baseline purposes, provided that the procedure meets the protocol-specified criteria and is performed within the timeframe defined in the SoA (Example 2.1). Such assessments should be recorded in the designated fields on the CRF.

[0451] Details of blood sampling, including volume for all laboratory assessments, will be provided in the informed consent form. Sampling may be repeated or unscheduled for safety reasons or technical issues with the samples. Example 2.6A - Efficacy Evaluation

[0452] All planned time points for efficacy assessments are provided in the SoA (Example 2.1).

[0453] Key efficacy assessments (e.g., EDSS) will be scored by the research team. The Expanded Disability Status Scale is a method for quantifying disability and monitoring disability levels over time (Kurtzke Neurology 1983, 33, 1444-1452). The Expanded Disability Status Scale is widely used in clinical trials and the assessment of patients with MS, NMO, and MOGAD. The EDSS scale ranges from 0 to 10, with 0.5 unit increments, which represent higher disability levels. Scoring is based on neurologists' examinations, and has a great impact on activity (spinal cord) and vision (optic nerve). EDSS (Bove et al. MultScler 2019, 25, 1526-1534) will be performed using a remote telephone video-supported examination.

[0454] The investigator will be responsible for confirmation of relapses. In these cases, MRI findings during the acute episode and local neurologist evaluation are required. MRI scans for relapse confirmation and follow-up relapse visits will be analyzed by the investigator.

[0455] The basic MRI scan will be performed locally and will consist of the following sequences: T2- and T1-weighted sequences before and after administration of Gd contrast (if there are no contraindications). The MRI scan should include the optic nerves and / or spinal cord and brain at baseline, and recurrent MRI should include relevant areas based on clinical presentation and associated neurological signs and symptoms.

[0456] If needed, researchers may ask participants to undergo optical coherence tomography (OCT) assessment to verify recurrence.

[0457] MOG antibody testing by cell-based assay includes a positive / negative result as well as a titer. The titer is reported as the highest dilution at which MOG antibodies are still detectable. Dilutions in Quest include 1:10, 1:20, 1:40, 1:80, 1:160, etc. The higher the titer, the greater the amount of MOG antibodies in the serum. Example 2.6 Definition of disease relapse with A1-MOG antibody

[0458] For the purposes of this study, MOG antibody disease relapse was defined as a monophasic, acute, or subacute onset of new neurologic symptoms, or worsening of previous neurologic symptoms with objective changes on neurologic examination. Symptoms must: · Disease attributable to MOG antibodies, · Lasts ≥ 24 hours, with or without recovery, Presents with normothermia (ie, without infection, excessive exercise, or elevated ambient temperature), has had ≥30 days of previous clinical stability (including no previous relapses), and • One or more new or enhancing MRI lesions attributed to the brain or spinal cord and / or optic nerves. NOTE: Worsening or recurrence of signs and symptoms in participants with MOG antibody disease that can reasonably be attributed to transient impairment of conduction through previously demyelinated pathways caused by an increase in core body temperature will not be considered a relapse.

[0459] Researchers will confirm MOG antibody disease relapse based on the following definitions: A confirmed MOG antibody disease relapse was a relapse that was accompanied by a clinically relevant change in EDSS score as assessed by a local neurologist, i.e., an increase in EDSS score of at least 0.5 points, an increase in 2 function scores of 1 point, or an increase in 1 function score of 2 points, excluding changes in scores involving bowel / bladder and brain function compared to the previous available assessment (the last EDSS assessment that did not occur during the relapse period). An MRI (brain and / or spinal cord and / or optic nerve) must be performed as soon as possible to support confirmation of recurrence. Example 2.6A2 - Relapse Assessment and Follow-up Relapse Visit

[0460] Participants must be instructed to report new neurological symptoms and recurrence or worsening of previous symptoms immediately to the investigator. In addition, participants will be proactively asked about possible recurrence of symptoms at each study visit.

[0461] If a relapse is suspected, a relapse evaluation visit with the investigator must be scheduled as soon as possible (within 7 days of symptom onset if possible). MOG antibody disease relapse will be assessed and confirmed by the investigator. Management of relapse will be accomplished locally by the treating neurologist according to local standards of care. Recommendations for treatment of relapse are detailed in Table 16 and are not mandatory.

[0462] MOG antibody disease relapse during diagnosis study: Instruct participants to immediately notify the research team of any new visual symptoms, weakness, numbness, or bowel / bladder function disorders. When participants report new or worsening neurological symptoms to the research team, a relapse assessment will be triggered ideally within 72 hours after the change / new symptoms begin. At this point, a virtual EDSS examination will be performed remotely. The PI will determine whether a series of signs and symptoms will prompt a relapse evaluation by MRI of the affected area. In this clinical setting, relapse in the test is confirmed by new T2 or enhanced lesions corresponding to signs and symptoms by means of MRI (see Example 2.6A1).

[0463] Regardless of whether an event is judged to be a relapse, the PI will not interfere with treatment with steroids or IVIG / PLEX if the local physician / neurologist insists on treatment. The PI is responsible for the final determination of relapse, but the decision to treat the relapse will be left to the local physician / neurologist.

[0464] Negative MRI or other clinical evidence of a pseudorelapse will not be counted as an adjudicated relapse for the purpose of this study. Pseudorelapses will be managed as routine clinical care by local physicians or neurologists.

[0465] All confirmed MOG antibody disease relapses must be reported on the Relapse eCRF page. A MOG antibody disease relapse should not be reported as an AE unless the investigator considers it to be unusually severe or medically unexpected, or matches the definition of an SAE. The exception to this SAE definition is that some sites routinely admit participants who require administration of intravenous medications to treat a relapse when the participant is hospitalized for standard care of the relapse. Therefore, the “hospitalization” SAE criteria will be met based on local practice and may not reflect the severity of the event. A MOG antibody disease relapse should be considered a serious adverse event when the relapse results in hospitalization for any reason other than routine relapse care (e.g., a course of treatment that exceeds standard care described in Table 16 or when the hospitalization is prolonged).

[0466] If no concurrent illness is suspected, safety laboratory testing is optional for this recurrence evaluation visit. If any concurrent illness is diagnosed, it will be reported as an AE in accordance with the safety reporting rules.

[0467] The investigator will conduct a follow-up relapse visit 4 weeks after confirmation of relapse according to the SoA (Example 2.1). Example 2.6B - Safety Assessment

[0468] All planned time points for safety assessments are provided in the SoA (Example 2.1). Example 2.6B1-ECG

[0469] An ECG will be obtained as outlined in the SoA (Example 1.1) using a smartphone-supported ECG home device that automatically calculates heart rate and measures PR, QRS, QT, and QTcF intervals. If the ECG device is not able to automatically calculate QTcF, it can be calculated manually using a nomogram or an automated website calculator (e.g., https: / / reference.medscape.com / calculator / 48 / ecg-corrected-qt). Example 2.6B2-Vital Signs

[0470] Participants will remotely assess their temperature, heart rate, and blood pressure at home using a smartphone-enabled home device.

[0471] Blood pressure and heart rate measurements will be assessed in the supine or sitting position using fully automated equipment. Manual techniques will be used only if automated equipment is not available.

[0472] Participants should rest for at least 5 minutes in a quiet environment without distractions (e.g., television, cell phones) before blood pressure and heart rate measurements.

[0473] Heart rate and blood pressure measurements will be taken before blood is collected for laboratory testing and will include 1 heart rate and 3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at least 1 minute apart). Example 2.6B3 - Clinical Safety Laboratory Evaluation

[0474] See Example 2.8A for a list of clinical laboratory tests to be performed. According to the SoA (Example 2.1), serological tests for hepatitis B and hepatitis C will be performed during screening.

[0475] In the event of an urgent safety event, the investigator may request local urgent laboratory data to make appropriate treatment decisions. All clinically relevant local urgent laboratory data requested will be recorded in the eCRF.

[0476] The investigator must review the laboratory reports, document this review, and record any clinically relevant changes that occur during the study in the AE section of the eCRF. Laboratory reports must be archived with the source documents. Clinically significant abnormal laboratory results are those that are not related to the underlying disease unless the investigator believes that the participant's condition is more severe than expected.

[0477] All laboratory tests with values ​​considered clinically significant abnormal should be repeated during study participation or within 28 days after the last dose of study intervention until such values ​​return to normal or baseline or are no longer clinically significant in the opinion of the investigator.

[0478] If abnormal laboratory test values ​​do not return to normal or baseline within a time that is reasonable in the investigator's judgment, the cause should be identified and the sponsor notified.

[0479] All protocol-required laboratory evaluations as defined in Example 2.8A must be performed per the SoA. If the laboratory evaluations in Example 2.8C indicate discontinuation of the IMP, a temporary interruption should be considered unless otherwise indicated.

[0480] If a laboratory value for a non-protocol-mandated laboratory assessment performed at the institution's local laboratory requires a change in participant management or is considered clinically significant by the investigator (e.g., a SAE or AE or dose modification), the result must be documented in the eCRF. Example 2.6C - Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reports Example 2.6 C1-MOG Antibody Disease Relapse Report

[0481] MOG antibody disease recurrences determined by the evaluations described in 2.6A1 will be exempted from reporting as AEs unless they meet the definition of an SAE or are unusually severe or medically unexpected. Hospitalization for recurrence will not be considered a severity criterion for this study if routinely completed on-site (e.g., high-dose IV methylprednisolone).

[0482] Data on MOG antibody disease relapse will be collected on the eCRF and analyzed as part of the efficacy analysis. Other worsening of neurological symptoms that do not meet the definition of MOG antibody disease relapse will be reported as AEs in accordance with general safety reporting rules. Example 2.6C2-Reporting of Safety Examination Results of Magnetic Resonance Imaging

[0483] Magnetic resonance imaging scans will need to be reviewed locally for any abnormalities. If there are clinically relevant findings, relevant information will need to be provided to the investigator for appropriate safety reporting and also to ensure appropriate management of the identified safety findings for the participant. If any, the diagnosis of the pathology or the findings themselves as the cause of such MRI findings will be reported as an AE, with guidance that the diagnosis is clear. Example 2.6C3 - Adverse Events of Special Interest

[0484] AEs of special interest (AESIs) are scientifically and medically relevant AEs (serious or non-serious) that are unique to the sponsor's product or procedure and require ongoing monitoring by the investigator and timely notification to the sponsor. Such events may require further investigation to characterize and understand them. Adverse events of special interest may be added, modified, or deleted by protocol amendments during a study.

[0485] Pregnancies in female participants taking part in the study and in female partners of male participants taking part in the IMP / NIMP study. • It will be classified as a SAE only if it meets one of the severity criteria (see Example 2.8B). If a female participant becomes pregnant, IMP should be discontinued. Female participants or female partners of male participants must be followed up for pregnancy before results can be confirmed.

[0486] Symptomatic overdose (serious or non-serious) of IMP. An IMP overdose (accidental or intentional) was an event suspected by the investigator or spontaneously notified by the participant (not based on systematic pill counting) and was defined as at least twice the intended dose within the intended treatment interval (e.g., >2 IMP tablets in a 12-hour interval).

[0487] Alanine aminotransferase (ALT) increased >3×ULN. ALT increase >3×ULN confirmed by retesting within 72 hours or no retesting within 72 hours.

[0488] The project-specific AESI or AESIs are: ECG observation of atrial fibrillation or atrial flutter Serious infections (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade 3 or higher) that may or may not meet the severity criteria (e.g., grade 3 opportunistic infections). Moderate or severe bleeding events (NCI CTCAE Grade 2 or above), including but not limited to symptomatic bleeding in critical areas or organs (e.g., CNS) or intraocular hemorrhage. Thrombocytopenia, platelet count <75,000 / mm 3 (See Example 2.8C for a management flow chart).

[0489] The definition of AE or SAE can be found in Example 2.8B.

[0490] Adverse events will be reported by the participant (or, when appropriate, by a caregiver, substitute, or the participant's legally authorized representative).

[0491] The Investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and for ongoing follow-up of AEs that are serious, considered related to the study intervention or study procedures, or that lead to a participant discontinuing a study intervention. Example 2.6D - Biomarkers

[0492] Blood samples for biomarker studies will be collected from all participants in this study as specified in the SoA (Example 2.1). Participants who have relapsed during the trial may elect to have blood samples collected for biomarkers from that time onwards.

[0493] Whole blood samples collected for biomarker studies were also part of this study.

[0494] Samples will be tested to evaluate biomarkers and their association with observed clinical response to tolebrutinib.

[0495] Additionally, samples will be stored and biomarker variants believed to play a role in MOG antibody disease, including but not limited to serum analytes, may be analyzed to assess their association with observed clinical responses to tolebrutinib (depending on local regulations). Example 2.7 - Statistical considerations Example 2.7A - Sample size determination

[0496] This is an exploratory, single-arm study. Based on clinical experience, it is estimated that patients with MOG antibody disease relapse on average once a year, meaning that in a given year, approximately 40% are expected to be relapse-free. For this study, approximately 25 participants will be recruited to receive the study intervention. Observing at least 65% (n=16) of participants relapse-free after 1 year of tolebrutinib treatment would be clinically meaningful. Example 2.7B - Populations for analysis

[0497] The definitions of the following groups used for analysis are shown in Table 17. Table 17 - Populations used for analysis

[0498] Participants who were exposed to the study intervention prior to recruitment or who were not recruited will not be considered recruited and will not be included in any analysis population. The safety experience of these participants will be reported separately.

[0499] For any participant who was recruited more than once, only data related to the first recruitment were used in any analysis population. Safety experiences related to any subsequent recruitment will be reported separately. Example 2.7C - Statistical Analysis

[0500] The Statistical Analysis Plan (SAP) will include a more technical and detailed description of the statistical analyses described in this chapter. This chapter is a summary of the planned statistical analyses of the most important endpoints, including the primary and key secondary endpoints. Given that this is a single-arm efficacy trial, most of the data will be presented as descriptive statistics. Example 2.7C1 - General Notes

[0501] The baseline value is defined as the last available value before the first dose of IMP. For enrolled but untreated participants, the baseline value is defined as the last available value before enrollment. Baseline EDSS will be calculated as the average of the screening and Day 1 assessment values.

[0502] The observation period will be divided into 3 stages: The pre-treatment period was defined as the period from signing of the ICF to the first IMP administration. The treatment-emergent (TE) period was defined as the period from the first IMP dose to the last IMP dose + 10 days. The post-treatment period was defined as the period from the end of the treatment-emergent period to the last study assessment of the participant. Example 2.7C2 - One or more primary endpoints

[0503] Point estimates and exact 95% confidence intervals for the proportion of participants in the PP population who are relapse-free at 1 year will be provided as the primary endpoint. The observed success rate will help inform decisions about whether to continue development of tolebrutinib for the treatment of MOG antibody disease.

[0504] Additional analysis of relapse will include calculation of relapse time after recruitment. A Kaplan-Meier (KM) diagram of cumulative incidence will be provided to depict the occurrence of relapse over time in the PP population. The proportion of participants who relapse at 3, 6, 9, and 12 months will be calculated using KM estimates. Participants who complete treatment without relapse will be examined at the end of the treatment date.

[0505] Sensitivity analyses including participants who discontinued study treatment early for reasons other than relapse will be provided in the following circumstances: All of these participants were censored on the date of early treatment cessation. Participants who experienced a relapse within 10 days of premature discontinuation of tolebrutinib (if any) were classified as having an event, and other participants were censored at the date of premature treatment cessation + 10 days.

[0506] Although prior treatment is variable, the time to relapse in participants who received tolebrutinib will be explored compared to the time to relapse in the same group of participants one year after starting first treatment for MOG antibody disease. In addition, the time to relapse in participants who received tolebrutinib will be explored compared to a propensity score-matched external control group one year after starting first treatment for MOG antibody disease. Crude KM curves and estimates will be provided. Various statistical methods will be explored to provide estimates of the reduction in the probability of relapse with tolebrutinib compared with "other treatments". Details will be provided in the SAP. Example 2.7C3 - One or more secondary endpoints

[0507] Changes from baseline in EDSS and MOG antibody titers after 1 year of tolebrutinib treatment will be summarized as secondary efficacy endpoints in the relapse-free PP population. Example 2.7C4 - One or more tertiary / exploratory endpoints

[0508] Details of any tertiary / exploratory endpoints will be included in the SAP. Example 2.7C5 - Safety Analysis

[0509] All safety analyses will be performed on the safety population. Example 2.7C6 - Adverse Events

[0510] General common rules for adverse events: A summary of AEs will be provided based on the number of events. If the number is small, a list of events will be provided.

[0511] AEs will be analyzed in the following 3 categories: Pre-treatment AEs: AEs that developed, worsened, or became severe during the pre-treatment period. TEAE: An AE that develops, worsens, or becomes serious during treatment emergencies. Post-treatment AEs: AEs that developed, worsened, or became severe during the post-treatment period.

[0512] Information on any deaths will be listed.

[0513] Analysis of all adverse events: Adverse event incidence tables will be provided for all types of TEAEs: all TEAEs, all treatment-emergent AESI (defined by PT or pre-specified group), all treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation.

[0514] An AE summary will be generated along with the number (%) of participants who experienced at least one event.

[0515] The number of deaths will also be analyzed. Example 2.7C7 - Laboratory variables, vital signs and electrocardiogram (ECG)

[0516] Quantitative Analyses: For laboratory variables, vital signs, and ECG variables, descriptive statistics of outcomes and changes from baseline will be provided for each planned visit during treatment. These analyses will be performed using central measurements of MOG antibody titers and other laboratory variables and local measurements of vital signs and ECG variables.

[0517] Analysis of Laboratory, ECG, and Vital Sign Abnormalities: Potentially clinically significant laboratory, ECG, and vital sign abnormalities will be summarized. Example 2.7C8 - Other Analysis

[0518] Exploratory analyses of biomarkers that will be included in the study report will be described in SAP. Example 2.7C9-Interim Analysis

[0519] No formal interim analysis is planned for this study. Example 2.8 - Support records and operational considerations Example 2.8A - Clinical Laboratory Testing

[0520] When feasible, the tests detailed in Table 18 below will be performed by the central laboratory. Local laboratory results are required only if the central laboratory results are not available in a timely manner for study intervention administration and / or response evaluation. In addition, if local laboratory results are used to make study intervention decisions or response evaluations, the results must be entered into the eCRF.

[0521] Tables 13 and 14 in the protocol detail the protocol-specific requirements for inclusion or exclusion of participants.

[0522] Additional testing as determined necessary by the Investigator or required by local regulations may be performed at any time during the study. Additional serum or urine pregnancy testing as determined necessary by the Investigator or required by local regulations may be performed to determine the absence of pregnancy at any time during the subject's participation in the study. Table 18 - Laboratory Assessments Required by the Protocol ALT: alanine aminotransferase; anti-HBc: antibody against hepatitis B core antigen; anti-HBs: hepatitis B surface antibody; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; BUN: blood urea nitrogen; β-hCG: human chorionic gonadotropin; FSH: follicle-stimulating hormone; IEC: independent ethics committee; INR: international normalized ratio; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus

[00136] ALT: ALT > 3 x ULN; 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 cellaThe details of the liver chemistry stopping criteria and required actions and follow-up assessments after ALT > 3 x ULN is observed are provided in Example 1.8C. If INR is measured, clinical laboratory test results of ALT > 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin) or ALT > 3 x ULN and international normalized ratio (INR) > 1.5 may indicate severe liver injury and must be reported as SAEs. bUnless serum testing is required by local regulations or the IRB / IEC, a local urine test for pregnancy will be standard of care for this protocol (except at the Screening Visit, when a serum pregnancy test is requested). c Further details are provided in Table 14, E 01.

[0523] Biomarkers (blood / serum): Neurofilament light chain and glial fibrillary acid protein levels. Optional for participants who have relapsed during the trial.

[0524] Researchers must document their review of each laboratory safety report. Example 2.8 B-AEs and SAEs: Definitions and Procedures for Recording, Evaluation, Follow-up, and Reporting Example 2.8 Definition of B1-AE Example 2.8B1a-AE Definition

[0525] An AE is any unfavorable medical event in a patient or clinical study participant that is temporally associated with the use of an investigational intervention, whether or not considered related to the investigational intervention.

[0526] NOTE: An AE may therefore be any unfavorable and unplanned sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally related to the use of the study intervention. Example 2.8B1b - Events meeting the definition of AE

[0527] Any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) or other safety assessment (e.g., ECG, radiology scan, vital sign measurement) that is considered clinically significant (i.e., not related to progression of underlying disease) based on the medical and scientific judgment of the investigator, including any result or assessment that is worse from baseline, such as: Lead to discontinuation or dose change of IMP, or meets the severity criteria, or Defined as AESI.

[0528] Aggravation of a chronic or intermittent pre-existing condition, including an increase in the frequency or intensity of the condition.

[0529] New conditions are detected or diagnosed after the study intervention is administered, even though they may have existed before the study began.

[0530] Signs, symptoms, or clinical sequelae of suspected drug interactions.

[0531] Suspected signs, symptoms, or clinical sequelae of overdose of the study intervention or concurrent medication.

[0532] "Lack of efficacy" or "failure of intended pharmacological action" per se will not be reported as an AE or SAE. These conditions will be reflected in the efficacy evaluation. However, signs, symptoms, or clinical sequelae resulting from the lack of efficacy will be reported as an AE or SAE if they meet the definition of an AE or SAE. Example 2.8B1c—Events that do not meet the AE definition

[0533] Any clinically significant abnormal laboratory test result or other abnormal safety assessment related to the underlying disease, unless the investigator believes that the participant's illness is more severe than expected.

[0534] The disease / condition being studied or the expected progression, signs, or symptoms of the disease / condition being studied, unless the participant's condition is more severe than expected.

[0535] Medical or surgical (eg, endoscopy, appendectomy): Conditions leading to surgery are AEs.

[0536] There were no adverse medical events (social or convenience hospitalizations).

[0537] Expected day-to-day fluctuations in one or more pre-existing diseases or one or more conditions that were present or detected at the start of the study without worsening. Example 2.8 Definition of B2-SAE

[0538] SAEs were defined as any adverse event at any dose that resulted in the following:

[0539] Leading to death.

[0540] Life-threatening: The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of death at the time of the event. The term does not refer to an event that could hypothetically have caused death if it were more serious.

[0541] Requirement of hospitalization of the patient or prolongation of an existing hospitalization: In general, a hospitalization indicates that a participant has been admitted to a hospital or emergency department for observation or treatment (usually involving at least an overnight stay) that would not be appropriate in a physician's office or outpatient setting. Complications that occurred during a hospitalization were AEs. An event was serious if the complication prolonged the hospitalization or met any other criteria for seriousness. When there is doubt as to whether a "hospitalization" occurred or was necessary, an AE should be considered serious. Hospitalizations for elective treatment of a pre-existing condition that did not worsen from baseline were not considered AEs.

[0542] Resulting in persistent or significant disability / incapacity. The term disability means a significant impairment in a person's ability to carry out normal life functions. This definition is not intended to include relatively minor medically significant experiences, such as simple headaches, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., a sprained ankle) that may interfere with or prevent daily functioning but do not constitute a serious disruption.

[0543] Congenital anomalies / birth defects.

[0544] Other cases: It should be determined by the investigator using medical or scientific judgment whether SAE reporting is appropriate in other circumstances, such as for medically significant events that could endanger a participant or that might require medical or surgical intervention to prevent one of the other outcomes listed in the definition above. These events should generally be considered serious. Note: The following list of medically significant events is intended as a guide to determine which conditions must be considered medically significant events. This list is not exhaustive. Intensive treatment in the emergency room or at home: - Allergic bronchospasm. - Blood disorders (i.e. agranulocytosis, aplastic anemia, bone marrow aplasia, bone marrow dysplasia, pancytopenia, etc.). - Convulsions (epilepsy, epilepsy, seizures, absences, etc.). Development of drug dependence or drug abuse. ALT > 3 × ULN + total bilirubin > 2 × ULN or asymptomatic ALT increase > 10 × ULN. Suicide attempt or any event suggestive of suicide. Syncope, loss of consciousness (unless recorded as due to blood sampling). Bullous rash. Cancer diagnosed during the study period or worsening during the study period. Example 2.8 Evaluation and Follow-up of B3-AEs and / or SAEs Example 2.8B3a-Severity Assessment

[0545] Investigators will assess the severity of each AE and SAE using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, published on November 27, 2017. The list of MedDRA terms in the NCI CTCAE should be consulted first to find the severity level description for a specific AE. For AEs not listed in the NCI CTCAE, investigators will be asked to assess the severity of the AE using general guidelines: Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; no intervention indicated. · Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limitations to age-appropriate instrumental ADL*. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limiting self-care ADL**. Level 4: Life-threatening consequences; urgent intervention indicated. Grade 5 death related to AEs. Note: Activities of daily living (ADL) *Instrumental ADLs include preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. **Self-care ADL refers to bathing, dressing and undressing, self-feeding, toileting, taking medications, and being bedridden.

[0546] Any Grade 4 or 5 event must be reported as an SAE. Grade 1 to 3 events are defined as “Serious” when they meet at least 1 of the predefined findings described in the SAE definition. Example 2.8B3b-Causality Assessment

[0547] The investigators were obligated to evaluate the relationship between the study intervention and the occurrence of each AE / SAE.

[0548] A “reasonable possibility” of a relationship indicates that there are facts, evidence, or arguments to suggest a causal relationship, not that a relationship cannot be ruled out.

[0549] The researcher will use clinical judgment to determine this relationship.

[0550] Other causes, such as underlying disease or diseases, concomitant treatments, and other risk factors, as well as the temporal relationship of the event to the administration of the study intervention, will be considered and investigated.

[0551] Researchers will also consult the Investigator Brochure (IB) or product information used to sell the product in their evaluation.

[0552] For each AE / SAE, the investigator must document in the medical note that they have reviewed the AE / SAE and provided an assessment of causality.

[0553] Investigators can change their opinion on causality based on follow-up information and send SAE follow-up reports with the updated causality assessment.

[0554] Causality assessment is one of the criteria used when determining regulatory reporting requirements. Example 2.8 Follow-up of B3c-AE and SAE

[0555] The investigator is obligated to perform or arrange for additional measurements or assessments, as medically indicated, to elucidate the nature or causality of the AE or SAE as fully as possible. This may include additional laboratory tests or studies, histopathology, or consultation with other health care providers. Example 2.8C—Hepatic and Other Safety: Recommended Actions and Follow-up Assessments

[0556] Table 19 and Figure 2 , Figure 3 , Figure 4B , Figure 5 and Figure 6 These actions are described only for events of ALT increase and thrombocytopenia. For all other safety events described, these are recommended based on the medical judgment of the investigator.

[0557] Only those who meet the general guidance for reporting adverse events in Example 2.8B ( Figure 3) was recorded as an AE only if at least 1 of the criteria listed in . Figure 3 Abbreviations in the literature: aPTT, activated partial thromboplastin time; EDTA, ethylenediaminetetraacetic acid; INR, international normalized ratio; PK, one or more pharmacokinetic parameters; PT, prothrombin time.

[0558] Neutropenia was recorded as an AE only if at least 1 of the criteria listed in the General Guidance for Reporting Adverse Events in Example 2.8B was met.

[0559] Figure 4B Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CMV: cytomegalovirus; CPK: creatine phosphokinase; CRF: case report form; EBV: Epstein-Barr virus; HAV: hepatitis A virus; HBV: hepatitis B virus; HCV: hepatitis C virus; IgM: immunoglobulin M; IMP: clinical trial drug; INR: international normalized ratio; LFT: liver function test; LKM: liver-kidney microsomal antibodies; PT: prothrombin time; ULN: upper limit of normal.

[0560] Note: Figure 4B In the , “baseline” refers to the ALT sampled at the baseline visit: or if a baseline value is not available, to the most recent ALT sampled before the baseline visit. This algorithm is not applicable to instances where ALT increases during the screening period.

[0561] exist Figure 4B In the , if the baseline value is >ULN, normalization is defined as ≤ULN or baseline value.

[0562] Only those who meet the general guidance for reporting adverse events in Example 1.8B ( Figure 5 ) was recorded as an AE only if at least 1 of the criteria listed in .

[0563] Figure 5 Abbreviations in the table: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, one or more pharmacokinetics.

[0564] An increase in CPK was recorded as an AE only if at least 1 criterion in the General Guidelines for Reporting Adverse Events in Example 2.8B was met.

[0565] If a participant has clinical presentation or MRI features suggestive of PML, the following diagnostic and action algorithm is suggested ( Figure 6 ).

[0566] Figure 6Abbreviations: CSF: cerebrospinal fluid; Gd: gadolinium; IMP: clinical trial drug; JCV: JC virus; MRI: magnetic resonance imaging; PCR: polymerase chain reaction; PML: progressive multifocal leukoencephalopathy.

[0567] Figure 8 Abbreviations in the table: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, one or more pharmacokinetic factors; ULN, upper limit of normal.

[0568] Table 19 presents the clinical presentation or MRI lesion features suspected of PML. Table 19 - Clinical and MRI features suggestive of PML

[0569] If PML is suspected based on imaging results, the local radiologist will inform the investigator directly. The investigator will obtain additional plasma, urine, and CSF samples for JC virus (JCV) analysis. The samples will be analyzed upon receipt, and the results will be provided directly to the study site and the sponsor. Further management will be deferred to the treating investigator. However, next steps will include discontinuation of study treatment. Additional imaging will be performed at the investigator's discretion based on the diagnostic workup and treatment plan.

[0570] Detection of JCV DNA in the CSF of patients with clinical and MRI features suggestive of PML can confirm the diagnosis of PML.

[0571] If JCV DNA is not detected in the CSF and if the clinical suspicion of PML remains high, another lumbar puncture should be performed.

[0572] If the diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may be considered to confirm the final diagnosis.

[0573] Clinical or MRI features suggestive of PML should be recorded as AEs / AESIs / SAEs according to the definitions and procedures in Example 1.8B. Example 2.8 Diagnostic criteria for D-MOG antibody disease

[0574] A definitive diagnosis of MOG antibody disease must meet all of the following criteria (Jarius et al. J Neuroinflammation 2018, 15, 134): Monophasic or recurrent acute ON, myelitis, brainstem encephalitis or encephalitis, or any combination of these syndromes. MRI or electrophysiologic (visual evoked potentials in patients with isolated ON) findings compatible with CNS demyelination. • Seropositivity for MOG-IgG detected by a cell-based assay using full-length human MOG as target antigen. Example 1.8E-Abbreviations Ab: Antibody ADL: Activities of Daily Living AE: Adverse event AESI: Adverse events of special interest ALT: Alanine aminotransferase aPTT: activated partial thromboplastin time ARF: Acute renal failure ARR: Annualized relapse rate BTK: Bruton's tyrosine kinase CDP: Confirmation of Disability Progression CK-MB: Creatine kinase (heart) CK-MM: Creatine kinase (skeletal muscle) CNS: Central nervous system CPK: Creatine phosphokinase CRF: Case Report Form CSF: cerebrospinal fluid CSR: Clinical Research Report C-SSRS: Columbia-Suicide Severity Rating Scale CYP: Cytochrome P450 DMC: Data Monitoring Committee DMT: disease modifying therapy DNA: deoxyribonucleic acid DTP: Direct to Patient ECG: electrocardiogram, electrocardiography eCRF: Electronic Case Report Form EDSS: Expanded Disability Status Scale eGFR: estimated glomerular filtration rate EOS: Research completed EOT: End of Treatment FSH: Follicle-stimulating hormone GCIPL: Ganglion cell-inner plexiform layer GCP: Good Clinical Practice Gd: Gadolinium HIV: Human Immunodeficiency Virus HR: Hazard ratio HRT: Hormone Replacement Therapy IB: Handbook for Researchers ICF: Informed Consent ICH: International Council for Harmonization IEC: Independent Ethics Committee Ig: immunoglobulin IL: interleukin IMP: Drugs for clinical trials INR: International Normalized Ratio IRB: Institutional Review Board ITT: intention to treat IUD: intrauterine device IUS: intrauterine hormone-releasing system IV: Intravenous IVIG: intravenous immunoglobulin JCV: JC virus KM: Kaplan-Meyer LFT: Liver function test LLN: Lower limit of normal MedDRA: Medical Dictionary for Regulatory Activities MOG: Myelin oligodendrocyte glycoprotein MOGAD: Myelin oligodendrocyte glycoprotein antibody-associated disease MRI: Magnetic resonance imaging MS: Multiple Sclerosis NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NfL: neurofilament light chain NIMP: Non-clinical medicine NMO: Neuromyelitis optica NSAID: Nonsteroidal anti-inflammatory drugs NYHA: New York Heart Association OCT: Optical computed tomography ON: Optic neuritis PBPK: Physiologically Based Pharmacokinetics PD: Pharmacodynamics PK: Pharmacokinetics (various) PML: Progressive multifocal leukoencephalopathy PP: Follow the protocol PT: prothrombin time QTcF: QT interval corrected using Fridericia's formula RMS: Relapsing multiple sclerosis RNFL: Retinal nerve fiber layer SAE: Serious Adverse Event SAP: Statistical Analysis Program SoA: Schedule of Activities SUSAR: Suspected unexpected serious adverse reaction TB: Tuberculosis TEAE: Treatment-emergent adverse event US:United States WOCBP: Women of childbearing potential

Claims

1. A method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising administering to a subject 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.

2. A method for reducing the frequency of MOGAD relapses in a subject suffering from MOGAD, the method comprising administering to a subject 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.

3. A method for reducing MOG antibody titer in a subject suffering from MOGAD, the method comprising administering to a subject 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.

4. The method of any one of claims 1-3, wherein the subject has at least one symptom of MOGAD prior to treatment.

5. The method of claim 4, wherein the at least one MOGAD symptom is selected from the group consisting of loss of color vision, loss or blurred vision, quadriplegia / paraplegia, and loss of bladder / bowel control.

6. The method of claim 5, wherein the treatment reduces or eliminates at least one symptom of MOGAD.

7. The method of any one of claims 1-6, wherein the subject is relapse-free for about 1 year.

8. The method of any one of claims 1-6, wherein the subject has at least one confirmed relapse within the past 12 months or 2 confirmed relapses within the past 24 months at the time of screening.

9. The method of claim 8, wherein a corticosteroid is administered to the subject who relapses.

10. The method of claim 9, wherein the corticosteroid is methylprednisone.

11. The method of any one of claims 1-10, wherein the BTK inhibitor is administered at a dose of about 5 mg to about 60 mg.

12. The method according to any one of claims 1-11, wherein the dose is 5 mg.

13. The method of any one of claims 1-11, wherein the dose is 15 mg.

14. The method of any one of claims 1-11, wherein the dose is 30 mg.

15. The method of any one of claims 1-11, wherein the dose is 60 mg.

16. The method of any one of claims 1-15, wherein the dosage is once daily.

17. The method of any one of claims 1-16, wherein the dose is administered once daily with food.

18. The method of any one of claims 1-11 and 15-17, wherein the dose is 60 mg and is administered once daily with food.

19. The method of any one of claims 1-8 and 11-18, wherein the BTK inhibitor compound is administered as a monotherapy.

20. The method of any one of claims 1-19, wherein MOGAD is selected from acquired demyelinating syndrome (ADS).

21. The method of claim 20, wherein the ADS is acute disseminated encephalomyelitis (ADEM).

22. The method of any one of claims 1-21, wherein the subject is a human.

23. The method of claim 22, wherein the subject is a human subject ranging in age from 12 to 55 years old.

24. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one according to any one of claims 1 and 4-32 for use in a method of treating MOGAD in a subject in need thereof.

25. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one according to any one of claims 2 and 4-23 for use in a method of reducing the frequency of MOGAD relapses in a subject with MOGAD in need thereof.

26. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one according to any one of claims 3 and 4-23 for use in a method of reducing or eliminating MOG antibody titer in a subject with MOGAD in need thereof.

27. A method for treating MOGAD, the method comprising the steps of: (a) Performing an iron detection panel test in the patient's blood or serum; (b) detecting the level of said iron test panel within the normal range; and (c) 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, wherein the iron panel test measures any one or more of iron level, ferritin level, transferrin saturation level, and total iron binding capacity (TIBC) in the patient's blood or serum, and wherein the normal range for the iron panel test includes one or more of: (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level ≤500 μg / L, (iii) a transferrin saturation level ≤50% for male patients or a transferrin saturation level ≤40% for female patients, and (iv) a TIBC of 240 to 450 μg / dL.

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

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

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

31. A method for treating MOGAD, the method comprising the steps of: (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) ALT levels >8x upper limit of normal (ULN) were detected; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring the patient's ALT level; and (f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

32. A method for treating MOGAD, the method comprising the steps of: (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) detection of ALT levels >5x upper limit of normal (ULN) for a period of at least two weeks; (d) ceasing administration of the compound to the patient; and optionally (e) monitoring the patient's ALT level; and (f) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

33. A method for treating MOGAD, the method comprising the steps of: (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) ALT levels >3x upper limit of normal (ULN) were detected; (d) measuring one or more of the patient's total bilirubin and international normalized ratio (INR); (e) one or more of total bilirubin >2x ULN and INR >1.5 was detected; (f) ceasing administration of the compound to the patient; and optionally (g) monitoring the patient's ALT level; and (h) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

34. A method for treating MOGAD, the method comprising the steps of: (b) 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); (c) measuring the level of alanine aminotransferase (ALT) in the patient; (d) ALT levels >3x upper limit of normal (ULN) were detected; (e) stopping administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally (f) monitoring the patient's ALT level; and (g) when it is determined that the patient's ALT level is < 1.5 x ULN, resuming administration of the therapeutically effective amount of the compound to the patient.

35. The method according to any one of claims 31 to 34, wherein the ALT level in step (b) is determined at least monthly.

36. The method of any one of claims 31 to 34, wherein the ALT level in step (d) is monitored at least weekly.

37. The method according to any one of claims 31 to 34, wherein the ALT level in step (d) is monitored every 2 to 3 days.

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

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

Images