A Bruton tyrosine kinase inhibitor for use in the treatment of myelin oligodendrocyte glycoprotein antibody disease (MOGAD)

Abstract

The present disclosure relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase (BTK) inhibitors, for treating subjects having myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

Description

Technical Field

[0001] The present disclosure relates to therapeutic tyrosine kinase inhibitors for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), particularly Bruton's tyrosine kinase ("BTK") inhibitors.

Background Art

[0002] Myelin oligodendrocyte glycoprotein (MOG) is a highly conserved protein that is exclusively expressed in oligodendrocytes of the central nervous system (CNS). MOG is located on the surface of the myelin sheath of the CNS (Fan et al. Mult Scler Relat Disord. 2018, 20, 144 - 152; Kezuka et al. Jpn J Ophthalmol. 2018, 62, 101 - 108). There are multiple isoforms of MOG that have the same extracellular immunoglobulin (Ig) domain but differentially spliced intracellular C - termini. The difference in the C - terminal amino acids is the basis for distinguishing the α or β isoforms of MOG. The function of MOG is not precisely known, but it is a target of the immune system in MOGAD (dos Passos et al. Front. Neurol. 2018, 9, 217). MOG - IgG antibodies (MOG - IgG) have been extensively studied over the past 20 years in various acquired demyelinating syndromes (ADS). The development and use of highly specific cell - based assays have enabled the explanation of a variety of clinical disease symptoms ranging from specific ADS, such as acute disseminated encephalomyelitis (ADEM) mainly in children or encephalitis with onset from optic neuritis mainly in adults. This broad range of clinical phenotypes associated with MOG - IgG has evolved into a new inflammatory CNS disease entity distinct from both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).

[0003] Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a recently characterized neurological disorder that preferentially causes inflammation in the optic nerve but can also cause inflammation in the spinal cord and brain. Diagnosis is confirmed when MOG antibodies in the blood are found in patients who have had repeated inflammatory attacks of the central nervous system (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 it causes, including damage to the brain, spinal cord, and optic nerve. Patients with persistently positive antibodies are at risk of recurrent events. Those with MOGAD do not test positive for the NMO antibody called aquaporin 4 (AQP-4). MOGAD and AQP-4 positive NMOSD are thought to have different immunological mechanisms. Furthermore, MOGAD patients appear to have a lower likelihood of having other autoimmune disorders (such as rheumatoid arthritis, Hashimoto's thyroiditis, etc.) than AQP-4 positive NMOSD patients.

[0004] Currently, about 4,000 patients are diagnosed each year in the United States and the EU, but MOGAD is thought to be underdiagnosed by about 10%, i.e., it is estimated to be spreading at about 40,000 people / year in the US / EU.

[0005] MOGAD itself presents symptoms including loss of color vision, loss of vision or blurriness, paralysis / paresis of the limbs, and loss of bladder / bowel control. This condition presents many unmet needs, including that MOGAD patients are often misdiagnosed and treatment is difficult. Currently, there are no therapeutics specifically approved or developed for MOGAD, and as a result, current standard treatment is intravenous administration of immunosuppressants such as methylprednisolone or oral prednisone. Thus, there is an unmet need for effective therapeutics for MOGAD.

[0006] The Bruton's tyrosine kinase (BTK) pathway is important for signal transduction in myeloid cells, including B lymphocytes and CNS microglia. Each of these cell types is involved in the pathophysiology of multiple sclerosis (MS). Furthermore, since BTK signaling is essential for the maturation of B cells into antibody-secreting plasma cells, BTK inhibition can regulate both cellular and humoral immunity. Thus, compounds that inhibit BTK, which can inhibit antigen-induced B cell activation involved in neuroinflammation and regulate maladaptive microglial cells associated with neuroinflammation in the brain and spinal cord, may be useful for the treatment of MOGAD and have excellent advantages compared to the few available treatments currently available. BTK inhibitors can modify the progression of MOGAD disease through two different mechanisms: 1) regulation of B cell-mediated autoinflammatory processes and 2) inhibition of Fc receptor-mediated microglial inflammatory demyelination.

[0007] Drug-induced liver injury has been identified in the ongoing phase 3 trial of trebrutinib. The reported events occurred between 2 and 3 months after the start of trebrutinib administration, and the elevation of liver enzymes appears to be reversible after interruption of trebrutinib. Therefore, it is necessary to reduce the risk of liver injury and provide a safe treatment for MOGAD patients.

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure relates to a method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), 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.

[0009] The present disclosure also relates to a method of reducing the frequency of MOGAD recurrence in a subject having 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 disclosure further relates to a method of reducing MOG antibody titers in a subject having 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 loss of color vision, loss or blurring of vision, paralysis / paresis of the limbs, 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 recurrence-free for about one year.

[0015] In some embodiments, the subject has had at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening.

[0016] In some embodiments, a recurrent subject is administered a corticosteroid.

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

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

[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 dose 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, MOGAD is selected from acquired demyelinating syndromes (ADS).

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

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

[0030] In some embodiments, the subject is a human subject in the range of 12 to 55 years of age.

[0031] The present disclosure also relates to a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one for use in a method of treating MOGAD in a subject in need of treatment for MOGAD.

[0032] The present disclosure 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 relapse in a subject having MOGAD in need of reducing the frequency of MOGAD relapse.

[0033] The present disclosure 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 having MOGAD in need of reducing or eliminating MOG antibody titer.

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

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

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

[0037] The present disclosure also relates to a method for treating MOGAD, comprising: (a) performing a liver function test in a patient; (b) detecting appropriate liver function in the patient; (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; comprising: The liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. A patient having appropriate liver function has one or more of ALT at 1.5x or less of the upper limit of normal value (ULN), AST at 1.5x or less of the ULN, alkaline phosphatase at 2x or less of the ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders), and total bilirubin at 1.5x or less of the ULN (except in the case of Gilbert's syndrome or non-liver-related disorders).

[0038] The present disclosure also relates to a method for treating MOGAD, comprising: (a) administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 8x the upper limit of normal value (ULN); (d) stopping the administration of the compound to the patient; and optionally, (e) monitoring the ALT level of the patient. When it is determined that the patient's ALT level is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; relates to a method for treating MOGAD, comprising.

[0039] The present disclosure also relates to a method for treating MOGAD, comprising: (a) administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting an ALT level above 5x the upper limit of normal (ULN) during a period of at least two weeks; (d) discontinuing the administration of the compound to the patient, and optionally, (e) monitoring the ALT level of the patient; (f) when it is determined that the patient's ALT level is less than 1.5x the ULN, restarting the administration of a therapeutically effective amount of the compound to the patient; relates to a method for treating MOGAD, comprising.

[0040] The present disclosure also relates to a method for treating MOGAD, comprising: (a) administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting an ALT level above 3x the ULN; (d) measuring one or more of the patient's total bilirubin and international normalized ratio (INR); (e) detecting one or more of a total bilirubin above 2x the ULN and an INR above 1.5; (f) Discontinuing the administration of the compound to the patient, and optionally, (g) Monitoring the ALT level of the patient; (h) Resuming the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN; relates to a method for treating MOGAD comprising.

[0041] The present disclosure also relates to a method for treating MOGAD, comprising: (a) Administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); (b) Measuring the level of alanine aminotransferase (ALT) in the patient; (c) Detecting an ALT level greater than 3x the upper limit of normal (ULN); (d) Discontinuing the administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia greater than 5%, and optionally, (e) Monitoring the ALT level of the patient; (f) Resuming the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN; relates to a method for treating MOGAD comprising.

[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 2-3 days.

[0045] The present disclosure 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 has not received a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 liver enzyme.

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

[0047]

Figure 1A

Figure 1B

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Figure 3

Figure 4A

Figure 4B

Figure 5

Figure 6

Figure 7

Figure 8

[0048] Here, specific embodiments are referred to in detail, and examples thereof are shown in the accompanying drawings. It will be understood that the present disclosure provides exemplary embodiments, but is not intended to limit the invention to those embodiments. On the contrary, the invention is intended to embrace all alternatives, modifications, and equivalents within the scope of the present disclosure as defined by the appended claims.

[0049] The section headings used herein are for organization purposes only and should in no way be construed as limiting the desired subject matter. Any document incorporated by reference shall be subordinate to this specification if it conflicts with any term defined herein. The present teachings are described in conjunction with various embodiments, but the present teachings are not intended to be limited to such embodiments. On the contrary, the present teachings embrace various alternatives, modifications, and equivalents as would be understood by those skilled in the art.

[0050] I. Definitions Unless otherwise specified, the following terms used in this specification and the claims are defined for the purposes of this disclosure and have the following meanings.

[0051] As used herein, "BTK inhibitor", "BTK inhibitor compound", and "the compound" refer to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one having the following structure:

Chemical formula

Chemical formula

[0052] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing a pharmaceutical composition, including carriers or excipients acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in this specification and the claims includes both one and two or more such excipients.

[0053] "Treating" or "treatment" of a disease includes the following. (1) Inhibiting the disease, e.g., stopping or reducing the onset of the disease or its clinical symptoms; or (2) Alleviating the disease, e.g., causing regression of the disease or its clinical symptoms.

[0054] "Optional" or "optionally" means that the subsequently described event or situation may or may not occur, and that its description includes both the case where the event or situation occurs and the case where it does not occur.

[0055] "Therapeutically effective amount" means an amount of a BTK inhibitor compound sufficient to affect such treatment of a disease when administered to a mammal for treating the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal being treated.

[0056] "Relapse of MOGAD" is defined as the acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms accompanied by objective changes in neurological examinations.

[0057] "Expanded Disability Status Scale (EDSS) score" is a method for quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments, with higher increments representing higher levels of disability. EDSS steps 1.0 through 4.5 refer to people with MS who can walk without assistance and have a measurement of disability in eight functional systems (FS). Pyramidal - limb muscle weakness or difficulty moving; cerebellar ataxia, loss of balance, coordination or tremor; brainstem - problems with speech, swallowing and nystagmus; sensory - numbness or loss of sensation; bowel and bladder function; visual function - problems with vision; brain function - problems with thinking and memory. EDSS steps 5.0 through 9.5 are defined by walking impairment. See, for example, FIG. 7. Information on this score can be found in Kurtzke et al. Neurology 1983, 33, 1444 - 1452.

[0058] "Serum aquaporin-4 antibody titer negative" means a subject tested negative for aquaporin-4 receptor antibodies in the serum, which is used for the diagnosis and evaluation of neuromyelitis optica, acute myelitis, spinal cord lesions, autoimmune encephalitis, or neuromyelitis spectrum (NMO) disorders. "Aquaporin-4 receptor antibody" is a highly specific serum marker for neuromyelitis optica that can facilitate the differential diagnosis of the above-mentioned diseases. If a patient tests positive for aquaporin-4 receptor antibodies in their serum, that patient has NMO rather than MOGAD.

[0059] Before explaining the present teachings in detail, it should be understood that the present disclosure is not limited to a particular composition or process step and may vary.

[0060] Also, as used in this specification and the appended claims, unless the context clearly dictates otherwise, singular forms such as "a", "an", and "the" include plural referents. Thus, for example, a reference to "a complex" includes a plurality of complexes, a reference to "a cell" includes a plurality of cells, and the like.

[0061] Numeric ranges include the numbers defining the range. Measured values and measurable values are understood to be approximate, taking into account significant figures and errors associated with the measurement. Also, the use of "comprise", "comprises", "comprising", "contain", "contains", "containing", "include", "includes", and "including" is not intended to be limiting. It should be understood that both the foregoing general description and the detailed description are exemplary and explanatory only and not restrictive of the teachings.

[0062] Unless otherwise specified in the above specification, embodiments in this specification that enumerate various components as "including" also contemplate being "consisting of" or "consisting essentially of" the enumerated components; embodiments in this specification that enumerate various components as "consisting of" also contemplate being "including" or "consisting essentially of" the enumerated components; embodiments in this specification that enumerate various components as "consisting essentially of" also contemplate being "consisting of" or "including" the enumerated components (this interchangeability does not apply to the use of such terms in claims).

[0063] As used herein, the terms "or combinations thereof" and "or combinations thereof" refer to any and all substitutions and combinations of the terms listed prior to such terms. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, where order is important in a particular situation, also BA, CA, CB, ACB, CBA, BCA, BAC, or CAB. Continuing with this example, combinations including repetitions of one or more items or terms such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. are explicitly included. One of ordinary skill in the art will understand that, unless otherwise apparent from the context, there is typically no limit to the number of items or terms in any combination.

[0064] "Or" is used in an inclusive sense, i.e., equivalent to "and / or", unless the context requires otherwise.

[0065] When used in connection with the administration of a BTK inhibitor compound, "discontinuing" or "discontinuation" means that the BTK inhibitor compound is no longer being administered to the patient, either temporarily or permanently.

[0066] "Monitoring" with respect to the evaluation of a patient's ALT level means confirming and / or detecting the patient's ALT level over at least two time points, in some embodiments, over a period of time, in some embodiments, monthly, in some embodiments, at least monthly, in some embodiments, weekly, in some embodiments, at least once a week, in some embodiments, every five days, in some embodiments, every three days, in some embodiments, every two to three days, in some embodiments, every two days, in some embodiments, daily.

[0067] II. Administered BTK Inhibitor Compound In some embodiments, the BTK inhibitor compound (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered to treat 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 dose of 5 to 60 mg of the BTK inhibitor compound is administered. In some embodiments, a dose of 60 mg of the BTK inhibitor compound is administered. In some embodiments, a dose of 60 mg of the BTK inhibitor compound is administered once daily.

[0068] In some embodiments, a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is provided for use in a method of treating MOGAD in a subject in need of treatment for MOGAD.

[0069] 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 for reducing the frequency of MOGAD recurrence in a subject having MOGAD who requires a reduction in the frequency of MOGAD recurrence.

[0070] 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 the MOG antibody titer in a subject having MOGAD who requires a reduction in the MOG antibody titer.

[0071] The BTK inhibitor compound can be prepared, for example, according to the methods and schemes described in U.S. Patent No. 9,688,676B2, particularly in accordance with the content from column 62, line 8 to column 65, line 32 and column 67, line 28 to column 69, which is incorporated herein by reference.

[0072] To enable those skilled in the art to prepare the BTK inhibitor compound, the preparation of the following compound of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is provided. The synthetic route should not be regarded as limiting the scope of the present disclosure, but rather as merely illustrative and representative thereof.

[0073] Exemplary synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one:

Chemical formula

[0074] III. Treatment method A method for treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), comprising administering to a subject in need thereof a therapeutically effective amount of a BTK inhibitor compound 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 is provided herein.

[0075] In some embodiments, the subject has at least one symptom of MOGAD before or during treatment. In some embodiments, the at least one MOGAD symptom is selected from loss of color vision, loss or blurring of vision, paralysis / paresis of the extremities, and loss of bladder / bowel control. In some embodiments, the treatment reduces or eliminates at least one symptom. In some embodiments, the reduction or elimination of at least one symptom occurs after daily treatment for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or after 6 months, 1 year, 1.5 years, or 2 years.

[0076] In some embodiments, the subject is recurrence-free for about 1 year. In some embodiments, the subject had at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening. In some embodiments, subjects who have had a recurrence are administered corticosteroids. In some embodiments, the corticosteroid is methylprednisolone.

[0077] In some embodiments, after about 1 year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) decreases. In some embodiments, after about 1 year of treatment, the EDSS score is the same as or decreased from baseline. In some embodiments, the subject has an EDSS score greater than 7.0 before treatment. In some embodiments, the subject has a negative serum aquaporin-4 antibody titer based on a cell-based assay. In some embodiments, the subject has a documented history of at least two confirmed MOGAD attacks.

[0078] In some embodiments, the therapeutically effective amount is from 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.

[0079] In some embodiments, the dosage is once daily. In some embodiments, the dosage is administered once daily with food. In some embodiments, the dosage is 60 mg and is administered once daily with food. In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0080] In some embodiments, MOGAD is selected from acquired demyelinating syndromes (ADS). In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0081] 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 old.

[0082] Also provided herein is a method of reducing the frequency of MOGAD relapse in a subject having 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.

[0083] In some embodiments, the subject has at least one symptom of MOGAD prior to treatment. In some embodiments, the at least one MOGAD symptom is selected from loss of color vision, loss or blurring of vision, paralysis / paresis of the extremities, and loss of bladder / bowel control. In some embodiments, the subject has at least one symptom of MOGAD prior to treatment and the treatment reduces or eliminates one or more symptoms.

[0084] In some embodiments, the subject is recurrence-free for about one year. In some embodiments, the subject has had at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening. In some embodiments, the subject has a recurrence and corticosteroids are administered. In some embodiments, the corticosteroid is methylprednisolone.

[0085] In some embodiments, after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) decreases. In some embodiments, after about one year of treatment, the EDSS score is the same as the baseline or has decreased from the baseline. In some embodiments, the subject has an EDSS score greater than 7.0 prior to treatment. In some embodiments, the subject has an EDSS score that is normalized without increasing after treatment. In some embodiments, the subject has an EDSS score that decreases to 9.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 9.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 8.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 8.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 7.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 7.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 6.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 6.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 5.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 5.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 4.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 4.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 3.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 3.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 2.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 2.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 1.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 1.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 0.5 or less after treatment.In some embodiments, the subject has a negative serum aquaporin-4 antibody titer based on a cell-based assay. In some embodiments, the subject has a documented medical history of at least two confirmed MOG antibody disease attacks. In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0086] In some embodiments, MOGAD is selected from acquired demyelinating syndromes (ADS). In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0087] In some embodiments, the therapeutically effective amount is from 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 old.

[0088] Also provided herein is a method of reducing or eliminating MOG antibody titers in a subject having 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.

[0089] In some embodiments, the subject has at least one symptom of MOGAD prior to treatment. In some embodiments, the at least one MOGAD symptom is selected from loss of color vision, loss of or blurring of vision, paralysis / paresis of the limbs, and loss of bladder / bowel control. In some embodiments, the subject has at least one symptom of MOGAD prior to treatment and the treatment reduces or eliminates one or more symptoms.

[0090] In some embodiments, the subject is recurrence-free for about 1 year. In some embodiments, the subject has had at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening. In some embodiments, the subject has a recurrence and corticosteroids are administered. In some embodiments, the corticosteroid is methylprednisolone.

[0091] In some embodiments, after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) decreases. In some embodiments, the EDSS score is the same as the baseline or decreases from the baseline after about one year of treatment. In some embodiments, the subject has an EDSS score greater than 7.0 prior to treatment. In some embodiments, the subject has an EDSS score that is normalized without increasing after treatment. In some embodiments, the subject has an EDSS score that decreases to 9.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 9.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 8.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 8.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 7.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 7.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 6.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 6.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 5.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 5.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 4.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 4.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 3.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 3.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 2.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 2.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 1.5 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 1.0 or less after treatment. In some embodiments, the subject has an EDSS score that decreases to 0.5 or less after treatment.In some embodiments, the subject has a negative serum aquaporin-4 antibody titer based on a cell-based assay. In some embodiments, the subject has a documented medical history of at least two confirmed MOG antibody disease attacks. In some embodiments, the BTK inhibitor compound is administered as monotherapy.

[0092] In some embodiments, MOGAD is selected from acquired demyelinating syndromes (ADS). In some embodiments, the ADS is acute disseminated encephalomyelitis (ADEM).

[0093] In some embodiments, the therapeutically effective amount is from 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 old. 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 old.

[0094] 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 relapse 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 the frequency of MOGAD relapse, and the treatment alleviates 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 relapse in a subject suffering from loss of color vision, loss of vision or blurring, paralysis / paresis of the extremities, 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 reduce the frequency of MOGAD relapse in a subject who has not relapsed for about one 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 relapse in a subject having at least one confirmed relapse in the past 12 months or two confirmed relapses in the past 24 months in 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 relapse in a subject receiving corticosteroid administration.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 relapse in a subject to whom methylprednisolone is administered. 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 relapse, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) decreases. 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 relapse, and about one year after treatment, the EDSS score is the same as or decreased from the 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 relapse, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale score (EDSS) decreases for subjects having an EDSS score greater than 7.0 before 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 relapse, and after about one year of treatment, the EDSS score is the same as or decreased from the baseline for subjects having an EDSS score greater than 7.0 before 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 relapse in a subject having a negative serum aquaporin-4 antibody titer based on 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 relapse in a subject having a documented medical history of at least two confirmed MOG antibody disease attacks.

[0095] 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 a subject suffering from loss of color vision, loss of vision or blurring, paralysis / paresis of the extremities, 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 reduce or eliminate MOG antibody titers in a subject who has not relapsed for about one 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 a subject having at least one confirmed relapse in the past 12 months or two confirmed relapses in the past 24 months in 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 the MOG antibody titer in a subject to whom corticosteroid is administered. 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 the MOG antibody titer in a subject to whom methylprednisolone is administered. 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 the MOG antibody titer, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale (EDSS) score decreases. 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 the MOG antibody titer, and about one year after treatment, the EDSS score is the same as or decreased from the 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 the MOG antibody titer, wherein after about one year of treatment, the rate of increase in the Expanded Disability Status Scale (EDSS) score decreases for subjects having an EDSS score greater than 7.0 before 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 after about one year of treatment, the EDSS score is the same as the baseline or decreased from the baseline for a subject having 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 reduce or eliminate MOG antibody titers in a subject having a negative serum aquaporin-4 antibody titer based on 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 a subject having a documented medical history of at least two confirmed MOG antibody disease attacks.

[0096] 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 having 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 having 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 in the range of 12 to 55 years old having 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 in the range of 12 to 55 years old having MOGAD and one or more symptoms of MOGAD before 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 in the range of 12 to 55 years old having MOGAD who suffers from loss of color vision, loss of vision or blurring, paralysis / paresis of the limbs, 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 in the range of 12 to 55 years old having MOGAD and having an EDSS score greater than 7.0 before 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 in the range of 12 to 55 years old with MOGAD having a negative serum aquaporin-4 antibody titer based on 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 in the range of 12 to 55 years old with MOGAD having a documented medical history of at least two confirmed MOG antibody disease attacks.

[0097] 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 that does not relapse for about one 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 having MOGAD in the range of 12 to 55 years old that does not relapse for about one 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 having MOGAD in the range of 12 to 55 years old that does not relapse for about one year 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 having MOGAD in the range of 12 to 55 years old that does not relapse for about one year and is suffering from loss of color vision, loss of vision or blurring, paralysis / paresis of the extremities, 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 having MOGAD in the range of 12 to 55 years old that does not relapse for about one year and has 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 having MOGAD in the range of 12 to 55 years old that does not relapse for about one year and has a negative serum aquaporin-4 antibody titer based on 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 having MOGAD in the range of 12 to 55 years old who has not relapsed for about one year and has a documented medical history of at least two confirmed MOG antibody disease attacks.

[0098] 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 in a screening to a subject having MOGAD with at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months. 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 having MOGAD in the range of 12 to 55 years old, having at least one confirmed recurrence in the past 12 months or two confirmed recurrences 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 having MOGAD in the range of 12 to 55 years old, having at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening and 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 a human subject having MOGAD in the range of 12 to 55 years old, having at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening and suffering from loss of color vision, loss of vision or blurring, paralysis / paresis of the extremities, 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 having MOGAD in the range of 12 to 55 years old, having at least one confirmed recurrence in the previous 12 months or two confirmed recurrences in the previous 24 months at screening, and having 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 having MOGAD in the range of 12 to 55 years old, having at least one confirmed recurrence in the previous 12 months or two confirmed recurrences in the previous 24 months at screening, and having a negative serum aquaporin-4 antibody titer based on 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 having MOGAD in the range of 12 to 55 years old, having at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at screening, and having a documented history of at least two confirmed MOG antibody disease attacks.

[0099] In some embodiments, the BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as a monotherapy. In some embodiments, the BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as a monotherapy at a dose of 60 mg. In some embodiments, the BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered once daily at a dose of 60 mg as a monotherapy. In some embodiments, the BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered once daily at a dose of 60 mg with food as a monotherapy.

[0100] In some embodiments, doses of about 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg or 55-60 mg are administered. In some embodiments, the dose is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg or 60 mg. In some embodiments, the dose is 5 mg. In some embodiments, the dose is 15 mg. In some embodiments, the dose is 30 mg. In some embodiments, the dose is 60 mg.

[0101] In some embodiments, the dosage is administered daily. The daily dosage can be delivered as a single dose or divided into multiple portions. For example, in some embodiments, the dosage is administered once a day (e.g., every about 24 hours). In some embodiments, the dosage is administered twice a day by subdividing the dosage into two portions that are to be administered twice a day (e.g., every about 12 hours). In some embodiments, the dosage is subdivided into three portions that are administered three times a day (e.g., every about 8 hours). In some embodiments, the dosage is subdivided into four portions that are administered four times a day (e.g., every about 6 hours).

[0102] In some embodiments, the dosage is administered orally. In some embodiments, the dosage is administered in the form of a tablet. In some embodiments, the dosage is administered in the form of a pill, capsule, semi-solid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0103] In some embodiments, the subject is administered a BTK inhibitor compound for a period of about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, or for life. In some embodiments, the subject is administered a BTK inhibitor compound for a period of about 12 months. In some embodiments, the dosage is once a day. In one embodiment, provided is a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprising administering to a subject in need thereof 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.

[0104] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) 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 is provided. In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) 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 daily for at least about 12 months is provided. In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprising administering to a subject in need thereof a daily dose of from 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 is provided. In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprising administering to a subject in need thereof a daily dose of from 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 is provided.

[0105] In some embodiments, the BTK inhibitor compound is administered as monotherapy. In some embodiments, the method comprises administering the BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent may be administered concurrently or sequentially with the BTK inhibitor compound.

[0106] The determination of the dosing frequency can be made by a person skilled in the art, such as a attending physician, taking into account the condition being treated, the age of the subject being treated, the severity of the condition being treated, the general health of the subject being treated, and the like. In some embodiments, the BTK inhibitor compound is administered in a therapeutically effective amount for the treatment of RMS. The therapeutically effective amount typically depends on the weight of the subject being treated, the physical or health condition of that person, the extensiveness of the condition being treated, or the age of the subject being treated, the pharmaceutical formulation method, or the method of administration (e.g., administration time and route of administration).

[0107] In some embodiments, there is provided a method of treating MOGAD, 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 or a pharmaceutically acceptable salt thereof in 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.

[0108] IV. Treatment methods for reducing the risk of liver injury In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprises performing an iron panel test using a patient's blood or serum, and, if the patient has an appropriate iron panel, 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 levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, an appropriate iron panel comprises one or more of the following: (i) an iron concentration of 60 μg / dL to 170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240 μg / dL to 450 μg / dL.

[0109] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprises performing an iron panel test with a patient's blood or serum, detecting levels 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 levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range of the iron panel test comprises one or more of (i) an iron level of 60 to 170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240 to 450 μg / dL.

[0110] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising performing an iron panel test on a patient's blood or serum, detecting levels of the iron panel test within a normal range, and administering to the patient a therapeutically acceptable amount of the compound. In some embodiments, the iron panel test measures any one or more of the levels of iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) in the patient's blood or serum. In some embodiments, the normal range of the iron panel test includes one or more of (i) an iron level of 60-170 μg / dL, (ii) a ferritin level of 500 μg / L or less, (iii) a transferrin saturation level of 50% or less in male patients or 40% or less in female patients, and (iv) a TIBC of 240-450 μg / dL.

[0111] In some embodiments, there is provided a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising determining the transferrin saturation level in the patient's blood or serum and, when 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, an appropriate transferrin saturation level in the blood or serum of a male patient is a transferrin saturation of 50% or less. In some embodiments, an appropriate transferrin saturation level in the blood or serum of a female patient is a transferrin saturation of 40% or less.

[0112] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, comprising detecting the transferrin saturation level in a patient's blood or serum within the normal range, 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 the normal range in the blood or serum of a male patient is 50% or less transferrin saturation. In some embodiments, the transferrin saturation level within the normal range in the blood or serum of a female patient is 40% or less transferrin saturation.

[0113] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (the compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), comprising detecting the transferrin saturation level in a patient's blood or serum within the normal range, and administering to the patient a therapeutically effective amount of the compound. In some embodiments, the transferrin saturation level within the normal range in the blood or serum of a male patient is 50% or less transferrin saturation. In some embodiments, the transferrin saturation level within the normal range in the blood or serum of a female patient is 40% or less transferrin saturation.

[0114] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprises determining the level of ferritin in a patient's blood or serum, and, if the level of ferritin 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, an appropriate ferritin level in the patient's blood or serum is 500 μg / L or less.

[0115] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprises detecting the level of ferritin in a patient's blood or serum within the 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, a ferritin level within the normal range in the patient's blood or serum is 500 μg / L or less.

[0116] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprising detecting the level of ferritin in a patient's blood or serum within the normal range, and administering to the patient a therapeutically acceptable amount of the compound. In some embodiments, a ferritin level within the normal range in the patient's blood or serum is 500 μg / L or less.

[0117] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprising the steps of performing a liver function test in a patient and, if the patient has appropriate 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 is provided. In some embodiments, the liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. In some embodiments, a patient having appropriate liver function has one or more of an ALT level of 1.5 times or less the upper limit of normal (ULN), an AST level of 1.5x or less the ULN, an alkaline phosphatase of 2x or less the ULN (except when caused by non-liver related disorders or when explained by stable chronic liver disorders), and a total bilirubin of 1.5x or less the ULN (except when due to Gilbert's syndrome or non-liver related disorders).

[0118] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, the method comprising: 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 transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. In some embodiments, a patient having appropriate liver function has one or more of an ALT level of 1.5 times or less the upper limit of normal (ULN), an AST level of 1.5x or less the ULN, an alkaline phosphatase of 2x or less the ULN (except when caused by a non-liver-related disorder or explained by a stable chronic liver disorder), and a total bilirubin of 1.5x or less the ULN (except in the case of Gilbert's syndrome or a non-liver-related disorder).

[0119] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound) for use in a method of treating 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 to the patient a therapeutically acceptable amount of the compound. In some embodiments, the liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood. In some embodiments, a patient having appropriate liver function has one or more of an ALT level of 1.5 times or less the upper limit of normal (ULN), an AST level of 1.5x or less the ULN, an alkaline phosphatase of 2x or less the ULN (except when caused by a non-liver related disorder or explained by stable chronic liver disease), and a total bilirubin of 1.5x or less the ULN (except when due to Gilbert's syndrome or a non-liver related disorder).

[0120] In some embodiments, the liver function test is performed at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about monthly. In some embodiments, the liver function test is performed at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about weekly.

[0121] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), comprising a) Administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; b) Measuring the level of alanine aminotransferase (ALT) in the patient; c) Detecting an ALT level that exceeds 8x the upper limit of normal (ULN); d) Discontinuing the administration of the compound to the patient, and optionally, e) Monitoring the ALT level of the patient; f) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN; A method for treating MOGAD is provided, which comprises the above steps.

[0122] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and the method comprises: a) Administering a therapeutically effective amount of the compound to a patient in need thereof; b) Measuring the level of alanine aminotransferase (ALT) in the patient; c) Detecting an ALT level that exceeds 8x the upper limit of normal (ULN); d) Discontinuing the administration of the compound to the patient, and optionally, e) Monitoring the ALT level of the patient; f) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN; A method for treating MOGAD is provided, which comprises the above steps.

[0123] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), comprising: a) administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting, during a period of at least two weeks, an ALT level that exceeds 5x the upper limit of normal (ULN); d) discontinuing the administration of the compound to the patient; and optionally, e) monitoring the ALT level of the patient; f) restarting the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x ULN. A method of treating MOGAD is provided.

[0124] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising: a) administering a therapeutically effective amount of the compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting, during a period of at least two weeks, an ALT level that exceeds 5x the upper limit of normal (ULN); d) discontinuing the administration of the compound to the patient; and optionally, e) monitoring the ALT level of the patient; f) restarting the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x ULN. A method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is provided, which comprises

[0125] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) comprises a) administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting an ALT level greater than 3 times the upper limit of normal (ULN); d) measuring one or more of total bilirubin and international normalized ratio (INR) in the patient; e) detecting one or more of total bilirubin greater than 2 times the ULN and INR greater than 1.5; f) stopping the administration of the compound to the patient, and optionally g) monitoring the ALT level of the patient; h) resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5 times the ULN. A method of treating MOGAD is provided, which comprises

[0126] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising a) administering a therapeutically effective amount of the compound to a patient in need thereof; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting an ALT level greater than 3 times the upper limit of normal (ULN); d) measuring one or more of the patient's total bilirubin and international normalized ratio (INR); e) detecting one or more of a total bilirubin more than 2x the ULN and an INR more than 1.5; f) stopping the administration of the compound to the patient, and optionally, g) monitoring the patient's ALT level; h) restarting the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN; A method of treating MOGAD is provided, which includes the above steps.

[0127] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) includes: a) administering to a patient in need thereof a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound); b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting an ALT level more than 3x the upper limit of normal (ULN); d) stopping the administration of the compound to the patient if the patient experiences one or more of fatigue greater than 5%, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia, and optionally, e) monitoring the patient's ALT level; f) restarting the administration of a therapeutically effective amount of the compound to the patient if it is determined that the patient's ALT level is less than 1.5x the ULN; A method of treating MOGAD is provided, which includes the above steps.

[0128] In some embodiments, the present disclosure provides a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising: a) administering to a patient in need thereof a therapeutically effective amount of the compound; b) measuring the level of alanine aminotransferase (ALT) in the patient; c) detecting an ALT level that exceeds 3x the upper limit of normal (ULN); d) if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia greater than 5%, discontinuing administration of the compound to the patient, and optionally, e) monitoring the patient's ALT level; f) if the patient's ALT level is determined to be less than 1.5x the ULN, restarting administration of a therapeutically effective amount of the compound to the patient. There is provided a method of treating MOGAD comprising:

[0129] In some embodiments, the patient's ALT level is measured at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about monthly. In some embodiments, the patient's ALT level is measured at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about weekly.

[0130] In some embodiments, after discontinuing administration of the compound, the patient's ALT level is monitored about every 2 - 3 days, about every 3 days, about every 2 days, or about daily.

[0131] In some embodiments, a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD) 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 has not been exposed to a strong and moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 hepatic enzyme is provided. In some embodiments, the strong CYP3A inducer is selected from rifampin, carbamazepine, phenobarbital, St John’s Wort extract, abacimib, lumacaftor, rifapentine, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semagacestat, asunaprevir, beclabuvir, daclatasvir, cenobamate, nafcillin, resinarate, modafinil, bosentan, telotristat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0132] In some embodiments, the present disclosure provides a Bruton's tyrosine kinase (BTK) inhibitor for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound), and comprising administering to a patient a therapeutically acceptable amount of the compound, wherein the patient has not been exposed to a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 hepatic enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampin, carbamazepine, phenobarbital, St John's Wort extract, abacimib, lumacaftor, rifapentine, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semagacestat, asunaprevir, beclabuvir, daclatasvir, cenobamate, nafcillin, resinarate, modafinil, bosentan, telotristat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0133] In some embodiments, provided is a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising advising a 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 intake to one drink or less per day. In some embodiments, one drink is about 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of spirits). In some embodiments, the patient is male and is advised to limit alcohol intake to two drinks or less per day. In some embodiments, two drinks are about 28 grams of alcohol.

[0134] In some embodiments, the present disclosure provides a Bruton's tyrosine kinase (BTK) inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Compound) for use in a method of treating myelin oligodendrocyte glycoprotein antibody disease (MOGAD), the method comprising advising a patient to restrict alcohol consumption during treatment and administering to the patient a therapeutically acceptable amount of the BTK inhibitor. In some embodiments, the patient is female and is advised to restrict alcohol intake to one drink or less per day. In some embodiments, one drink is about 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of spirits). In some embodiments, the patient is male and is advised to restrict alcohol intake to two drinks or less per day. In some embodiments, two drinks are about 28 grams of alcohol.

[0135] The selection of a formulation depends on various factors such as the drug administration mode (for example, for oral administration, a formulation in the form of tablets, pills or capsules is preferred) and the bioavailability of the active ingredient. Recently, pharmaceutical formulations for drugs showing low bioavailability have been particularly developed based on the principle that bioavailability can be increased by increasing the surface area, that is, by reducing the particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 nm to 1,000 nm, wherein the active substance is supported on a polymeric cross-linked matrix. U.S. Patent No. 5,145,684 describes that after pulverizing an active ingredient into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersing it in a liquid medium, a pharmaceutical formulation with significantly high bioavailability is produced. The bioavailability of a drug that decomposes at the pH of the stomach can be increased by administering such a drug in a formulation that releases the drug into the duodenum.

[0136] The composition generally comprises a BTK inhibitor compound or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, such as a binder, surfactant, diluent, buffer, antiadherent, glidant, hydrophilic or hydrophobic polymer, retardant, stabilizer or stabiliser, disintegrant or superdisintegrant, antioxidant, defoamer, filler, flavor, colorant, lubricant, adsorbent, preservative, plasticizer or sweetener, or a mixture thereof, facilitating the processing of the BTK inhibitor compound or a pharmaceutically acceptable salt thereof into a pharmaceutically usable preparation. Any well-known techniques and excipients are suitable and can be used as understood in the art, see, for example, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005); Liberman, H.A., Lachman, L., and Schwartz, J.B. Eds., Pharmaceutical Dosage Forms, Vol. 1-2 Taylor & Francis 1990; and R.I. Mahato, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Second Ed. (Taylor & Francis, 2012).

[0137] In certain embodiments, the formulation may include one or more pH adjusters or buffers, such as acids like acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid and hydrochloric acid; bases like sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride. Such buffers used as bases may have other counterions than sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases and buffers are included in the amounts necessary to maintain the pH of the composition within an acceptable range.

[0138] In certain embodiments, the formulation may also include one or more salts in an amount necessary to bring the weight osmolality of the composition within an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0139] In certain embodiments, the formulation may also include one or more antifoaming agents to reduce foaming during processing, which can lead to coagulation of the aqueous dispersion, air bubbles in the finished film, or generally impair the process. Exemplary antifoaming agents include silicone emulsions or sorbitan sesquioleate.

[0140] In certain embodiments, the formulation may also include one or more antioxidants such as non-thiol antioxidants, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivatives, and tocopherol or its derivatives. In certain embodiments, the antioxidant enhances chemical stability as needed. Other agents such as citric acid or citrate or EDTA can also be added to retard oxidation.

[0141] In certain embodiments, the formulation may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, cetylpyridinium chloride, etc.

[0142] In certain embodiments, the formulation may also include one or more binders. The binder imparts cohesiveness and includes, for example, alginic acid and its salts; carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and cellulose derivatives such as microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrins; amylose; magnesium aluminum silicate; polyuronic acids; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; sugars such as tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose; natural or synthetic gums such as acacia, tragacanth, isapol husk galactogum mucilage, polyvinylpyrrolidone (e.g., polyvidone® CL, kollidon® CL, polyplasdone® XL-10), triticum aestivum, Veegum®, polyethylene glycol, polyethylene oxide, waxes, sodium alginate, etc.

[0143] In certain embodiments, the formulation may also include a dispersant or a viscosity modifier. Dispersants or viscosity modifiers include materials that control the diffusion and uniformity of the drug by the liquid medium or the granulation or blending method. In some embodiments, these agents also enhance the effectiveness of the coating or erosion matrix. Exemplary diffusion promoters / dispersants include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially available as Plasdone®), and carbohydrate-based dispersants such as hydroxypropylcellulose (e.g., HPC, H-PC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMCK100, RPMCK4M, HPMCK15M, and HPMCK100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), amorphous cellulose, polyethylene oxide, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer having ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®).F10 (registered trademark) 8, which is a block copolymer of ethylene oxide and propylene oxide; and poloxamine (for example, Tetronic 908 (registered trademark), also known as Poloxamine 908 (registered trademark), is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol, for example, 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-80, sodium alginate, gums, such as tragacanth gum and acacia gum, guar gum, xanthan gum including xanthan, saccharides, celluloses, such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginate, chitosan and combinations thereof. Plasticizers such as cellulose or triethylcellulose can also be used as dispersants. Dispersants particularly useful in liposome dispersions and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol and isopropyl myristate. Generally, a binder level of about 10 to about 70% is used in powder-filled gelatin capsule formulations. The level of binder used in tablet formulations varies depending on any of direct compression, wet granulation, roller compression, or the use of other excipients such as fillers that can act as moderate binders themselves. One of ordinary skill in the art can determine the binder level of the formulation, but a binder usage level of up to 90%, more typically up to 70%, is common in tablet formulations.

[0144] In certain embodiments, the formulation may also include one or more diluents that refer to chemical compounds used to dilute the compound of interest prior to delivery. The diluents can also be used to stabilize the compounds, since they can provide a more stable environment (and can also provide pH control or maintenance). Salts dissolved in buffer solutions, including but not limited to phosphate buffered saline, are utilized as diluents in the art. In certain embodiments, the diluent increases the bulk of the composition to facilitate compression or creates sufficient bulk for a homogeneous blend for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, dibasic calcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); hydroxypropyl-methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectionery; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrate; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0145] In certain embodiments, the formulation may also include one or more disintegrants that include both dissolution and dispersion of the dosage form when contacted with gastrointestinal fluids. The disintegrant or disintegrants facilitate the disintegration or breakup of the substance. Examples of disintegrants include starches such as natural starches like corn starch or potato starch, pregelatinized starches such as National 1551, or sodium starch glycolates such as Promogel® or Explotab®, celluloses such as wood products, methylcellulose crystalline, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked cellulose sodium carboxymethyl (Ac-Di-Sol®), cross-linked celluloses such as cross-linked carboxymethyl cellulose or cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginates such as alginic acid or sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), agar, guar, locust bean, karaya, pectin, tragacanth, gums such as sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.

[0146] In certain embodiments, the formulation may also include erosion promoters. Erosion promoters include materials that control the erosion of certain materials in gastrointestinal fluids. Erosion promoters are generally known to those of ordinary skill in the art. Exemplary erosion promoters include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0147] In certain embodiments, the formulation may also include one or more fillers including compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0148] In certain embodiments, the formulation may also include one or more flavoring agents or sweeteners, such as acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, babylock cream berry, blackcurrant, 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, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizinate, glycyrrhizic acid (licorice) syrup, grape, grapefruit, honey, isomaltol, lemon, lime, lemon cream, monoammonium glycyrrhizinate, maltol, mannitol, maple, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, xylitol, sucralose, sorbitol, swiss cream, tagatose, tangelo, thaumatin, tutti frutti, vanilla, walnut, watermelon, European cranberry, wintergreen, xylitol, or any combination of these flavor components, such as anisementhol - menthol, cherry anis, cinnamon - orange, cherry - cinnamon, chocolate - mint, honey lemon, lemon - lime, lemon - mint, menthol - eucalyptus, orange - cream, vanilla - mint and mixtures thereof.

[0149] In certain embodiments, the formulation may also include one or more lubricants and flow promoters that are compounds that prevent, reduce, or inhibit the adhesion or friction of materials. 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 their alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG4000) or methoxypolyethylene glycol such as Carbowax®, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid®, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and the like.

[0150] In certain embodiments, the formulation may also include one or more plasticizers that are compounds used to soften enteric or sustained-release coatings to reduce brittleness. Suitable plasticizers include, for example, polyethylene glycol such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethyl citrate, dibutyl sebacate, triethyl cellulose, and triacetin. In some embodiments, the plasticizer can also function as a dispersant or wetting agent.

[0151] In certain embodiments, the formulation may also contain one or more solubilizing agents, such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium deoxycholate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, such as Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200 - 600, glycocholate, transcutol, propylene glycol, dimethyl isosorbide, etc. In one embodiment, the solubilizing agent is vitamin E TPGS or Captisol® or β-hydroxypropyl cyclodextrin.

[0152] In certain embodiments, the formulation may also contain one or more suspending agents, such as polyvinylpyrrolidone, such as polyvinylpyrrolidone K112, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol, such as polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum and gum arabic, xanthan gum, xanthan gum containing xanthan, xanthan gum, sugar, cellulose, etc., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, povidone and other compounds.

[0153] 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, polysorbate, polaxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide such as Pluronic® (BASF), etc. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil as well as polyoxyethylene alkyl ethers and alkyl phenyl ethers such as octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0154] In certain embodiments, the formulation may also include one or more thickeners including, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol alginate, acacia, chitosan, and combinations thereof.

[0155] In certain embodiments, the formulation may also include one or more wetting agents including compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts, etc.

[0156] The pharmaceutical preparations disclosed herein can be obtained by mixing one or more solid excipients such as a carrier, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrant, dispersant, surfactant, lubricant, coloring agent, diluent, solubilizing agent, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or a combination of one or more thereof with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules to obtain tablets after adding appropriate excipients as necessary.

[0157] The pharmaceutical preparations disclosed herein also include gelatin capsules and soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The capsules may also be made of a polymer such as hypromellose. The capsules may contain the active ingredient mixed with a binder such as lactose, starch, or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, lipid, solubilizing agent, or liquid polyethylene glycol. Further, a stabilizer may be added. All preparations for oral administration need to be in a dosage form suitable for such administration.

[0158] These preparations can be manufactured by conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, (6) fusion, or (7) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd ed. (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (e.g., Wurster coating), tangential coating, top spray, tableting, extrusion, extrusion / spheronization, etc.

[0159] It should be recognized that there is a significant overlap among the excipients used in the solid dosage forms described herein. Accordingly, the additives listed above should be construed as merely illustrative of the types of excipients that can be included in the solid dosage forms described herein, and not as limiting. The types and amounts of such excipients can be readily determined by one of ordinary skill in the art in accordance with the particular desired properties.

[0160] In some embodiments, the solid dosage forms described herein are enteric-coated oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions described herein that utilize enteric coating to affect the release of the compound in the intestine of the gastrointestinal tract. An “enteric-coated” drug or tablet refers to a drug or tablet coated with a substance that remains intact in the stomach but dissolves and releases the drug when it reaches the intestine (in one embodiment, the small intestine). As used herein, “enteric coating” is a material such as one or more polymeric materials that encapsulate the therapeutic active agent core either as a dosage form or as particles. Typically, a substantial or all of the enteric coating material is dissolved before the therapeutic active agent is released from the dosage form in order to achieve delayed dissolution of the therapeutic active agent core or particles in the small intestine or large intestine. For enteric coatings, see, e.g., Loyd, V. Allen, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005); and P.J. Tarcha, Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991. Methods of applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, U.S. Patent Application Publication No. 2006 / 0045822.

[0161] An enteric-coated dosage form can be a compressed or molded or extruded tablet (coated or uncoated) containing granules, powders, pellets, beads or particles of a BTK inhibitor compound or a pharmaceutically acceptable salt or other excipient thereof, which may or may not be coated itself as long as at least the tablet or the BTK inhibitor compound is coated. An enteric-coated oral dosage form can also be a capsule (coated or uncoated) containing pellets, beads or granules of a BTK inhibitor compound or a pharmaceutically acceptable salt or other excipient thereof, which may or may not be coated itself as long as at least one of them is coated. Some examples of coatings first used as enteric coatings are beeswax and glyceryl monostearate. Beeswax, shellac and cellulose; and cetyl alcohol, mastic, and shellac, and shellac and stearic acid (U.S. Patent No. 2,809,918); polyvinyl acetate and ethyl cellulose (see U.S. Patent No. 3,835,221). More recently, coatings used are neutral copolymers of polymethacrylic acid esters (Eudragit L30D). (F.W. Goodhart et al, Pharm. Tech., p. 64-71, April 1984); copolymers of methacrylic acid and methyl methacrylate ester (Eudragit S), or neutral copolymers of polymethacrylic acid esters containing metal stearates (Mehta et al, U.S. Patent Nos. 4,728,512 and 4,794,001), cellulose acetate succinate, and hypromellose phthalate.

[0162] Any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the intestine. In one embodiment, the delivery can be delivery to the small intestine. In another embodiment, the delivery can be delivery to the duodenum. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers, and their compatible mixtures, and some of their properties include, but are not limited to, the following.

[0163] Shellac: Also called purified lac, it is a purified product obtained from the resin secretion of insects. This coating dissolves in a medium with pH > 7.

[0164] Acrylic polymers: The performance of acrylic polymers (mainly their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include copolymers of methacrylic acid and ammonium methacrylate. The Eudragit series L, S, and RS (manufactured by Rohm Pharma, known as Evonik®) are available solubilized in organic solvents, aqueous dispersions, or dry powders. The RL, NE, and RS of the Eudragit series are insoluble but permeable in the gastrointestinal tract and are mainly used for colon targeting. The Eudragit series L, L-30D, and S are insoluble in the stomach, dissolve in the intestine, and can be selected and formulated to dissolve at pH values greater than 5.5, or as low as greater than 5, or as high as greater than 7.

[0165] Cellulose derivatives: Examples of suitable cellulose derivatives are ethyl cellulose; a reaction mixture of a partial acetic acid ester of cellulose and phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH > 6. Aquateric is an aqueous system and is a spray-dried CAP pseudo-latex having particles < 1 μm. Other components of Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate tritonates (Eastman); methyl cellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, HP-55F are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF) which dissolves at pH 5, AS-MG (MF) which dissolves at pH 5.5, and AS-HG (HF) which dissolves at a higher pH. These polymers are provided as granules or as fine powders for aqueous dispersions.

[0166] Polyvinyl acetate phthalate (PVAP): PVAP dissolves at pH > 5 and is much less permeable to water vapor and gastric juice. A detailed description of the above polymers and their pH-dependent solubility can be found in the article "Enteric coated hard gelatin capsules" by Professor Karl Thoma and Karoline Bechtold at http: / / pop.www.capsugel.com / media / library / enteric-coated-hard-gelatin-capsules.pdf. In some embodiments, the coating can, and usually does, include a plasticizer and optionally other coating excipients such as colorants, talc, or magnesium stearate well known in the art. Suitable plasticizers include triethyl citrate (Citroflex2), triacetin (glyceryl triacetate), acetyltriethyl citrate (CitroflecA2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglyceride, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers usually contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as fluid bed or Urster coater, or spray or pan coating are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired site of local delivery in the intestinal tract.

[0167] In addition to the plasticizer, colorants, surfactants, anti-blocking agents, defoaming agents, lubricants (e.g., carnauba wax or PEG), and other additives may be added to the paint to solubilize or disperse the paint and improve the paint performance and the coated article.

[0168] To promote the dissolution of the enteric coat, a double coat with half the thickness of an enteric polymer (e.g., Eudragit L30D-55) may be applied. The inner enteric coat may have a buffer up to pH 6.0 in the presence of 10% citric acid, followed by a final layer of standard Eudragit L30D-55. Liu and Basit, who applied a two-layer enteric coat that is half the thickness of a typical enteric coat, were able to promote the dissolution of the enteric coating compared to a similar unbuffered coating system applied as a single layer (Liu, F. and Basit, A. Journal of Controlled Release. 147 (2010) 242-245).

[0169] The integrity of the enteric coating can be measured, for example, by the degradation of the drug within the micropellets. Enteric-coated dosage forms or pellets can be tested in dissolution tests first in gastric fluid and separately in intestinal fluid, as described in the USP, to determine their function.

[0170] Enteric-coated tablet and capsule formulations containing the disclosed compounds can be prepared by methods well known in the art. For example, tablets containing the compounds disclosed herein can be enterically coated with a coating solution containing Eudragit®, diethyl phthalate, isopropyl alcohol, talc, and water using a side-vented coating pan (Freund Hi-Coater).

[0171] Alternatively, a multi-unit dosage form containing enteric-coated pellets that can be incorporated into tablets or capsules can be prepared as follows.

[0172] Core material: The core material of the individually enteric-coated layered pellets can be constructed according to different principles. The active agent (i.e., the BTK inhibitor compound or its pharmaceutically acceptable salt) and the layered seeds can optionally be mixed with an alkaline substance or buffer solution and used as the core material for further processing. The seeds to be layered with the active agent can be water-insoluble seeds containing different oxides, celluloses, organic polymers and other materials alone or in mixtures, or water-soluble seeds containing different inorganic salts, sugars, nonpareils and other materials alone or in mixtures. Further, the seeds may contain the active agent in the form of crystals, aggregates, compacts, etc. The size of the seeds is not essential to the present disclosure, but may range from about 0.1 to 2 mm. The seeds laminated with the active agent are produced by either powder or solution / suspension lamination, for example, using a granulation or spray coating lamination device.

[0173] Before layering the seeds, the active agent may be mixed with additional components. Such components can be binders, surfactants, fillers, disintegrants, alkali additives or other pharmaceutically acceptable components alone or in mixtures. Binders are, for example, polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), or sugars, starches, or other pharmaceutically acceptable substances having agglomerating properties. Suitable surfactants are found, for example, in the group of pharmaceutically acceptable non-ionic or ionic surfactants such as sodium lauryl sulfate.

[0174] Alternatively, the active agent can be optionally mixed with suitable components and incorporated into the core material. The core material may be produced by extrusion / spheronization, balling or compression using conventional processing equipment. The size of the incorporated core material is from about 0.1 to 4 mm, for example 0.1 to 2 mm. The produced core material can be further laminated with additional components containing the active agent or used for further processing.

[0175] The active agent is mixed with pharmaceutical ingredients to obtain favorable handling and processing characteristics and an appropriate concentration of the active agent in the final preparation. Pharmaceutical components such as fillers, binders, lubricants, disintegrants, surfactants, and other pharmaceutically acceptable additives can be used.

[0176] Alternatively, the above core material can be prepared using spray drying or spray congealing techniques.

[0177] Enteric coating layer: Before applying the enteric coating layer in the form of individual pellets onto the core material, the pellets may optionally be covered with one or more separating layers containing pharmaceutical excipients including alkaline compounds such as pH buffering compounds. These separating layers separate the core material from the outer enteric coating layer. These separating layers that protect the core material of the active agent need to be water-soluble or rapidly disintegrate in water.

[0178] The separating layer can be optionally applied to the core material by coating or lamination procedures using suitable equipment such as coating pans, coating granulators, or fluidized bed equipment using water or organic solvents for the coating process. Alternatively, the separating layer can be applied to the core material by using powder coating techniques. The materials for the separating layer are pharmaceutically acceptable compounds such as sugars, polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, water-soluble salts of enteric coating polymers, etc., and are used alone or as mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-adhesion agents, and anti-static agents, for example magnesium stearate, titanium dioxide, talc, and other additives, may also be included in the separating layer.

[0179] When any separating layer is applied to the core material, it may constitute a variable thickness. The maximum thickness of the separating layer is usually limited only by the processing conditions. The separating layer can function as a diffusion barrier and can act as a pH buffering zone. The optionally applied separating layer is not essential to the embodiments of the present disclosure. However, the separating layer can improve the chemical stability of the active substance or the physical properties of the novel multi-unit tablet dosage form.

[0180] Alternatively, the separating layer may be formed in situ by the reaction between an enteric coating polymer layer applied on the core material and an alkali-reactive compound in the core material. Thus, the formed separating layer contains a water-soluble salt formed between the enteric coating layer polymer and the alkali-reactive compound located at the position of forming the salt.

[0181] One or more enteric coating layers are applied onto the core material or the core material covered with the separating layer by using appropriate coating techniques. The enteric coating layer material can be dispersed or dissolved in either water or an appropriate organic solvent. As the enteric coating layer polymer, for example, one or more of a solution or dispersion of a methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable enteric coating polymers can be used separately or in combination.

[0182] The enteric coating layer contains a pharmaceutically acceptable plasticizer to obtain desired mechanical properties such as the flexibility and hardness of the enteric coating layer. Such plasticizers are, for example, but not limited to, triacetin, citrate esters, phthalate esters, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate or other plasticizers.

[0183] The amount of plasticizer is optimized for each enteric coating layer formulation with respect to the selected enteric coating layer polymer, the selected plasticizer, and the appropriate amount of the polymer such that the mechanical properties, i.e., the flexibility and hardness of the enteric coating layer, exemplified as Vickers hardness, for example, are such that the acid resistance of the pellets coated with the enteric coating layer does not significantly decrease during compression of the pellets into tablets when tablets are desired. The amount of plasticizer is usually more than 5% by weight of the enteric coating layer polymer, for example 15 - 50%, more preferably 20 - 50%. Additives such as dispersants, colorants, pigment polymers, for example poly(ethyl acrylate, methyl methacrylate), anti-adhesion agents, and defoaming agents can also be included in the enteric coating layer. Other compounds may be added to increase the film thickness and reduce the diffusion of the acidic gastric juice into the acid-sensitive material. The maximum thickness of the applied enteric coating is usually limited only by the processing conditions and the desired dissolution profile.

[0184] Overcoat layer: The pellets coated with the enteric coating layer may optionally be further coated with one or more overcoat layers. The overcoat layer should be water-soluble or rapidly disintegrate in water. The overcoat layer can be applied to the enteric coating laminated pellets by a coating or lamination procedure in a suitable apparatus such as a coating pan, a coating granulator, etc., or in a fluidized bed apparatus using water or an organic solvent for the coating or lamination process. The material of the overcoat layer is selected from pharmaceutically acceptable compounds such as sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc., and is used alone or as a mixture. Additives such as plasticizers, colorants, pigments, fillers, anti-adhesion agents, and anti-static agents, for example magnesium stearate, titanium dioxide, talc and other additives may also be included in the overcoat layer. The overcoat layer can further prevent potential aggregation of the enteric coating layer pellets, further protect the enteric coating layer from cracking during the compression process, and enhance the tableting process. The maximum thickness of the applied overcoat layer is usually limited by the processing conditions and the desired dissolution profile. The overcoat layer can also be used as a tablet film coating layer.

[0185] The enteric coating of soft gelatin capsules may contain emulsions, oils, microemulsions, self-emulsifying systems, lipids, triglycerides, polyethylene glycol, surfactants, other solubilizing agents, etc., and combinations thereof, in order to solubilize the active agent. The flexibility of soft gelatin capsules is maintained by residual water and plasticizers. Further, in the case of gelatin capsules, the spraying must be achieved at a relatively low relative humidity rate such that the gelatin is dissolved in water and can be achieved in a fluidized bed or Wurster. Further, drying should be achieved without removing residual water or plasticizers and causing cracking of the capsule shell. Commercially available blends optimized for the enteric coating of soft gelatin capsules such as Instamodel EPD (enteric polymer dispersion) are available from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a laboratory scale, enteric-coated capsules can be prepared as follows. a) rotating the capsules in a flask, or dipping the capsules in a gently heated solution of an enteric coating material containing a plasticizer at the lowest possible temperature, or b) rotating the capsules in a laboratory-scale nebulizer / fluidized bed and then drying them.

[0186] In the case of aqueous active agents, it may be particularly desirable to incorporate the drug into the aqueous phase of the emulsion. Such "water-in-oil" emulsions can provide a biophysical environment suitable for the drug and can provide an oil-water interface that protects the drug from the harmful effects of pH or enzymes that can degrade the drug. Further, such water-in-oil formulations can provide a lipid layer that can advantageously interact with the lipids in the body's cells and can increase the partitioning of the formulation onto the cell membrane. Such partitioning can increase the absorption of the drug in such formulations into the circulation and thus increase the bioavailability of the drug.

[0187] In some embodiments, the water-in-oil emulsion contains an oil phase composed of medium-chain or long-chain carboxylic acids or esters or alcohols thereof, surfactants or surfactants, and an aqueous phase mainly containing water and an active agent.

[0188] The medium-chain and long-chain carboxylic acids are in the range of C8-C22 and have up to 3 unsaturated bonds (or branches). Examples of saturated straight-chain acids are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid, and melissic acid. Unsaturated monoolefin straight-chain monocarboxylic acids are also useful. Examples of these are oleic acid, gadoleic acid, and erucic acid. Unsaturated (polyolefinic) straight-chain monocarboxylic acids are also useful. Examples of these are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid, and behenolic acid. Examples of useful branched acids include, for example, diacetyl tartaric acid. The unsaturated olefinic chain may also be hydroxylated or ethoxylated to prevent oxidation or to change the surface properties.

[0189] Examples of long-chain carboxylic acid esters include, but are not limited to, glyceryl monostearate; glyceryl monopalmitate; a mixture of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoate; glyceryl monooleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate and glyceryl monolinoelaidate; glyceryl linolenate; glyceryl monogadoleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoelaidate, glyceryl linolenate and glyceryl monogadoleate; acetylated glycerides such as distilled acetylated monoglyceride; a mixture of propylene glycol monoesters, distilled monoglycerides, sodium stearoyl lactate and silicon dioxide; d-alpha tocopherol polyethylene glycol 1000 succinate; a mixture of mono- and di-glyceride esters such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and di-glycerides; lactic acid mono- and di-glycerides; lactic acid carboxylic acid esters of glycerin and propylene glycol; lactic acid esters of long-chain carboxylic acids; polyglycerol esters of long-chain carboxylic acids, propylene glycol mono- and di-esters of long-chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long-chain carboxylic acids; succinylated monoglyceride; stearylmonoglyceryl citrate; stearyl heptanoate; cetyl ester of wax; stearyl octanoate; C8-C30 cholesterol / lanosterol ester; and sucrose long-chain carboxylic acid ester. Self-emulsifying long-chain carboxylic acid esters include, for example, those of the group such as stearic acid ester, palmitic acid ester, ricinoleic acid ester, oleic acid ester, behenic acid ester, ricinoleic acid ester, myristic acid ester, lauric acid ester, caprylic acid ester, caproic acid ester and the like. In some embodiments, the oily phase may include a combination of two or more long-chain carboxylic acids or their esters or alcohols.In some embodiments, a medium-chain surfactant may be used, and the oil phase may include a mixture of caprylic / capric triglyceride and C8 / C10 mono- / di-glycerides of caprylic acid, glyceryl caprylate or propylene glycol monocaprylate or mixtures thereof.

[0190] Alcohols that can be used are also exemplified by the hydroxyl forms of the carboxylic acids exemplified above and stearyl alcohol.

[0191] Surfactants or surfactants are long-chain molecules that can accumulate at the hydrophilic / hydrophobic (water / oil) interface and reduce the surface tension of the interface. As a result, the emulsion can be stabilized. In some embodiments, the surfactant is of the Tween® (polyoxyethylene sorbitan) family of surfactants, the Span® (sorbitan long-chain carboxylic acid ester) family of surfactants, the Pluronic® (ethylene or propylene oxide block copolymer) family of surfactants, the Labrasol®, Labrafil® and Labrafac® (each polyglycolized glyceride) family of surfactants, sorbitan esters of oleic acid, stearic acid, lauric acid or other long-chain carboxylic acids, poloxamers (polyethylene-polypropylene glycol block copolymers or Pluronic®), other sorbitan or sucrose long-chain carboxylic acid esters, mono- and diglycerides, PEG derivatives of caprylic / capric triglyceride and mixtures thereof or mixtures of two or more of the above. In some embodiments, the surfactant phase may include a mixture of polyoxyethylene (20) sorbitan monooleate (Tween80®) and sorbitan monooleate (Span80®).

[0192] The aqueous phase may optionally contain an activator and a buffer suspended in water.

[0193] In some embodiments, such emulsions are coarse emulsions, microemulsions, and liquid crystal emulsions. In other embodiments, such emulsions may optionally include a permeation enhancer. In other embodiments, spray-dried dispersions or microparticles or nanoparticles containing encapsulated microemulsions, coarse emulsions, or liquid crystals can be used.

[0194] In some embodiments, the solid dosage forms described herein are non-enteric time-delayed release dosage forms. As used herein, the term "non-enteric time-delayed release" refers to delivery such that drug release can be achieved at some generally predictable locations within the distal intestine than would have been achieved in the absence of a delayed release modification. In some embodiments, the method for delaying release is a coating that becomes permeable, dissolves, ruptures, or is no longer intact after a designed duration. The coating in a time-delayed release dosage form can have a defined time to erode, after which the drug is released (examples of suitable coatings include polymeric coatings such as HPMC, PEO, etc.), or a core composed of a superdisintegrant or osmotic agent, or salts, hydrophilic polymers, typically water-attracting agents such as polyethylene oxide or alkyl cellulose, salts such as sodium chloride, magnesium chloride, sodium acetate, sodium citrate, sugars such as glucose, lactose or sucrose, or acids such as citric acid or gas-generating agents such as citric acid and sodium bicarbonate that draw water through a semipermeable membrane regardless of the presence or absence of any of the aforementioned acids incorporated into the dosage form. The semipermeable membrane allows little drug or osmotic agent to permeate, but allows water to permeate at a nearly constant rate into the dosage form, increasing the pressure and rupturing after the swelling pressure exceeds a specific threshold over the desired delay time. The permeability of the drug through this membrane should be less than 1 / 10, and in one embodiment less than 1 / 100, of that of water. Alternatively, the membrane can become porous by leaching out an extractable aqueous phase over the desired delay time.

[0195] Osmotic dosage forms are described in Theeuwes U.S. Patent No. 3,760,984, and osmotic burst dosage forms are described in Baker U.S. Patent No. 3,952,741. These osmotic burst dosage forms can provide a single release pulse or multiple pulses when different devices with different timings are used. The timing of the osmotic burst can be controlled by the choice of polymer and the thickness or area of the semipermeable membrane surrounding the core containing both the drug and the osmotic agent or attractant. As the pressure in the dosage form increases with additional permeating water, the membrane stretches to its breaking point and then the drug is released. Alternatively, specific break regions can be created in the membrane by having thinner and weaker regions of the membrane or by adding a weaker material to regions of the coating membrane. Some preferred polymers with high water permeability that can be used as semipermeable membranes are cellulose acetate, cellulose acetate butyrate, cellulose nitrate, crosslinked polyvinyl, alcohol, polyurethane, nylon 6, nylon 6.6, and aromatic nylon. Cellulose acetate is a particularly preferred polymer.

[0196] In another embodiment, the time-delay coating that initiates the delay of drug release after at least partial dissolution of the enteric coating is composed of a hydrophilic erodible polymer that begins to erode gradually over time upon contact with water. Examples of such polymers include 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, particularly high molecular weight polyethylene glycol; chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly(vinyl pyrrolidone); starch and starch-based polymers; maltodextrin; poly(2-ethyl-2-oxazoline); poly(ethylene imine); polyurethane; hydrogel; crosslinked polyacrylic acid; and cellulose polymers and their derivatives including, but not limited to, any combination or blend of the above.

[0197] Some preferred erodible hydrophilic polymers suitable for forming an erodible coating are poly(ethylene oxide), hydroxypropyl methylcellulose, and combinations of poly(ethylene oxide) and hydroxypropyl methylcellulose. Poly(ethylene oxide) is used herein to refer to a linear polymer of unsubstituted ethylene oxide. The molecular weight of the poly(ethylene oxide) polymer can range from about 105 Daltons to about 107 Daltons. The preferred molecular weight range of the poly(ethylene oxide) polymer is from about 2x105 to 2x106 Daltons and is commercially available from The Dow Chemical Company (Midland, Mich.) under the name SENTRYR POLYOX (trademark) water-soluble resin, NF (National Formulary) grade. When higher molecular weight polyethylene oxide is used, other hydrophilic agents, such as salts or sugars, such as glucose, sucrose, or lactose, which promote erosion or disintegration of this coating, are also included.

[0198] The time-delayed dosage form can be an Enterion® capsule or a mechanical pill, such as a pH-sensitive capsule, that can release the drug after a pre-programmed time, or when a signal that can be transmitted is received, or when leaving the stomach.

[0199] The amount of the compounds of the present disclosure in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains from about 0.01 to 99.99 weight percent of the BTK inhibitor compound on a weight percent (wt%) basis based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80 weight percent.

[0200] The foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding. Accordingly, it is to be understood that the foregoing description is intended to be illustrative and not limiting. Accordingly, the scope of the present disclosure should not be determined with reference to the foregoing description, but instead should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Example

[0201] The following examples are provided to illustrate certain disclosed embodiments and should in no way be construed as limiting the scope of the present disclosure. In the examples discussed below, the BTK inhibitor defined above may sometimes be referred to interchangeably as a "compound" or a "drug".

[0202] Example 1 - MOG Antibody Disease (MOGAD) Test of Tolebrutinib, a BTK Inhibitor Example 1.1 - Rationale for Introduction and Test Tolebrutinib is a brain-penetrant inhibitor of Bruton's tyrosine kinase (BTK). This compound has been developed for the treatment of MOG antibody disease (MOGAD). This test is designed to collect evidence of its efficacy and safety in the active relapse MOGAG population.

[0203] MOGAD is a recurrent immune-mediated disease of the central nervous system that results in vision loss, weakness, sensory loss, bowel / bladder dysfunction, and cognitive impairment (Narayan et al. Mult Scler Relat Disord 2018, 25, 66 - 72). Within the spectrum of CNS autoimmune diseases, MOG antibody disease overlaps with multiple sclerosis (MS). Pathologically, anti-MOG appears to be similar to MS with macrophage infiltration and limited humoral deposits with demyelination and intact axons (Hoftberger et al. Acta Neuropathol 2020, 139, 875 - 892). Clinically, MOGAD attacks show a predilection for the optic nerve (66% of attacks), and unlike MS, there is no known progressive course of the disease for MOG. That is, if relapses can be prevented, the disease is effectively in remission.

[0204] The graphical scheme of the study design is shown in Figure 1A. Table 1 shown below describes the activity schedule during a series of tests. Table 2 below describes the objectives and endpoints of the entire study.

[0205] [Table 1]

[0206] [Table 2]

[0207] [Table 3]

[0208] [Table 4]

[0209] The objectives and endpoints of the treatment are shown in Table 2.

[0210] [Table 5]

[0211] Validity of measurement MOG antibody disease appears to accumulate impairments in a stepwise progression caused by relapses that sometimes result in persistent loss of neurological function (Jurynczyk et al. Brain 2017, 140, 3128 - 3138). Therefore, reducing the relapse frequency is a clinically important outcome and the goal of any potential disease-modifying therapy.

[0212] Monophasic patients never relapse. These monophasic patients may not be part of the trial (inclusion criteria require at least two attacks). Approximately half of the patients will experience a second attack and / or further relapses. See, for example, Akaishi et al. J Neurol 2021; Kornberg et al. Neurology, 2021. Reducing the relapse frequency is the goal, and the residual disability of the patient worsens after an attack. The treatment goal is to administer treatment to prevent and / or reduce the likelihood of further attacks in the patient. For further 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 866824.

[0213] Persistent MOG antibody titers over 6 months are associated with a higher risk of a relapse phenotype that can be present in nearly 88% of patients with MOG antibody disease (Lopez-Chiriboga et al. JAMA Neurol 2018.75,1355-1363). There is also preliminary evidence indicating that high MOG antibody titers may be associated with a more aggressive disease (Tea et al. Acta Neuropathol Commun 2019,7,145). Therefore, reducing or eliminating MOG antibody titers could be a positive outcome of treatment with potential disease-modifying therapies.

[0214] The presence of MOG antibodies is analyzed by extracellular live cell staining immunofluorescence technology using transfected MOG-expressing cells. Antibody titers are evaluated by measuring fluorescence intensity signals by serial dilution flow cytometry.

[0215] A decrease in MOG antibody titers has been observed. Whether this biomarker can be reliably used to monitor disease status has not yet been established. If the antibody titer decreases or is eliminated (conversion from positive to negative), it constitutes a decrease in MOG titer. Technically speaking, if the MOG antibody titer level forms a negative slope after 1 year of treatment with trebrutinib, it would constitute a decrease in MOG antibody titer. Similarly, in technical terms, elimination of MOG antibody titer is the case where the fluorescence intensity signal from flow cytometry shows the same level as non-transfected negative control cells after 1 year of treatment with trebrutinib.

[0216] Measurement of the accumulation of neurological deficits is an important clinical endpoint in demyelinating diseases of the central nervous system. The EDSS is widely used to measure neurological deficits in clinical trials and in daily situations. Considering the short duration of this pilot study, the change from baseline in the Expanded Disability Status Scale score (EDSS) 1 year after the start of treatment with trebrutinib will be measured as a secondary endpoint.

[0217] In addition to the above evaluations, the findings of MRI and OCT as well as the measurements of serum / blood biomarkers will be analyzed in this trial as exploratory supportive efficacy data.

[0218] Example 1.2 - Study Design Example 1.2A - Overall Design This is a Phase 2 open-label single-arm single-site trial to evaluate the efficacy and safety of trehalostatinib treatment for 1 year in participants with MOG antibody disease. Participants will be screened to assess their eligibility based on the inclusion and exclusion criteria of the trial. After screening, eligible participants will be enrolled to receive a daily oral dose of 60 mg of trehalostatinib. The primary endpoint is the proportion of recurrence-free participants 1 year after enrollment.

[0219] The trial will be conducted entirely remotely without the need for in-person visits to the site. Limited neurological function, MOG antibody titers, and safety measurements will be evaluated by virtual visits every 3 months after enrollment. In addition to the regular virtual evaluations, participants will report new neurological symptoms consistent with a recurrence of MOG antibody disease, and if the clinical symptoms and related neurological signs and symptoms warrant, an MRI of the optic nerve or spinal cord or brain will be included, and a recurrence evaluation will be initiated. Participants who meet the criteria for recurrence will be treated for the recurrence by a physician in their region (according to local standard treatment), receive a recurrence visit for remote follow-up scheduled 4 weeks after the onset of recurrence symptoms, and will then be advised to discontinue the investigational drug. Participants will be encouraged to remain in the trial even if they discontinue the investigational drug.

[0220] Example 1.2B - Number of Participants Approximately 30 participants will be screened to achieve 25 who are enrolled to receive the trial intervention.

[0221] Example 1.2C - Intervention Group and Duration All participants are screened over a 4-week period, the consent form is re-reviewed, background immunotherapy is discontinued, and eligibility for the trial is confirmed. Participants use 20 mg of prednisone daily throughout the 4-week screening period while discontinuing background immunotherapy. Prednisone will then be tapered by 5 mg per week at the start of the 1-year treatment period, concurrent with the use of 60 mg of daily trebrutinib. Except for the treatment of confirmed relapses, no additional prednisone or background immunotherapy is allowed during the 1-year study period.

[0222] Example 1.2D - Theoretical Basis This is a Phase 2 trial with a non-blind design selected to avoid unnecessary exposure of participants to placebo and to preliminarily investigate the efficacy and safety of trebrutinib in populations not receiving adequate treatment. Male and female participants with a diagnosis of MOGAD in the age range of 12 to 55 years are selected for this trial. The age range is limited to participants 55 years of age or younger to reduce confounding neurological conditions (e.g., spinal degenerative lesions, vascular disorders, other neurodegenerative processes) that are more common in the elderly. The dose for participants in the age range of 12 to 17 years is informed by the results of PK extrapolation modeling. The intended duration of the treatment period is 12 months and is fixed for all individual participants. Participants will be encouraged to remain in the trial until M12 visit and to comply with all trial visits if they discontinue the trial intervention early. With an average relapse rate of once a year, 12 months is an appropriate period to evaluate the efficacy of trebrutinib for preventing relapses.

[0223] Example 1.2E - Dose Regimen The selection of the dose of 60 mg of BTK inhibitor taken with food is based on the results of the Phase 2b dose - ranging trial of tolebrutinib in participants with relapsing multiple sclerosis (DRI15928). See, for example, Reich, D.S., et al., Safety and efficacy of tolebrutinib, an oral brain - penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double - blind, placebo - controlled trial. Lancet Neurol, 2021. 20(9): p.729 - 738.

[0224] Analysis of PK data and the effect of feeding status on tolebrutinib exposure showed a positive diet effect with an approximately 2 - fold increase in AUC0 - 24. Furthermore, the correlation between treatment response and exposure to tolebrutinib showed that higher exposure was associated with fewer new gadolinium - enhancing T1 hyperintense lesions after 12 weeks of treatment. Overall, these data support the recommendation to take tolebrutinib with food.

[0225] There was no correlation between the dose of tolebrutinib administered and the number of TEAE. The most common events (preferred terms) observed in participants in the tolebrutinib treatment 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.

[0226] Example 1.2 F - Definition of trial completion Participants are considered to have completed the trial if they complete all stages of the trial, including M12. Participants who relapse during the course of the trial are considered completers if they discontinue the investigational drug and complete an early termination of the treatment visit. This trial will end when approximately 25 participants have completed their M12 visit. With an approximately 12 - month planned enrollment period and an approximately 12 - month per - participant trial period, the expected duration of the trial is approximately 24 months.

[0227] Example 1.3 - Test Group Example 1.3A - Incorporation Criteria Participants are eligible to be included in the test only if all of the following criteria are applied as shown in Table 3.

[0228] [Table 6]

[0229] [Table 7]

[0230] [Table 8]

[0231] Example 1.3B - Exclusion Criteria If any of the following criteria are applied as shown in Table 4, the participant will be excluded from the test.

[0232] [Table 9]

[0233] [Table 10]

[0234] [Table 11]

[0235] [Table 12]

[0236] [Table 13]

[0237]

Table 14

[0238]

Table 15

[0239] Example 1.3 Considerations for a 3C Lifestyle Diet and dietary restrictions: Tolebrutinib (IMP) shall be taken with a normal diet. If possible, the meal at which IMP is taken (e.g., breakfast, lunch, or dinner) should be consistent throughout the entire trial. A typical meal at which IMP is taken is collected at each visit. If it is necessary to change the meal time for IMP administration, a minimum gap of 12 hours should be maintained between two administrations.

[0240] Example 1.4 - Test Intervention and Concomitant Therapy The test intervention was defined as any test intervention, marketed product, placebo, or medical device intended to be administered to the trial participants according to the trial protocol.

[0241] Example 1.4A - Administered Test Intervention and Concomitant Therapy This test intervention includes IMP and investigational medicinal products (NIMP). To maintain blinding, participants are administered 4 tablets of a BTK inhibitor or placebo once a day in a blinded manner. The details of the intervention are shown in Table 5.

[0242]

Table 16

[0243] The details of the investigational medicinal products are shown in Table 6.

[0244]

Table 17

[0245] Example 1.4B - Measures to Minimize Bias: Randomization and Blinding This is an unblinded trial, and the potential bias is reduced by the following procedures. An objective measure is used to determine the primary outcome of recurrence. Recurrence is clinically defined, but MRI confirmation of seizures explaining the clinical symptoms is also required.

[0246] Example 1.4C - Dose Modification Dose modification is not anticipated in this trial. If it is considered necessary due to an AE, treatment may need to be interrupted or permanently discontinued.

[0247] Example 1.4D - Continued Access to Interventions after Trial Completion Post-trial access may be considered if required by local regulations.

[0248] Example 1.4E - Concomitant Therapy Any medications or vaccines (including over-the-counter or prescription drugs, vitamins, or herbal supplements) that the participant is receiving at the time of enrollment or during the trial must be recorded along with: reason for use, dates of administration including start and end dates, and dosing information including dose and frequency.

[0249] Live (attenuated) vaccines should not be administered during the intervention period.

[0250] Exclusion Criteria The treatment of MOG antibody disease described in Example 1.3B is not permitted after randomization while the participant is on study treatment. Short-term use (3 - 7 days) of glucocorticoids (e.g., for relapse treatment or acute disease) and topical corticosteroids (e.g., topical, nasal, ocular, otic, intra-articular) is permitted.

[0251] If there are questions regarding concomitant therapy or previous therapy, it is necessary to contact the medical monitor.

[0252] Participants must refrain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days prior to the start of the trial intervention (or 14 days if the drug is a potential enzyme inducer) or within 5 half-lives (whichever is longer) until the completion of the follow-up visit, as long as the drug does not interfere with the trial, in the opinion of the principal investigator and the sponsor of the trial.

[0253] Drugs for the treatment of MOG antibody disease symptoms (e.g., gait disturbance, spasticity, incontinence, pain) should be maintained at a stable dose before screening and during the treatment period, if clinically feasible.

[0254] Anticoagulant / antiplatelet therapy is not permitted to be conducted simultaneously with IMPs including: acetylsalicylic acid (aspirin) > 81 mg / day; antiplatelet drugs (e.g., clopidogrel); warfarin (vitamin K antagonist); heparin including low molecular weight heparin (antithrombin agent); dabigatran (direct thrombin inhibitor); apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitor).

[0255] Paracetamol / acetaminophen at a dose of 3 grams / day or less is permitted for use at any time during the trial. If clinically necessary for the treatment of existing medical conditions or new events, non-steroidal anti-inflammatory drugs (NSAIDs) (other than acetylsalicylic acid), preferably selective cyclooxygenase-2 inhibitors at the lowest effective dose, etc., may be administered for a short period (maximum 5 days) during the trial. The principal investigator must record the use of NSAIDs (and other uses) in the eCRF.

[0256] CYP inhibitor / inducer: Strong and moderate inducers of CYP3A or strong inhibitors of the CYP2C8 hepatic enzyme are not permitted throughout the trial.

[0257] Example 1.5 - Termination of Trial Intervention and Withdrawal / Discontinuation of Participants Example 1.5A - Termination of Trial Intervention Example 1.5A1 - Permanent Interruption The trial intervention should be continued for as long as possible. Permanent interruption of the intervention is any interruption of treatment related to a final decision by the principal investigator or the participant not to re-expose the participant to the trial intervention at any time. In rare cases, it may be necessary for the participant to permanently discontinue the trial intervention. If the trial intervention is permanently discontinued, the participant is required to remain in the trial being evaluated until the follow-up visit. For this set of participants (participants who interrupted the IMP or switched to another immunomodulatory / immunosuppressive drug), biomarker samples are not collected after the early termination of the treatment visit. This is important to continue to assess safety. For data collected at the time of discontinuation of the trial intervention, see SoA (Example 1.1). If the trial intervention is permanently interrupted, the participant should be treated for MOGAD according to the best judgment of the local clinical practice and the principal investigator of the treatment trial.

[0258] The legitimate reasons for the principal investigator to discontinue the administration of the investigational drug to the participant may be as follows. · An adverse event that poses a risk to the safety of the participant, or when the principal investigator or the participant wishes or considers it necessary to discontinue the trial intervention. · When the IMP discontinuation criteria are met according to the guidance for follow-up of abnormal test results (Example 1.8A). · In the opinion of the principal investigator, the participant is no longer deriving a therapeutic / clinical benefit. · At the request of the participant, i.e., withdrawal of consent to treatment. · When a female participant becomes pregnant during the trial or wishes to become pregnant. · Severe opportunistic infections (e.g., PML (Example 1.8C), HIV). · Continuing need for chronic use of prohibited concomitant medications.

[0259] When the participant meets one of the conditions outlined in the algorithm (Example 1.8C), or when the principal investigator considers it to be in the best interest of the participant, the principal investigator should consider discontinuing the trial intervention for abnormal liver function.

[0260] Clinically significant abnormal clinical test values or ECG parameters are immediately retested for confirmation after 24 hours before determining the final discontinuation of the IMP for the participating subject concerned.

[0261] If clinically significant findings are confirmed on ECG (including, but not limited to, changes from baseline in the QT interval corrected using the formula [QTcF] of Friedreich) after registration, the principal investigator or qualified designee shall determine whether the participant can continue in the trial and whether any changes to the management of the participant are required. Review of the ECG findings by a cardiologist may be considered for the decision to finally discontinue the trial intervention due to the ECG changes. This review of the ECG printed at the time of collection must be documented. Any new clinically relevant findings should be reported as an AE. For data collected at the time of discontinuation of the intervention and at follow-up and any further evaluations that need to be completed, refer to the SoA (Example 1.1).

[0262] Treatment of participants after permanent discontinuation of the intervention: Participants are followed in accordance with the trial procedures specified in this protocol. · Until the planned date of trial completion, or · Whichever is later of the recovery or stabilization of any AE to be followed as per what is specified in this protocol.

[0263] Participants should be treated for MOG antibody disease in accordance with the best judgment of the local clinical practice and the principal investigator of the treatment trial.

[0264] If possible, after the final discontinuation of the investigational medicinal product, evaluate the participant using the procedures planned for the early termination of the treatment visit.

[0265] Participants are required to continue the trial by attending all scheduled visits for each SoA (Example 1.1), if possible, until the end of the trial. If a participant does not agree to the full visit schedule after deciding on a permanent end of treatment, a reduced visit schedule may be agreed upon with the participant. Every effort should be made to collect endpoint information and vital status as frequently as possible.

[0266] For participants who do not consent to remain in the trial after an early end of a treatment visit and have a complete interruption of the IMP, if the early end of the treatment visit is less than 3 weeks after the last administration of the investigational medicinal product, additional visits should be made at the evaluations normally planned for follow-up visits.

[0267] Patients being treated with non-investigational medicinal products who decide to discontinue their participation in the trial early and permanently before the end of the trial should be evaluated as soon as possible using the procedures normally planned for the early end of treatment visits. For participants who prematurely and permanently discontinue the investigational medicinal product and do not consent to remain in the trial after having made visits similar to those for the early end of treatment visits, if the last trial visit was less than 3 weeks after the last administration of the unblinded IMP, additional visits should be made at the evaluations normally planned for follow-up visits.

[0268] All cases of final discontinuation of the investigational medicinal product, if considered confirmed, must be recorded by the treating investigator on the appropriate page of the eCRF.

[0269] Example 1.5A2 - Liver Chemistry Stop Criteria If a participant meets one of the conditions outlined in Example 1.8C or if the investigator considers it to be in the best interest of the participant, the investigator requests the discontinuation of the trial intervention for abnormal liver tests in the presence of abnormal liver chemistry substances that do not meet the protocol-specified discontinuation rules.

[0270] Example 1.5A3 - QTc Stop Criteria If clinically significant findings are identified after registration (including, but not limited to, changes from baseline in the QT interval corrected using the Fridericia formula [QTcF]), the principal investigator of the clinical trial or a qualified designee (e.g., a local physician) will determine whether the participant can continue in the study and whether any changes in the management of the participant are necessary. This review of the ECG printed at the time of collection must be documented. Any newly identified clinically relevant findings should be reported as AEs.

[0271] Example 1.5A4 - Temporary Interruption Interruption of temporary interventions due to suspected AEs or interruption of clinical trials due to declared regional or national emergencies by government agencies: Emergency measures for declared regional or national emergencies by government agencies) may be considered by the treating principal investigator of the clinical trial. For all temporary intervention interruptions, the duration should be recorded by the principal investigator of the clinical trial on the appropriate page of the eCRF.

[0272] If surgery is required during the study, beneficial risks of withholding IMP for at least 3 - 7 days before and after surgery are considered, depending on the type of surgery and the risk of bleeding.

[0273] The following shall lead to temporary treatment discontinuation. · Cytopenia: Follow the Sanofi algorithm for neutropenia and thrombocytopenia according to Example 1.8C. · Increases in serum creatinine, creatine phosphokinase (CPK), and liver enzymes: Follow the corresponding Sanofi algorithm according to Example 1.8C. · Cardiac arrhythmia (atrial fibrillation): Any grade 3 event (symptomatic and urgent intervention is indicated; device [e.g., pacemaker]; ablation; new initiation). · Suicide risk according to C - SSRS: If the participant scores "Yes" for item 4 or 5 in the suicide attempt column, or "Yes" for any item in the suicide behavior column.

[0274] If necessary, the principal investigator or participant may consider a temporary treatment interruption for any other reason, including concerns about safety due to disruptions in clinical trials caused by local or national emergencies declared by government agencies such as COVID-19 or another illness, or the need for prohibited concomitant medications. Treatment can be resumed later if it is considered safe and appropriate.

[0275] Example 1.5A5 - Re-challenge Restart of the IMP is carried out under careful and appropriate clinical and / or laboratory monitoring after consideration by the principal investigator in accordance with their best medical judgment, when the likelihood of IMP's responsibility in the occurrence of the related event is low, there are no safety concerns, and the criteria for permanent treatment discontinuation are not met.

[0276] Example 1.5A6 - Restart or re-challenge of the trial intervention after meeting the liver discontinuation criteria After a participant in this trial meets the liver chemistry test discontinuation criteria, restart or re-challenge of the trial intervention is not permitted.

[0277] Example 1.6 - Evaluation and procedures of the trial The trial procedures and their timing are summarized in the SoA (Example 1.1). Waiver or exemption of the protocol is not permitted.

[0278] Adherence to the trial design requirements, including those specified in the SoA (Example 1.1), is essential and required for the conduct of the trial.

[0279] All screening evaluations must be completed and considered to confirm that potential participants meet all eligibility criteria. The principal investigator shall maintain a screening log, as necessary, to record details of all screened participants, to confirm eligibility, or to record reasons for screening failure.

[0280] Procedures that are part of the participant's routine clinical management (e.g., blood cell count) and are obtained before signing the ICF can be used for screening or baseline purposes if the procedures meet the criteria specified in the protocol and are performed within the time frame defined in the SoA (Example 1.1). Such evaluations shall be recorded in the designated fields of the CRF.

[0281] Details of blood sampling, including volumes for all laboratory evaluations, shall be provided in the informed consent form. Repeat or unscheduled samples can be taken for safety reasons or technical issues related to the sample.

[0282] Example 1.6A - Efficacy Evaluation All planned time points for all efficacy evaluations shall be provided in the SoA (Example 1.1).

[0283] Important efficacy evaluations (e.g., EDSS) shall be scored by the trial team.

[0284] The principal investigator of the clinical trial shall be responsible for confirming relapses. In these cases, MRI findings during acute attacks and the evaluation by local neurologists are required.

[0285] The principal investigator of the clinical trial shall analyze the MRI scans for efficacy analysis (relapse evaluation and follow-up relapse visits).

[0286] Basic MRI scans shall be performed locally and consist of the following sequences: T2 and T1 weighted sequences before and after administration of Gd contrast agent (if there are no contraindications).

[0287] Example 1.6A1 - Definition of relapse in MOG antibody disease For the purposes of this trial, relapse in MOG antibody disease is defined as a new neurological symptom that is monophasic, acute or subacute in onset, or a worsening of a previous neurological symptom with objective changes in neurological examination. The symptoms must be as follows: · Due to MOG antibody disease, · Persisting for more than 24 hours, regardless of the presence of recovery, · Present at normal body temperature (i.e., without infection, excessive exercise, or overly high ambient temperature), · Preceded by clinical stability for more than 30 days (excluding previous relapses), · Caused by new or enhancing MRI lesions in the brain or spinal cord or optic nerve. Note: Worsening or recurrence of symptoms and signs in participants with MOG antibody disease that can reasonably be attributed to transient impairment of conduction in previously demyelinated pathways due to elevation of deep body temperature are not considered relapses.

[0288] Confirmation of relapse in MOG antibody disease will be done by the investigator in charge of the clinical trial based on the following definitions: · A confirmed relapse of MOG antibody disease is a clinically relevant change in the EDSS score performed by a regional neurologist, i.e., an increase of at least 0.5 points in the EDSS score, an increase of 1 point in two functional scores, or an increase of 2 points in one functional score, excluding changes in bowel / bladder and brain function scores compared to the previously available assessment (the last EDSS assessment that did not occur during the relapse). · MRI (brain or spinal cord or optic nerve) must be performed as soon as possible to assist in the confirmation of relapse.

[0289] Example 1.6A2 - Relapse Assessment and Follow - up Relapse Clinic Visits Participants must be instructed to report immediately to the investigator in charge of the clinical trial any new neurological symptoms and recurrence or worsening of previous symptoms. The reported symptoms are collected. If a participant reports symptoms that could be consistent with a relapse, the investigator in charge of the clinical trial must schedule a relapse assessment clinic visit as soon as possible (within 7 days of symptom onset if possible). The assessment and reporting of MOG antibody disease relapse are done by the investigator in charge of the clinical trial. Management of relapse is done locally by a neurologist's treatment according to local standard treatment. Recommendations for the treatment of relapse are detailed in Table 6 and are not mandatory.

[0290] The diagnosis of MOG antibody disease recurs during the trial. The local neurologist assesses whether the reported episode is consistent with the definition of recurrence, including MRI findings. If it is consistent with the definition of recurrence of MOG antibody disease, or if there is any suspicion and the possibility of recurrence cannot be excluded, a standard neurological examination (for the EDSS score) is performed by the local neurologist, and the case is discussed with the trial responsible physician. If the participant is not referred for EDSS assessment, this is documented with an explanation of the reason. Whenever possible, the local neurologist should perform an EDSS assessment and request at least an MRI before the participant comes to the trial responsible physician for recurrence assessment.

[0291] All recurrences of MOG antibody disease must be reported on the recurrence eCRF page. Recurrences of MOG antibody disease should not be reported as AEs unless, in the judgment of the trial responsible physician, they are unusually severe or medically unexpected or do not meet the definition of SAE.

[0292] If no concurrent disease is suspected, safety laboratory tests are optional for this recurrence assessment visit. If any concurrent disease is diagnosed, it is reported as an AE according to the safety reporting rules.

[0293] Participants are actively questioned about possible recurrence symptoms at each trial visit. If recurrence is suspected, the above decision-making and reporting rules apply.

[0294] The follow-up recurrence visit is conducted by the trial responsible physician 4 weeks after the recurrence confirmed by the SoA (Example 1.1).

[0295] Example 1.6B - Safety Assessment All planned time points for safety assessment are provided in the SoA (Example 1.1).

[0296] Example 1.6B1 - Electrocardiogram An ECG device that automatically calculates the heart rate and measures the PR, QRS, QT, and QTcF intervals is used to acquire a 12-lead ECG as outlined in the SoA (Example 1.1). If the ECG device does not automatically calculate the QTcF, manual calculation using a nomogram or an automated web-based calculator (e.g., https: / / reference.medscape.com / calculator / 48 / ecg-corrected-qt) is permitted.

[0297] ECG and 30-second rhythm strips are obtained locally.

[0298] Example 1.6B2 - Vital Signs Assess body temperature, heart rate, and blood pressure.

[0299] Blood pressure and heart rate measurements are taken using a fully automated device with the participant evaluated in the supine or seated position. Manual techniques are used only if an automated device is not available.

[0300] Prior to blood pressure and heart rate measurements, participants should be given at least a 5-minute rest in a quiet environment without distractions (e.g., TV, mobile phone).

[0301] Heart rate and blood pressure measurements are taken prior to blood sampling for laboratory testing and consist of one heart rate and three blood pressure measurements (three consecutive blood pressure measurements are recorded at intervals of at least 1 minute).

[0302] Example 1.6B3 - Clinical Safety Laboratory Evaluation See Example 1.8A for the list of clinical tests to be performed. For each SoA (Example 1.1), serological tests for hepatitis B and C should be performed during screening, and if necessary, other infectious disease tests should be performed locally during screening.

[0303] The principal investigator of the clinical trial shall, in the case of an urgent safety event, request urgent local examination data to enable appropriate treatment decisions. All clinically relevant requested urgent local examination data shall be recorded in the eCRF.

[0304] The principal investigator of the clinical trial shall review the clinical examination report, document this review, and record any clinically relevant changes that occur during the trial in the AE section of the eCRF. The examination report shall be submitted together with the source documents. Clinically significant abnormal examination findings are those not related to the underlying disease, unless judged by the principal investigator of the clinical trial to be more severe than expected for the participant's condition.

[0305] All clinical examinations with values considered to be clinically significantly abnormal during participation in the trial or within 28 days after the last dose of the trial intervention shall be repeated until the values return to normal or baseline, or until they are no longer considered clinically significant by the principal investigator of the clinical trial.

[0306] If abnormal clinical examination values do not return to normal or baseline within the period judged appropriate by the principal investigator of the clinical trial, the cause shall be identified and the sponsor of the trial notified.

[0307] All laboratory evaluations required by the protocol defined in Example 1.8A shall be performed in accordance with the SoA. If the laboratory evaluation in Example 1.8C indicates discontinuation of the IMP, a temporary discontinuation shall be considered unless otherwise specified.

[0308] If test values from laboratory evaluations not specified in the clinical trial implementation plan conducted at the local laboratory of the facility require a change in the management of the participant, or are considered clinically important by the principal investigator of the clinical trial (e.g., SAE or AE or dose change), the results shall be recorded in the eCRF.

[0309] Example 1.6C - Adverse Events (AE), Serious Adverse Events (SAEs) and Other Safety Reports Example 1.6C1 - Report of Relapse of MOG Disease MOG disease recurrence determined from the assessments described in Example 1.5A1 is exempt from being reported as an AE, except if it meets the definition of an SAE or is unusually severe or medically unexpected. Hospitalizations for recurrence are not considered part of the severity criteria for this trial if they are routine at that site (e.g., high-dose IV methylprednisolone).

[0310] Data on MOG disease recurrence will be collected in the eCRF and analyzed as part of the efficacy analysis. Worsening of other neurological symptoms that do not meet the definition of MS recurrence will be reported as AEs according to the general safety reporting rules.

[0311] Example 1.6C2 - Reporting of Safety Findings from Magnetic Resonance Imaging Magnetic resonance imaging scans need to be reviewed locally for any pathology. In the case of clinically relevant findings, relevant information needs to be provided to the principal investigator of the clinical trial for appropriate safety reporting and to ensure proper management of the identified safety findings in the participants. If available, the diagnosis of the pathology as the cause of such MRI findings or the findings themselves will be reported as AEs until the diagnosis is clarified.

[0312] Example 1.6C3 - Adverse Events of Special Interest Adverse events of special interest (AESIs) are AEs (severe or non-severe) of scientific and medical interest specific to the sponsor's product or program that require continuous monitoring and immediate notification by the principal investigator of the clinical trial to the sponsor. Such events may require further investigation to characterize and understand them. Adverse events subject to special interest can be added, amended, or removed by protocol amendment during the trial.

[0313] Pregnancy in female participants who participated in the trial and pregnancy in the female partners of male participants who participated in the trial using IMP / NIMP. · Is eligible as an SAE only if it meets one of the severity criteria (see Example 1.8B). · If a female participant becomes pregnant, the IMP should be discontinued. · Observation of the course of pregnancy of a female participant or the female partner of a male participant is essential until the results are determined.

[0314] Symptomatic overdose (severe or non-severe) due to IMP. · Overdose of IMP (accidental or intentional) is an event suspected by the principal investigator of the clinical trial or spontaneously reported by the participant (not based on the total number of pills taken), and is defined as at least twice the intended dose within the intended treatment interval (e.g., more than 2 pills of IMP within 12 hours).

[0315] Increase in alanine transaminase (ALT) > 3x ULN. · An increase in ALT exceeding 3x ULN was confirmed by retesting within 72 hours or the absence of retesting within 72 hours.

[0316] Project-specific AESIs are as follows. · ECG observation of atrial fibrillation or atrial flutter · Severe infection (grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]), which may or may not meet the severity criteria (e.g., grade 3 community-acquired infection). · Moderate or severe hemorrhagic events (NCI CTCAE grade 2 or higher) (including but not limited to symptomatic hemorrhage in important regions or organs such as the CNS or intraocular hemorrhage). · Thrombocytopenia, platelet count < 75,000 / mm 3 (See Example 1.8C for the management flowchart).

[0317] The definitions of AE or SAE can be found in Example 1.8B.

[0318] Adverse events are reported by the participant (or, where appropriate, by the caregiver, proxy, or legally authorized representative of the participant).

[0319] The principal investigator and qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE, and for following up on serious AEs that are considered to be related to the study intervention or procedure, or AEs that caused the participant to discontinue the study intervention.

[0320] Example 1.6 D - Biomarkers Blood samples for the biomarker study are collected from all participants in this study as specified in the SoA (Example 1.1). Participants who relapse during the course of the study have the option to have blood samples taken for biomarkers from that point forward.

[0321] The collection of plasma and serum samples for the biomarker study is also part of this study.

[0322] The samples will be tested to evaluate their association with the observed clinical response to the biomarker and tolebrutinib.

[0323] Furthermore, the samples can be stored and analyzed for biomarker variants that are thought to play a role in MOG antibody disease, including but not limited to serum analytes, to evaluate their association with the observed clinical response to tolebrutinib (in accordance with local regulations).

[0324] Samples can be stored for up to two years (or in accordance with local regulations) after the last visit of the last participant in the study at the facility selected by the principal investigator to enable further analysis of biomarker responses to tolebrutinib.

[0325] Example 1.7 - Statistical Considerations Example 1.7A - Sample Size Determination Approximately 25 participants will be enrolled in the trial intervention. This is a pilot, single-group, exploratory trial with little existing data in MOG antibody disease patients on which to base the calculation of sample size. Clinically, MOG antibody disease patients are estimated to relapse on average once a year. Assuming that 60% of patients have at least one relapse in a one-year period (i.e., 40% have no relapses), 25 patients provide 80% power to detect the difference between the null and alternative hypotheses, H0: π = 0.4 and H1: π ≥ 0.66 (where π represents the proportion of patients without relapse at the end of a one-year treatment period); based on an exact binomial test with a nominal 5% one-sided significance level. The inventors will reject the null hypothesis that tolebrutinib is not effective in preventing relapses in MOG antibody disease if at least 14 out of 25 patients enrolled and treated in this trial have no relapse in one year.

[0326] Example 1.7B - Populations for Analysis Define the following populations for analysis as shown in Table 7.

[0327] [Table 18]

[0328] Participants exposed to the trial intervention before or without registration are not considered registered and are not included in any analysis population. The safety experience of these participants is reported separately.

[0329] For any participant registered multiple times, only the data related to the first registration is used in any analysis population. The safety experience related to subsequent registrations is reported separately.

[0330] Example 1.7C - Statistical Analysis The Statistical Analysis Plan (SAP) contains a more technical and detailed description of the statistical analysis described in this section. This section is a summary of the planned statistical analysis of the most important endpoints, including the primary endpoints and the major secondary endpoints. Assuming this is a single-arm efficacy trial, most of the data will be presented as descriptive statistics.

[0331] Example 1.7C1 - General Considerations The baseline value is defined as the last available value before the first dose of the IMP. For enrolled but untreated participants, the baseline value is defined as the last available value before enrollment. The baseline EDSS is calculated as the average of the screening and Day 1 assessment values.

[0332] The observation period is divided into three segments. · The pre-treatment period is defined as the period from the signed ICF to the first administration of the IMP. · The on-treatment expressed (TE) period is defined as the period from the first administration of the IMP to the last administration of the IMP + 10 days. · The post-treatment period is defined as the period from the end of the treatment-urgent period to the last study assessment of the participant.

[0333] Example 1.7C2 - Primary Endpoints Provide point estimates and exact 95% confidence intervals for the proportion of participants who have not relapsed at 1 year in the PP population. The observed success rate will help in the decision of whether to continue the development of trehalostatinib in MOG antibody disease.

[0334] Calculate the time to relapse after enrollment and provide a Kaplan-Meier (KM) plot of the cumulative incidence to show the course of relapse onset over time in the PP population. The proportion of participants who relapsed at 3, 6, 9, and 12 months is calculated using the KM estimates. Participants who completed treatment without relapse are censored at the end of treatment.

[0335] A sensitivity analysis will be provided that includes participants who discontinued the investigational treatment for reasons other than recurrence. · All of these participants will be censored at the date of early treatment discontinuation. · If any, participants who experienced recurrence within 10 days after early discontinuation of trebentini will be included as having an event, and other participants will be censored at early treatment discontinuation date + 10 days.

[0336] The time to recurrence in trebentini will be investigated compared to the time to recurrence in the same group of participants at 1 year after the start of their first treatment for MOG antibody disease, although their previous treatments will be variable. Further, the time to recurrence in trebentini will also be investigated compared to the time to recurrence at 1 year after the start of the first treatment for MOG antibody disease in an external control group with matching propensity scores. Crude KM curves and estimates will be provided. Various statistical methods will be explored to provide an estimate of the reduction in the probability of recurrence in trebentini compared to "other treatments". Details will be described in the SAP.

[0337] Example 1.7C3 - Secondary endpoints The changes in EDSS and MOG antibody titers from baseline after 1 year of trebentini treatment will be summarized for secondary efficacy endpoints in the recurrence-free PP population.

[0338] Example 1.7C4 - Tertiary / exploratory endpoints Details of any tertiary / exploratory endpoints are included in the SAP.

[0339] Example 1.7C5 - Safety analysis All safety analyses will be performed on the safety population.

[0340] Example 1.7C6 - Adverse events General common rules for adverse events: An AE summary will be provided according to the number of events. In a few cases, a list of events will be provided.

[0341] AE is analyzed in the following three categories. · Pre-treatment AE: AE that developed, worsened, or became severe during the pre-treatment period. · TEAE: AE that developed, worsened, or became severe during the period of manifestation under treatment. · Post-treatment AE: AE that developed, worsened, or became severe during the post-treatment period.

[0342] List information regarding death.

[0343] Analysis of all adverse events: An adverse event incidence table is provided for all types of TEAE. All TEAE, all AESI manifested under treatment (defined by PT or predefined grouping), all SAE manifested under treatment, and all TEAE resulting in permanent treatment discontinuation.

[0344] The AE summary is generated in terms of the number (%) of participants who experienced at least one event.

[0345] Death is also analyzed.

[0346] Example 1.7C7 - Test variables, vital signs, and electrocardiogram (ECG) Quantitative analysis: For test variables, vital signs, and ECG variables, descriptive statistics of the results and changes from baseline are provided for each planned visit during the treatment period. These analyses are performed using central measurements for MOG antibody titers and other test variables and local measurements for vital signs and ECG variables.

[0347] Analysis of test, ECG, and vital sign abnormalities: Summarize potentially clinically significant test, ECG, and vital sign abnormalities.

[0348] Example 1.7C8 - Other safety Provide a summary of participants regarding the C-SSRS categories of suicidal thoughts or suicidal behavior.

[0349] Example 1.7C9 - Other analyses The biomarker discovery analysis included in the test report is described in the SAP.

[0350] Example 1.7C10 - Interim Analysis There is no planned interim analysis for this test.

[0351] Example 1.8 - Documentation and Operational Considerations Support Example 1.8A - Clinical Tests The tests detailed in the following table of Table 8, if feasible, are performed by the central laboratory. Local test results are only required if the central test results are not available in time for either test intervention administration and / or response assessment. Further, if local test results are used to perform either test intervention determination or response assessment, the results must be entered into the eCRF.

[0352] Protocol - specific requirements regarding inclusion or exclusion of participants are detailed in Tables 3 and 4.

[0353] Additional tests can be performed at any time during the trial if the principal investigator of the clinical trial determines it is necessary or if required by local regulations. Additional serum or urine pregnancy tests can be performed at any point during a subject's participation in the trial to establish the absence of pregnancy if determined necessary by the principal investigator of the clinical trial or if required by local regulations.

[0354]

Table 19

[0355]

Table 20

[0356] Biomarkers (Blood / Serum): Neurofilament light chain, glial fibrillary acidic protein level, tau, S100B, and B / T cell profiling (potentially for future analysis). Optional for participants who relapse during the course of the trial.

[0357] The principal investigator of the clinical trial must document the review of each laboratory safety report.

[0358] Example 1.8B - AE and SAE: Definitions and Procedures for Recording, Evaluation, Follow - up, and Reporting Definition of Example 1.8B1 - AE Definition of Example 1.8B1a - AE An AE is any adverse medical event in a patient or clinical trial participant that is temporally associated with the use of the test intervention, regardless of whether it is considered related to the test intervention.

[0359] Note: Thus, an AE can be any unfavorable, unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally associated with the use of the test intervention.

[0360] Events Meeting the Definition of Example 1.8B1b - AE Any abnormal clinical test result (hematology, clinical chemistry, or urine test) or other safety assessment (e.g., ECG, radiation scan, vital sign measurement), e.g., those that deteriorate from baseline and are considered clinically significant (i.e., not related to the progression of the underlying disease) in the medical and scientific judgment of the principal investigator of the clinical trial: · Leading to discontinuation or change in administration of the IMP, or · Meeting the severity criteria, or · Defined as an AESI.

[0361] Worsening of a chronic or intermittent existing condition, including an increase in the frequency or intensity of the condition.

[0362] A new condition was detected or diagnosed after administration of the test intervention, although it may have been present before the start of the trial.

[0363] Signs, symptoms, or clinical sequelae suggesting a drug - drug interaction.

[0364] Signs, symptoms, or clinical sequelae suggesting overdose of either the test intervention or a concomitant medication.

[0365] "Lack of efficacy" or "failure of the expected pharmacological effect" per se is not reported as an AE or SAE. Such examples are captured in the efficacy assessment. However, signs, symptoms, or clinical sequelae resulting from lack of efficacy are reported as an AE or SAE if they meet the definition of an AE or SAE.

[0366] Example 1.8B1c - Events not meeting the AE definition Clinically significant abnormal laboratory findings or other abnormal safety assessments related to pre - existing conditions, unless judged by the investigator to be more severe than expected for the participant's condition.

[0367] The disease / disorder being tested or the expected progression, signs, or symptoms of the disease / disorder being tested are those of the disease / disorder being tested or its expected progression, signs, or symptoms, unless more severe than expected for the participant's condition.

[0368] Medical or surgical treatment (e.g., endoscopy, appendectomy): The conditions leading to the procedure are AEs.

[0369] Situations where no adverse medical events occurred (social or convenient hospitalization).

[0370] The expected daily fluctuations of an existing disease or condition are present or detected at the start of the trial and do not worsen.

[0371] Example 1.8B2 - Definition of SAE SAE is defined as any adverse event at any dose that results in the following.

[0372] Results in death.

[0373] Life - threatening: The term "life - threatening" in the definition of "severe" refers to an event where, at the time of the event, the participant was at risk of death. This does not refer to an event that, hypothetically, could have caused death if it had been more severe.

[0374] The participant requires hospitalization or an extension of an existing hospitalization. Generally, hospitalization means that the participant was admitted to a hospital or emergency ward (usually including a stay of at least one night) for observation or treatment that was not appropriate in a physician's clinic or outpatient setting. Complications that occur during hospitalization are AEs. If the complication prolongs the hospitalization or meets some other significant criterion, the event is serious. If there is any doubt as to whether "hospitalization" occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of an existing condition that did not deteriorate from the baseline is not considered an AE.

[0375] Results in a permanent or significant disability / incapacity. · The term "disability" means a substantial interference with the ability of a person to perform normal life functions. · This definition is not intended to include relatively minor medical significance experiences such as uncomplicated headaches, nausea, vomiting, diarrhea, influenza, and accidental injuries (e.g., sprained ankle) that interfere with or have the potential to interfere with daily life functions but do not constitute a substantial disruption.

[0376] Is a congenital anomaly / birth defect.

[0377] Other situations. · In other situations such as other significant medical events that may place the participant at risk or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, the principal investigator of the clinical trial should make a medical or scientific judgment in determining whether an SAE report is appropriate. These events should generally be considered serious. · Note: The following list of medically important events is intended to serve as a guide in determining which conditions should be considered medically important events. This list is not intended to be exhaustive. · Intensive treatment in the emergency department or at home: - Allergic bronchospasm. - Blood disorders (i.e., agranulocytosis, aplastic anemia, myelodysplasia, myelodysplastic syndrome, pancytopenia, etc.). - Convulsions (seizures, epilepsy, epileptic seizures, syncope, etc.). · Occurrence of drug dependence or drug abuse. · ALT > 3xULN + total bilirubin > 2xULN or asymptomatic ALT increase > 10xULN. · Any event suggesting suicidal attempt or suicidal tendency. · Syncope, loss of consciousness (except when recorded as a result of blood sampling). · Vesicular skin rash. · Cancer diagnosed during the trial or deteriorated during the trial.

[0378] Example 1.8B3 - Evaluation and follow - up of AE and / or SAE Example 1.8B3a - Severity evaluation The principal investigator of the clinical trial will evaluate the severity of each AE and SAE using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, which was published on November 27, 2017. The list of MedDRA terms should first be referred to in NCI CTCAE to find the description of the severity grade of a specific AE. For AEs not listed in NCI CTCAE, the principal investigator of the clinical trial needs to evaluate the severity of the AE using general guidelines. · Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated. · Grade 2 Moderate; minimal local or non - invasive intervention indicated; limitation of instrumental ADL* according to age. · Grade 3 Severe or medically significant but not immediately life - threatening; indicated hospitalization or extension of hospitalization; invalidation; limitation of self - care ADL**. · Grade 4 Life - threatening outcome; emergency intervention indicated. · Grade 5 Death related to the AE. Note: Activities of daily living (ADL) * Instrumental ADL refers to preparation of meals, shopping for groceries or clothing, use of the telephone, money management, etc. **Self-care ADLs refer to bathing, dressing and undressing, self-nutrition, toilet use, drug intake, and not being bedridden.

[0379] Example 1.8B3b - Evaluation of Causality The principal investigator of the clinical trial has the obligation to evaluate the relationship between the test intervention and each occurrence of each AE / SAE.

[0380] "A reasonable possibility" of a relationship does not mean that the relationship cannot be excluded, but conveys that there are facts, evidence, or opinions that suggest a causal relationship.

[0381] The principal investigator of the clinical trial uses clinical judgment to determine the relationship.

[0382] Alternative causes such as underlying diseases, concomitant therapies, and other risk factors, as well as the temporal relationship between the event and the administration of the test intervention, are considered and investigated.

[0383] The principal investigator of the clinical trial also refers to the investigational medicinal product brochure (IB) or product information for the marketed product during the evaluation.

[0384] For each AE / SAE, the principal investigator of the clinical trial must record in the medical notes that the principal investigator of the clinical trial reviewed the AE / SAE and provided an evaluation of the causal relationship.

[0385] The principal investigator of the clinical trial can change their opinion on the causal relationship in light of the follow-up information and send an SAE follow-up report with an updated causal relationship evaluation.

[0386] The evaluation of causal relationship is one of the criteria used when determining regulatory reporting requirements.

[0387] Example 1.8B3c - Follow-up of AEs and SAEs The investigator is obliged to perform or arrange for the performance of supplementary measurements or evaluations as medically indicated to clarify as completely as possible the nature or causal relationship of an AE or SAE. This may include additional tests or investigations, histopathological examinations, or consultations with other medical specialists.

[0388] Example 1.8C - Liver and Other Safety: Recommended Actions and Follow - up Assessments These operations 2, 3, 4A, 5, and 6 described in Table 10 and the figures below are only required for ALT increases and thrombocytopenia events. For all other safety events described, these are suggested by the medical judgment of the investigator.

[0389] Thrombocytopenia should only be recorded as an AE if at least one of the criteria listed in the general guidelines for reporting adverse events in Example 1.8B is met (Figure 3).

[0390] Neutropenia should only be recorded as an AE if at least one of the criteria listed in the general guidelines for reporting adverse events in Example 1.8B is met.

[0391] Abbreviations in Figure 4A: 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: Investigational medicinal product; INR: International normalized ratio; LFT: Liver function test; LKM: Liver - kidney microsomal antibody; PT: Prothrombin time; ULN: Upper limit of normal

[0392] Note: In Figure 4A, "baseline" refers to the ALT sampled at baseline visit, or, if the baseline value is not available, the most recent ALT sampled before the baseline visit. This algorithm is not applicable in case of an increase in ALT during screening.

[0393] In Figure 4A, normalization is defined as ≤ ULN or as the baseline value if the baseline value is > ULN.

[0394] An increase in serum creatinine is recorded as an AE only if at least one of the criteria listed in the general guidelines for reporting adverse events in Example 1.8B is met (Figure 5).

[0395] An increase in CPK should be recorded as an AE only if at least one of the criteria of the general guidelines for reporting adverse events in Example 1.8B is met.

[0396] If either the clinical symptoms or the MRI features of a participant suggest PML, the following diagnostic and action algorithm is recommended (Figure 6).

[0397] Abbreviations in Figure 6: CSF: cerebrospinal fluid; Gd: gadolinium; IMP: investigational drug; JCV: John Cunningham virus; MRI: magnetic resonance imaging; PCR: polymerase chain reaction; PML: progressive multifocal leukoencephalopathy.

[0398] Table 9 proposes the characteristics of clinical symptoms or MRI lesions suspected of PML.

[0399]

Table 21

[0400] If PML is suspected based on the imaging results, the local radiologist should notify the principal investigator directly, and intensive MRI review is not required. The principal investigator will obtain additional plasma, urine, and CSF samples for JCV analysis. Samples will be analyzed upon receipt, and the results will be provided directly to the trial facility and the sponsor. Further management is delegated to the principal investigator. However, the next step includes discontinuation of the investigational treatment. Additional imaging is at the discretion of the principal investigator depending on the post-diagnostic workup and treatment plan.

[0401] Detection of JCV DNA in the CSF of patients with clinical and MRI features suggestive of PML establishes the diagnosis of PML.

[0402] If JCV DNA is not detected in the CSF and the clinical suspicion of PML remains high, another lumbar puncture should be performed.

[0403] If the diagnosis remains uncertain and the suspicion of PML remains high, a brain biopsy can be considered to establish a definitive diagnosis.

[0404] Clinical or MRI features suggestive of PML should be recorded as AE / AESI / SAE according to the definitions and procedures of Example 1.8B.

[0405]

Table 22

[0406]

Table 23

[0407] Example 1.8D - Diagnostic Criteria for MOG Antibody Diseases For a definitive diagnosis of MOG antibody disease, all of the following criteria must be met (Jarius et al. J Neuroinflammation 2018, 15, 134): · Monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, or encephalitis, or any combination of these syndromes. · MRI or electrophysiological (visual evoked potentials in patients with isolated optic neuritis) findings consistent with CNS demyelination. · Serum positivity rate of MOG-IgG detected by a cell-based assay using full-length human MOG as the target antigen.

[0408] Example 1.8E - Abbreviations ADL: Activities of daily living AE: Adverse event AESI: Adverse event of special interest ALT: Alanine aminotransferase aPTT: Activated partial thromboplastin time ARF: Acute renal failure ARR: Annual relapse rate BTK: Bruton's tyrosine kinase CDP: Confirmed 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 study 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 (electrocardiogram), electrocardiography (electrocardiography) eCRF: Electronic case report form EDSS: Expanded Disability Status Scale EDTA: Ethylenediaminetetraacetic acid eGFR: Estimated glomerular filtration rate EOS: End of study 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: Pamphlet for principal investigators ICF: Informed consent form ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use IEC: Independent ethics committee Ig: Immunoglobulin IL: Interleukin IMP: Investigational medicinal product INR: International normalized ratio IRB: Institutional review board ITT: Intention to treat IUD: Intrauterine device IUS: Intrauterine system IV: Intravenous IVIg: Intravenous immunoglobulin JCV: John Cunningham virus KM: Kaplan–Meier 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-investigational medicinal product NMO: Neuromyelitis optica NSAID: Non-steroidal anti-inflammatory drug NYHA: New York Heart Association OCT: Optical coherence tomography ON: Optic neuritis PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive multifocal leukoencephalopathy PP: Per protocol PT: Prothrombin time QTcF: QTc interval corrected using Fridericia's formula RMS: Relapsing-remitting multiple sclerosis RNFL: Retinal nerve fiber layer SAE: Serious adverse event SAP: Statistical analysis plan 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

[0409] Example 2 - Trial of Tolebrutinib, a BTK Inhibitor, in Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) Example 2.1 - Rationale for Introduction and Trial Tolebrutinib is a brain-penetrant inhibitor of Bruton's tyrosine kinase (BTK). This compound has been developed for the treatment of myelin oligodendrocyte glycoprotein antibody disease (MOGAD). This trial is designed to collect evidence of its efficacy and safety in an active relapsing MOGAD population.

[0410] MOGAD is a recurrent immune-mediated disease of the central nervous system that causes vision loss, weakness, sensory loss, bowel / bladder dysfunction, and cognitive impairment (Narayan et al. Mult Scler Relat Disord 2018, 25, 66-72). Within the spectrum of CNS autoimmune diseases, MOG antibody disease overlaps with multiple sclerosis (MS). Pathologically, anti-MOG appears to be similar to MS with macrophage infiltration and limited humoral deposits with demyelination and intact axons (Hoftberger et al. Acta Neuropathol 2020, 139, 875-892). Clinically, MOGAD attacks show a predilection for the optic nerve (66% of attacks), and unlike MS, there is no known progressive course of the disease for MOG. That is, if relapses can be prevented, the disease is effectively in remission.

[0411] The graphical scheme of the test design is shown in Figure 1B. Table 11 shown below describes the activity schedule during a series of tests. Table 12 below describes the objectives and endpoints of the entire test.

[0412]

Table 24

[0413]

Table 25

[0414]

Table 26

[0415]

Table 27

[0416]

Table 28

[0417]

Table 29

[0418]

Table 30

[0419]

Table 31

[0420]

Table 32

[0421] The treatment objectives and endpoints are shown in Table 12.

[0422]

Table 33

[0423]

Table 34

[0424] Validity of measurement Patients with MOG antibody disease appear to accumulate deficits in a stepwise progression caused by relapses that sometimes result in a persistent loss of neurological function (Jurynczyk et al. Brain 2017, 140, 3128 - 3138). Therefore, prevention of relapse is a clinically important outcome and the goal of any potential disease-modifying therapy.

[0425] The measurement of the accumulation of neuropathy is an important clinical endpoint in demyelinating diseases of the central nervous system. The EDSS is widely used to measure neurological impairment in clinical trials and in daily situations. In this test, the EDSS is evaluated by a limited neurological test conducted via remote video (Bove et al. Mult Scler 2019, 25, 1526 - 1534). Considering the number of participants and the duration of this pilot study, the change from baseline in EDSS after 1 year of treatment with trehalosamine will be measured as an exploratory endpoint.

[0426] MOG antibody levels over time can be transient in the course of monophasic disease and persistence is associated with patients who are most likely to experience a relapsing disease course or incomplete recovery, or relapse (Reindl and Waters Nat Rev Neurol. 2019, 15, 89 - 102). Persistent MOG Ab titers over 6 months are associated with a higher risk of a relapsing phenotype that can be present in nearly 88% of patients with MOGAD disease (Lopez - Chiriboga et al. JAMA Neurol 2018, 75, 1355 - 1363). There is also preliminary evidence indicating that high MOG antibody titers may be associated with a more aggressive disease (Tea et al. Acta Neuropathol Commun. 2019, 7, 145). Therefore, reducing or eliminating MOG antibody titers could be a positive outcome of treatment with potential disease - modifying therapies.

[0427] MRI imaging of the brain, optic nerve, and spinal cord plays an important role in MOGAD diagnosis and the management of relapses with severe seizures associated with large T2 lesions in the brain or spinal cord. In MOG antibody disease, disease lesions are likely to resolve completely, for example, compared to other demyelinating conditions (MS and NMO) (Sechi et al. Neurology 2021, 97, e1097-e1109). Optic neuritis is the most common clinical manifestation of MOG antibody disease; thus, optical coherence tomography (OCT) is applicable for the confirmation of acute attacks and the evaluation of damage to the optic nerve (Chen et al. Mult Scler Relat Disorder. 2022, 58, 103525).

[0428] The BDI-II is a widely used 21-item self-report inventory for measuring the severity of depression in adolescents and adults (Beck and Steer 1993 Beck Anxiety Inventory Manual. San Antonio, TX: Psychological Corporation). It can be administered orally and is suitable for use in a virtual clinic setting.

[0429] In addition to the above evaluations, serum / blood biomarker measurements are analyzed in this trial as exploratory supportive efficacy data.

[0430] Example 2.2 - Study Design Example 2.2A - Overall Design This is a Phase 2 open-label single-arm single-site trial to evaluate the efficacy and safety of 60 mg of tolebrutinib once daily in participants with MOG antibody disease. During screening, participants will discontinue any ongoing immunosuppressive therapy and will receive prednisone treatment daily for 4 weeks during this washout period. After screening, eligible participants will be enrolled to receive a 60 mg oral daily dose of tolebrutinib and will complete a steroid taper over the first 4 weeks of the trial. The primary endpoint is the proportion of participants who are treatment-naïve and relapse-free 1 year after enrollment. Participants who consult with the principal investigator of the study may choose to continue study treatment after 1 year of enrollment and remain in the study until the final data collection for the primary analysis. When the last enrolled participant completes 1 year of treatment, a study end-of-study (EOS) will occur for all participants. Thus, the total treatment period will vary by individual depending on the enrollment time, and the maximum possible period is 24 months of treatment (e.g., for the first enrolled subjects).

[0431] The trial will be conducted entirely remotely without the need for in-person visits to the site. All participants will participate in virtual visits every 3 months, which will include limited neurological examinations, relapse, and adverse event monitoring conducted via remote video (Bove et al. Mult Scler 2019, 25, 1526–1534). Participants will receive sample kits at home and will visit a remote central laboratory service for collection of samples for MOG antibody titers and other laboratory monitoring. In addition to the regular virtual visits, if a participant reports new neurological symptoms consistent with a relapse of MOG antibody disease, a relapse evaluation will be initiated if it includes MRI of the optic nerve and / or spinal cord and / or brain according to the clinical symptoms and related neurological signs and symptoms. Optical coherence tomography (OCT) may also be performed if needed to confirm a relapse.

[0432] Participants who meet the recurrence criteria will be treated for recurrence by physicians in their region (in accordance with local standard treatment) and will attend a recurrence visit for remote follow-up scheduled 4 weeks after the onset of recurrence symptoms. The principal investigator and the participant may choose for the participant to continue taking trebananib until the end of the trial, based on the individual symptoms and the assessed risk of further disease activity.

[0433] The principal investigator should document in the source documents the discussion with the participant and the decision on recurrence treatment. If discontinuation of the investigational medicinal product is decided, the participant will complete the end of the trial visit within 4 to 8 weeks after the last administration of the investigational medicinal product.

[0434] Example 2.2B - Number of Participants Approximately 30 participants will be screened to achieve 25 enrollments.

[0435] Example 2.2C - Intervention Group and Duration All participants will be screened over a 4-week period to review the consent form and confirm eligibility for the trial. Participants must complete a washout of any background immunotherapy, and since this period depends on the half-life of each treatment, it may need to start before the 4-week screening period (see Exclusion Criterion E07 in Table 14). Participants will be administered 20 mg of prednisone daily throughout the 4-week screening period while completing a washout of any background immunotherapy. Prednisone will then be tapered by 5 mg per week to complete discontinuation at the start of the treatment period, concurrent with the use of 60 mg of trebananib daily.

[0436] Except for the treatment of confirmed recurrence, no further prednisone or immunotherapy will be permitted during the 1-year study period.

[0437] Example 2.2D - Rationale The objective of this open-label, single-arm Phase 2 trial is to evaluate the efficacy and safety of 60 mg of tolebrutinib daily in the MOGAD patient population. Efficacy assessment will primarily focus on evaluating the proportion of patients maintaining remission over a 1-year treatment period. Relapse is confirmed by objective evidence of lesions on brain or spinal cord MRI corresponding to acute symptoms. This trial provides a preliminary assessment of evidence of the potential efficacy of the compound in the MOGAD population.

[0438] Example 2.2E - Dose Regimen The selection of a 60 mg dose of tolebrutinib taken with food is based on the results of a Phase 2b dose - ranging trial of tolebrutinib in adult participants with relapsing multiple sclerosis (DRI15928).

[0439] Analysis of PK data and the effect of feeding status on tolebrutinib exposure showed a positive diet effect with an approximately 2 - fold increase in AUC0 - 24. Furthermore, the correlation between treatment response and exposure to tolebrutinib showed that higher exposure was associated with fewer new gadolinium - enhancing T1 hyperintense lesions after 12 weeks of treatment. Overall, these data support the recommendation to take tolebrutinib with food.

[0440] There was no correlation between the dose of tolebrutinib administered and the number of TEAE. The most common events (preferred terms) observed in participants in the tolebrutinib treatment 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.

[0441] Example 2.2F - End of Trial Definition Participants are considered to have completed the trial by completing all stages of the trial, including 12 months of clinic visits. However, participants who relapsed during the trial and discontinued the trial treatment are considered to have completed the trial if they participated in an early - termination clinic visit.

[0442] This trial has a common purpose for all participants after the last data collection of the primary endpoint. The last data collection of the primary endpoint is conducted when the last participant without recurrence has completed the 12-month visit. With an approximately 12-month planned recruitment period, a 1-year core trial treatment period, and follow-up visits 4 to 8 weeks after the last administration, the estimated total duration of the trial is approximately 28 to 32 months.

[0443] The trial period for an individual will also vary based on the occurrence of recurrence and the timing of enrollment. The minimum and maximum treatment periods for individual participants who have not experienced recurrence are 12 months and 24 months, respectively. In addition, follow-up visits are conducted 4 to 8 weeks after the last administration.

[0444] Example 2.3 - Test Population Example 2.3A - Inclusion Criteria Participants are eligible to be included in the trial only if all of the following criteria are applied as shown in Table 13.

[0445] [Table 35]

[0446] [Table 36]

[0447] [Table 37]

[0448] Example 2.3B - Exclusion Criteria If any of the following criteria are applied as shown in Table 14, the participant will be excluded from the trial.

[0449] [Table 38]

[0450]

Table 39

[0451]

Table 40

[0452]

Table 41

[0453]

Table 42

[0454]

Table 43

[0455]

Table 44

[0456]

Table 45

[0457] Example 2.3 Considerations for C-Lifestyle Diet and dietary restrictions: Tretinib (IMP) shall be taken with a normal diet. If possible, the meal at which IMP is taken (e.g., breakfast, lunch, or dinner) should be consistent throughout the entire study. A typical meal at which IMP is taken is collected at each visit. If it is necessary to change the meal time for IMP administration, a minimum 12-hour gap should be maintained between two administrations.

[0458] Caffeine, alcohol, and tobacco: Throughout the trial, IMP should be used with caution in participants who are warned not to consume a significant amount of alcohol, defined as > 20 gr per day (14 grams in 2 glasses (1 standard drink)) in female participants, or > 30 gr per day (28 grams in 3 glasses (2 standard drinks)), or in some cases > 40 gr per day (4 glasses).

[0459] Example 2.4 - Test Intervention and Combination Therapy The test intervention was defined as any test intervention, commercial product, placebo, or medical device intended to be administered to the test participants according to the test protocol.

[0460] Example 2.4A - Administered Test Intervention and Combination Therapy This test intervention includes IMP and investigational medicinal products (NIMP). To maintain blinding, participants are administered 4 tablets of the BTK inhibitor or placebo once a day in a blinded manner. The details of the intervention are shown in Table 15.

[0461]

Table 46

[0462] The details of the investigational medicinal products are shown in Table 16.

[0463]

Table 47

[0464] Example 2.4B - Measures to Minimize Bias: Randomization and Blinding This is an unblinded trial, and the potential bias is reduced by the following steps. An objective scale is used to determine the primary outcome of recurrence. Recurrence is clinically defined, but MRI confirmation of the seizure explaining the clinical symptoms is also required.

[0465] Example 2.4C - Dose Modification Changes in dosage are not anticipated in this trial. If it is considered necessary due to AE or recurrence, treatment may need to be interrupted or permanently discontinued.

[0466] Example 2.4 D - Continued access to interventions after the end of the trial Currently, after the end of the trial, no trial intervention with trebrutinib is planned.

[0467] Example 2.4 E - Combination therapy Any medications or vaccines (including over-the-counter or prescription medications, vitamins, or herbal supplements) that participants are receiving at the time of registration or during the trial must be recorded along with: reason for use, administration dates including start and end dates, dosing information including dose and frequency

[0468] Live (attenuated) vaccines should not be administered during the intervention period.

[0469] Treatment of MOG antibody disease as described in exclusion criterion E07 is not permitted after registration and during the core trial intervention period. Short-term use (3 - 7 days) of glucocorticoids (e.g., in the case of acute disease) and topical corticosteroids (e.g., topical, nasal, ocular, otic, intra-articular) is permitted. In the case of recurrence, acute treatment may be considered as recommended in Table 16 of the recurrence treatment recommendations. Additionally, in consultation with the trial physician in charge, participants being treated by a neurologist should evaluate the benefits and risks of continuing trial treatment.

[0470] Participants should refrain from taking prescription or non-prescription medications (including vitamins and dietary or herbal supplements) within 7 days before the start of trial intervention (or 14 days if the drug is a potential enzyme inducer) or within 5 half-lives (whichever is longer) until the completion of follow-up visits, in the opinion of the trial physician in charge and the trial sponsor, unless the drug interferes with the trial.

[0471] For the treatment of MOG antibody disease symptoms (e.g., gait disorder, spasticity, incontinence, pain), the drug should be maintained at a stable dose before screening and during the treatment period, provided that it is clinically feasible.

[0472] Anticoagulant / antiplatelet therapy is not permitted to be carried out simultaneously with IMPs including: acetylsalicylic acid (aspirin) > 81 mg / day; antiplatelet drugs (e.g., clopidogrel); warfarin (vitamin K antagonist); heparin including low molecular weight heparin (antithrombin agent); dabigatran (direct thrombin inhibitor); apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitor).

[0473] Paracetamol / acetaminophen at a dose of 3 grams / day or less is permitted for use at any point during the trial. If clinically necessary for the treatment of existing medical conditions or new events, during the trial, a non-steroidal anti-inflammatory drug (NSAID) (other than acetylsalicylic acid), preferably a selective cyclooxygenase-2 inhibitor at the lowest effective dose, etc., may be administered for a short period (maximum 5 days). The investigator in charge of the clinical trial must record the use of NSAIDs (and other uses) in the eCRF.

[0474] CYP inhibitor / inducer: Potent and moderate inducers of CYP3A or potent inhibitors of CYP2C8 hepatic enzymes are not permitted throughout the trial.

[0475] Example 2.5 - Discontinuation of trial participation and discontinuation / withdrawal of participants Example 2.5A - Discontinuation of trial intervention Example 2.5A1 - Permanent interruption Except in the case of recurrence of MOG antibody disease, the trial intervention should be continued as much as possible. In the case of recurrence, participants being treated by a neurologist in consultation with the investigator in charge of the clinical trial should evaluate the benefits and risks of continuing the trial treatment, or may choose to switch to another immunomodulatory / immunosuppressive therapy. Permanent interruption of the intervention is any treatment interruption related to the final decision by the investigator in charge of the clinical trial or the participant not to re-expose the participant to the trial intervention at any time.

[0476] The legitimate reasons for the principal investigator of the clinical trial to discontinue the administration of the investigational drug to the participant may be as follows. · An adverse event that poses a risk to the safety of the participant, or when the principal investigator and / or the participant consider it desirable or necessary to discontinue the trial intervention. · When the IMP discontinuation criteria are met in accordance with the guidance for follow-up of abnormal test results (Example 2.8A). · In the opinion of the principal investigator of the clinical trial, the participant is no longer deriving a therapeutic / clinical benefit. · At the request of the participant, i.e., withdrawal of consent for treatment. · When a female participant becomes pregnant during the trial or wishes to become pregnant. · Severe opportunistic infection · Continuing need for chronic use of a prohibited concomitant medication.

[0477] When the participant meets one of the conditions outlined in the algorithm (Example 2.8C), or when the principal investigator of the clinical trial considers it to be in the best interest of the participant, the principal investigator of the clinical trial should consider discontinuing the trial intervention for abnormal liver function.

[0478] Clinically significant abnormal clinical test values or ECG parameters are immediately retested for confirmation 24 hours later before determining the final discontinuation of the IMP for the relevant participant.

[0479] If clinically significant findings are confirmed on ECG after registration (including changes from the baseline of the QT interval corrected using, but not limited to, the Fridericia formula [QTcF]), the principal investigator or qualified designee shall determine whether the participant can continue in the study and whether any changes to the participant's management are required. Review of the ECG findings by a cardiologist may be considered for the final decision to discontinue the study intervention due to ECG changes. This review of the ECG printed at the time of collection must be documented. Any new clinically relevant findings should be reported as an AE. For data collected at the time of intervention discontinuation and follow-up and any additional evaluations that need to be completed, refer to the SoA (Example 2.1).

[0480] If the study intervention is permanently discontinued, the participant is required to complete early termination of the treatment visit. For data collected at the time of the visit and follow-up and any additional evaluations that need to be completed, refer to the SoA (Example 2.1). All cases of final study drug discontinuation must be recorded on the appropriate page of the eCRF if considered confirmed.

[0481] Example 2.5A2 - Temporary Interruption Interruption of the temporary intervention due to suspicion of an AE or interruption of the clinical trial due to a regional or national emergency declared by a government agency: Emergency measures for a regional or national emergency declared by a government agency) may be considered by the principal investigator of the treatment study. For all temporary intervention interruptions, the duration should be recorded by the principal investigator on the appropriate page of the eCRF.

[0482] If surgery is required during the study, consider the beneficial risk of withholding the IMP for at least 3 to 7 days before and after surgery depending on the type of surgery and the risk of bleeding.

[0483] The following shall lead to temporary treatment discontinuation. · Cytopenia: Follow the Sanofi algorithm for neutropenia and thrombocytopenia according to Example 2.8C. · Increase 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 and requiring urgent intervention; device [e.g., pacemaker]; ablation; new onset). · Suicide risk according to BDI: If the participant's score is 1 or more.

[0484] If necessary, the principal investigator or the participant may consider a temporary treatment interruption for any other reason, including concerns about safety due to disruptions in the clinical trial caused by regional or national emergencies declared by government agencies such as COVID-19 or another illness, or the need for a prohibited concomitant medication. Treatment can be resumed later if it is considered safe and appropriate and taking into account the remaining duration of the entire trial.

[0485] Example 2.5A3 - Re-challenge The restart of the IMP is carried out under careful and appropriate clinical and / or laboratory monitoring after consideration by the principal investigator in accordance with their best medical judgment, when the likelihood of the IMP's responsibility in the occurrence of the related event is low, there are no safety concerns, and the criteria for permanent treatment discontinuation are not met.

[0486] Example 2.6 - Evaluation and Procedures of the Trial The trial procedures and their timing are summarized in the SoA (Example 2.1). Waiver or exemption of the protocol is not permitted.

[0487] Compliance with the trial design requirements, including those specified in the SoA (Example 2.1), is essential and required for the conduct of the trial.

[0488] All screening evaluations must be completed and considered to confirm that potential participants meet all eligibility criteria. The principal investigator of the clinical trial shall, as necessary, maintain a screening log to record details of all screened participants, to confirm eligibility, or to record reasons for screening failure.

[0489] Procedures that are part of a participant's routine clinical management (e.g., blood counts) and are obtained prior to signing the ICF may be used for screening or baseline purposes if the procedures meet the criteria specified in the protocol and are performed within the time frame defined in the SoA (Example 2.1). Such evaluations shall be recorded in the designated fields of the CRF.

[0490] Details of blood sampling, including volumes for all laboratory evaluations, shall be provided in the informed consent form. Repeat or unscheduled samples may be taken for safety reasons or technical problems with the sample.

[0491] Example 2.6A - Efficacy Assessment The planned time points for all efficacy assessments are provided in the SoA (Example 2.1).

[0492] Key efficacy assessments (e.g., EDSS) are scored by the study team. The Expanded Disability Status Scale is a method of quantifying disability and monitoring changes in the level of disability over time (Kurtzke Neurology 1983,33,1444 - 1452). It is widely used in clinical trials and evaluations of people with MS, NMO, and MOGAD. The EDSS scale ranges from 0 to 10 in 0.5 unit increments, with higher levels of disability represented by higher scores. Scoring is based on an examination by a neurologist, with emphasis on motor (spinal cord) and visual (optic nerve) function. The EDSS is performed using a remote telephone - video - enabled examination (Bove et al.Mult Scler 2019,25,1526 - 1534).

[0493] The principal investigator of the clinical trial is responsible for confirming recurrence. In these cases, MRI findings during the acute attack and the evaluation by a local neurologist are required. MRI scans for the confirmation of recurrence and follow-up recurrence visits will be analyzed by the principal investigator of the clinical trial.

[0494] Basic MRI scans are performed locally and consist of the following sequences: T2 and T1 weighted sequences before and after administration of Gd contrast agent (if there are no contraindications). The MRI scan is to include the optic nerve and / or spinal cord and brain at baseline, and the MRI for recurrence is to include the relevant area according to the clinical symptoms and related neurological signs and symptoms.

[0495] The principal investigator of the clinical trial may, if necessary, request that participants undergo optical coherence tomography (OCT) evaluation to verify recurrence.

[0496] The MOG antibody test performed by cell-based assay includes both positive / negative results and titers. The titer is reported as the maximum dilution at which the MOG antibody is still detectable. Dilutions at Quest include 1:10, 1:20, 1:40, 1:80, 1:160, etc. The higher the titer, the greater the amount of MOG antibody in the serum.

[0497] Example 2.6A1 - Definition of recurrence of MOG antibody disease For the purposes of this trial, recurrence of MOG antibody disease is defined as the appearance of new neurological symptoms, either monophasic, acute or subacute onset, or worsening of previous neurological symptoms with objective changes on neurological examination. The symptoms must be as follows: · Due to MOG antibody disease · Persist for more than 24 hours regardless of recovery · Present at normal body temperature (i.e., without infection, excessive exercise, or overly high ambient temperature) · Preceded by at least 30 days of clinical stability (excluding previous recurrences) · Due to new or enhancing MRI lesions in the brain or spinal cord and / or optic nerve. Note: Worsening or recurrence of symptoms and signs in participants with MOG antibody disease that could reasonably be attributed to a transient conduction impairment in a previously demyelinated pathway due to an increase in deep body temperature is not considered a relapse.

[0498] Confirmation of relapse in MOG antibody disease will be made by the Investigator according to the following definition: · A confirmed relapse of MOG antibody disease is a clinically relevant change in the EDSS score performed by a local neurologist, i.e., an increase of at least 0.5 points in the EDSS score, an increase of 1 point in two functional scores, or an increase of 2 points in one functional score, excluding changes in bowel / bladder and brain function scores compared to the previously available assessment (the last EDSS assessment that did not occur during the relapse). · MRI (brain and / or spinal cord and / or optic nerve) must be performed as soon as possible to assist in the confirmation of relapse.

[0499] Example 2.6A2 - Relapse Assessment and Follow - up Relapse Clinic Visits Participants must be instructed to report immediately to the Investigator any new neurological symptoms and recurrence or worsening of previous symptoms. Furthermore, participants will be actively asked about possible relapse symptoms at each study visit.

[0500] If a relapse is suspected, an Investigator - led relapse assessment visit should be scheduled as soon as possible (within 7 days of symptom onset if possible). Assessment and confirmation of relapse of MOG antibody disease will be made by the Investigator. Management of relapse will be done locally by a neurologist's treatment according to local standard of care. Recommendations for the treatment of relapse are detailed in Table 16 and are not mandatory.

[0501] The diagnosis of MOG antibody disease recurs during the trial. Participants are instructed to immediately notify the trial team of any new visual symptoms, weakness, numbness, or bowel / bladder dysfunction. The recurrence assessment is ideally initiated within 72 hours of the onset of the change / new symptoms when the participant reports new or worsening neurological symptoms to the trial team. At this point, a virtual EDSS examination is performed remotely. The PI determines whether a series of signs and symptoms should prompt a recurrence assessment by MRI of the affected area. Recurrences during the trial are confirmed by new T2 or enhancing lesions on MRI corresponding to the signs and symptoms in this clinical context (see Example 2.6A1).

[0502] Regardless of whether the event is adjudicated as a recurrence, if the local physician / neurologist advocates for treatment, the PI does not interfere with treatment using steroids or IVIG / PLEX. The final determination of recurrence is the responsibility of the PI, but the final decision on whether to treat the recurrence is determined by the local physician / neurologist.

[0503] MRI-negative or other clinical clues of pseudo-recurrence are not counted as adjudicated recurrences for the purposes of this trial. Pseudo-recurrences are managed by the local physician or neurologist as part of routine clinical care.

[0504] All confirmed recurrences of MOG antibody disease must be reported on the recurrence eCRF page. Recurrences of MOG antibody disease should not be reported as AEs unless, in the judgment of the trial responsible physician, they are unusually severe or medically unexpected, or do not meet the definition of an SAE. An exception to this definition of an SAE is when the participant is hospitalized for standard treatment for the recurrence, and some facilities routinely hospitalize participants who require intravenous medication for treatment of the recurrence. Therefore, the SAE criterion of "hospitalization" is met based on local practice and does not reflect the severity of the event. If a recurrence results in hospitalization for any reason other than routine treatment of the recurrence (e.g., for a treatment course beyond the standard treatment described in Table 16), or if the hospitalization is prolonged, the recurrence of MOG antibody disease should be considered a serious adverse event.

[0505] If no comorbidities are suspected, safety laboratory tests are optional for this recurrence evaluation visit. If any comorbidities are diagnosed, they are reported as AEs according to the safety reporting rules.

[0506] Follow-up recurrence visits are conducted by the principal investigator of the clinical trial 4 weeks after the recurrence confirmed by the SoA (Example 2.1).

[0507] Example 2.6B - Safety Assessment All planned time points for safety assessments are provided in the SoA (Example 2.1).

[0508] Example 2.6B1 - Electrocardiogram ECG is obtained using a smartphone-compatible ECG home device that automatically calculates the heart rate and measures the PR, QRS, QT, and QTcF intervals as outlined in the SoA (Example 1.1). If the ECG device does not automatically calculate QTcF, manual calculation using a nomogram or an automated website calculator (e.g., https: / / reference.medscape.com / calculator / 48 / ecg-corrected-qt) is permitted.

[0509] Example 2.6B2 - Vital Signs Temperature, heart rate, and blood pressure are remotely evaluated by the participants at home using a smartphone-compatible home device.

[0510] Measurements of blood pressure and heart rate are evaluated with the participant in the supine or seated position using a fully automated device. Manual techniques are used only if an automated device is not available.

[0511] Prior to measuring blood pressure and heart rate, the participant should be given at least a 5-minute rest in a quiet environment without distraction (e.g., TV, mobile phone).

[0512] Heart rate and blood pressure measurements are taken before blood sampling for laboratory tests and consist of one heart rate and three blood pressure measurements (with three consecutive blood pressure measurements recorded at intervals of at least one minute).

[0513] Example 2.6B3 - Clinical Safety Laboratory Evaluation For the list of clinical tests to be performed, see Example 2.8A. For each SoA (Example 2.1), serological tests for hepatitis B and C are performed during screening.

[0514] The principal investigator of the clinical trial can request urgent local test data in cases of urgent safety events that enable appropriate treatment decisions. All required urgent local test data that are clinically relevant are recorded in the eCRF.

[0515] The principal investigator of the clinical trial shall review the clinical test report, document this review, and record any clinically relevant changes that occur during the trial in the AE section of the eCRF. The test report must be submitted together with the source documents. Clinically significant abnormal test findings are those not related to underlying diseases unless the principal investigator of the clinical trial determines that they are more severe than expected for the participant's condition.

[0516] All clinical tests with values considered clinically significantly abnormal during participation in the trial or within 28 days after the last dose of the trial intervention should be repeated until the values return to normal or baseline, or until the principal investigator of the clinical trial determines that they are no longer clinically significant.

[0517] If abnormal clinical test values do not return to normal or baseline within the period determined by the principal investigator of the clinical trial to be appropriate, the cause must be identified and the sponsor of the trial notified.

[0518] All laboratory evaluations required by the protocol defined in Example 2.8A must be performed according to the SoA. If the laboratory evaluation in Example 2.8C indicates discontinuation of the IMP, a temporary interruption should be considered unless otherwise specified.

[0519] If test values from laboratory evaluations not specified in the clinical trial protocol implemented in the local investigation of the facility require a change in the management of the participant, or are considered clinically significant by the principal investigator of the clinical trial (e.g., SAE or AE or dose change), the results must be recorded in the eCRF.

[0520] Example 2.6C - Adverse Events (AE), Serious Adverse Events (SAEs) and Other Safety Reports Example 2.6C1 - Report of Relapse of MOG Antibody Disease Relapses of MOG antibody disease determined from the evaluations described in 2.6A1 are exempt from being reported as AEs, except when they meet the definition of SAE, or are unusually severe or medically unexpected. Hospitalizations for relapses are not considered part of the severity criteria of this trial if they are routinely performed at that site (e.g., high-dose IV methylprednisolone).

[0521] Data on relapses of MOG antibody disease will be collected in the eCRF and analyzed as part of the efficacy analysis. Worsening of other neurological symptoms that do not meet the definition of relapse of MOG antibody disease are reported as AEs according to the general safety reporting rules.

[0522] Example 2.6C2 - Report of Safety Findings from Magnetic Resonance Imaging Magnetic resonance imaging scans need to be reviewed locally for abnormalities. In the case of clinically relevant findings, relevant information needs to be provided to the principal investigator of the clinical trial for appropriate safety reporting and to ensure appropriate management of the identified safety findings of the participant. If available, the diagnosis of the pathology as the cause of such MRI findings or the findings themselves are reported as AEs until the diagnosis is clarified.

[0523] Example 2.6C3 - Adverse Events of Special Interest Adverse events of special interest (AESIs) are adverse events (severe or non-severe) of scientific and medical interest specific to the sponsor's product or program for which continuous monitoring and immediate notification by the investigator to the sponsor are required by the principal investigator of the clinical trial. Such events may require further investigation to characterize and understand them. Adverse events of special interest can be added, amended, or removed by protocol amendment during the trial.

[0524] Pregnancy of female participants who participated in the trial, and pregnancy of female partners of male participants who participated in the trial using IMP / NIMP. · Is eligible as an SAE only if it meets one of the severity criteria (see Example 2.8B). · If a female participant becomes pregnant, the IMP should be discontinued. · Observation of the course of pregnancy of female participants or female partners of male participants is essential until the results are determined.

[0525] Symptomatic overdose (severe or non-severe) with IMP. · Overdose of IMP (accidental or intentional) is an event suspected by the investigator of the clinical trial or spontaneously reported by the participant (not based on the total number of pills taken systemically) and is defined as at least twice the intended dose within the intended treatment interval (e.g., more than 2 pills of IMP within 12 hours).

[0526] Increase in alanine transaminase (ALT) > 3x ULN. · An increase in ALT exceeding 3x ULN was confirmed by retesting within 72 hours or the absence of retesting within 72 hours.

[0527] Project-specific AESIs are as follows. · ECG observation of atrial fibrillation or atrial flutter · Severe infections (grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]), which may or may not meet the severity criteria (e.g., grade 3 febrile neutropenia). · Moderate or severe hemorrhagic events (NCI CTCAE grade 2 or higher) (including, but not limited to, symptomatic bleeding in important regions or organs such as the CNS, or intraocular hemorrhage). · Thrombocytopenia, platelet count < 75,000 / mm 3 (For the management flowchart, refer to Example 2.8C).

[0528] The definitions of AE or SAE can be found in Example 2.8B.

[0529] Adverse events are reported by the participant (or, where appropriate, by the caregiver, proxy, or legally authorized representative of the participant).

[0530] The principal investigator and qualified designees are responsible for detecting, documenting, and recording events that meet the definitions of AE or SAE, and for following up on serious AEs that are considered related to the study intervention or procedure, or AEs that cause the participant to discontinue the study intervention.

[0531] Example 2.6D - Biomarker Blood samples for biomarker testing are collected from all participants in this study as specified in the SoA (Example 2.1). Participants who relapse during the course of the study have the option to have blood samples taken for biomarkers from that point forward.

[0532] The collection of whole blood samples for biomarker testing is also part of this study.

[0533] The samples will be tested to evaluate their association with the observed clinical response to the biomarker and tolebrutinib.

[0534] Furthermore, the samples will be stored and analyzed for biomarker variants that are thought to play a role in MOG antibody disease, including but not limited to serum analytes, to evaluate their association with the observed clinical response to tolebrutinib (in accordance with local regulations).

[0535] Example 2.7 - Statistical Considerations Example 2.7A - Sample Size Determination This is an exploratory single - group trial. From clinical experience, it is estimated that patients with MOG antibody disease relapse on average once a year, which means that about 40% are expected to be relapse - free in a given year. In this trial, approximately 25 participants will be registered to receive the trial intervention. It would be clinically meaningful to observe that at least 65% (n = 16) of the participants are relapse - free after one year of treatment with trehalizumab.

[0536] Example 2.7B - Populations for Analysis Define the following populations for analysis as shown in Table 17.

[0537] [Table 48]

[0538] Participants exposed to the trial intervention before or without registration are not considered registered and are not included in any analysis population. The safety experience of these participants will be reported separately.

[0539] For any participant registered multiple times, only the data related to the first registration will be used in any analysis population. The safety experience related to subsequent registrations will be reported separately.

[0540] Example 2.7C - Statistical Analysis The Statistical Analysis Plan (SAP) contains a more technical and detailed description of the statistical analysis described in this section. This section is a summary of the planned statistical analysis of the most important endpoints, including the primary endpoint and the main secondary endpoints. Assuming this is a single - group efficacy trial, most of the data will be presented as descriptive statistics.

[0541] Example 2.7C1 - General Considerations 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. The baseline EDSS is calculated as the average of the screening and Day 1 assessment values.

[0542] The observation period is divided into three segments. · The pre-treatment period is defined as the period from the signed ICF to the first IMP administration. · The on-treatment-emergent (TE) period is defined as the period from the first IMP administration to the last IMP administration + 10 days. · The post-treatment period is defined as the period from the end of the treatment-urgent period to the participant's last study assessment.

[0543] Example 2.7C2 - Primary Endpoint Point estimates and exact 95% confidence intervals for the proportion of participants who have not relapsed at 1 year in the PP population will be provided for evaluation as the primary endpoint. The observed success rate will help in the decision of whether to continue the development of tolebrutinib in MOG antibody disease.

[0544] Further analysis of relapse will include the calculation of time to relapse after enrollment. A Kaplan-Meier (KM) plot of the cumulative incidence will be provided to depict the course of relapse onset over time in the PP population. The proportion of participants who relapsed at 3, 6, 9, and 12 months will be calculated using the KM estimates. Participants who completed treatment without relapse will be censored at the end of treatment.

[0545] A sensitivity analysis will be provided that includes participants who prematurely discontinued the study treatment for reasons other than relapse. · All of these participants will be censored at the early treatment discontinuation date. · If any, participants who experienced relapse within 10 days after early discontinuation of tolebrutinib will be included as having an event, and other participants will be censored at early treatment discontinuation date + 10 days.

[0546] The time to recurrence in tolebrutinib will be investigated compared to the time to recurrence in the same group of participants at 1 year after the start of their first treatment for MOG antibody disease, although their previous treatments will be variable. Further, the time to recurrence of tolebrutinib will also be investigated compared to the time to recurrence at 1 year after the start of the first treatment for MOG antibody disease in an external control group with matching propensity scores. Crude KM curves and estimates will be provided. Various statistical methods will be explored to provide an estimate of the reduction in the probability of recurrence in tolebrutinib compared to "other treatments". Details will be described in the SAP.

[0547] Example 2.7C3 - Secondary endpoints The changes in EDSS and MOG antibody titers from baseline after 1 year of tolebrutinib treatment will be summarized for secondary efficacy endpoints in the PP population without recurrence.

[0548] Example 2.7C4 - Tertiary / exploratory endpoints Details of any tertiary / exploratory endpoints are included in the SAP.

[0549] Example 2.7C5 - Safety analysis All safety analyses will be performed on the safety population.

[0550] Example 2.7C6 - Adverse events General common rules for adverse events: An AE summary will be provided according to the number of events. In a few cases, a list of events will be provided.

[0551] AEs will be analyzed in the following 3 categories. · Pre-treatment AEs: AEs that occurred, worsened, or became severe during the pre-treatment period. · TEAEs: AEs that occurred, worsened, or became severe during the period of manifestation under treatment. · Post-treatment AEs: AEs that occurred, worsened, or became severe during the post-treatment period.

[0552] List information on deaths.

[0553] Analysis of all adverse events: An adverse event incidence table is provided for all types of TEAEs. All TEAEs, AESIs that occur under all treatments (PT or as defined by a specified grouping), all SAEs that occur under all treatments, and all TEAEs that result in permanent treatment discontinuation.

[0554] The AE summary is generated by the number (%) of participants who have experienced at least one event.

[0555] Deaths are also analyzed.

[0556] Example 2.7C7 - Test variables, vital signs, and electrocardiogram (ECG) Quantitative analysis: For test variables, vital signs, and ECG variables, descriptive statistics of the results and changes from baseline are provided for each planned visit during the treatment period. These analyses are performed using central measurements for MOG antibody titers and other test variables and local measurements for vital signs and ECG variables.

[0557] Analysis of test, ECG, and vital sign abnormalities: Summarize potentially clinically important test, ECG, and vital sign abnormalities.

[0558] Example 2.7C8 - Other analyses The biomarker discovery analysis included in the study report is described in the SAP.

[0559] Example 2.7C9 - Interim analysis There is no formal interim analysis planned for this study.

[0560] Example 2.8 - Support for documentation and operational considerations Example 2.8A - Clinical tests The tests detailed in the following table of Table 18, if feasible, are to be conducted by the Central Laboratory. Local test results are only required if the Central test results are not in time for either the test intervention dosing and / or response assessment. Further, if local test results are used for either making the test intervention decision or response assessment, the results must be entered into the eCRF.

[0561] Protocol-specific requirements for inclusion or exclusion of participants are detailed in Tables 13 and 14 of the protocol.

[0562] Additional tests can be conducted at any time during the trial if the Principal Investigator determines it is necessary or if required by local regulations. Additional serum or urine pregnancy tests can be performed to establish non-pregnancy at any point during a subject's participation in the trial if determined necessary by the Principal Investigator or required by local regulations.

[0563]

Table 49

[0564]

Table 50

[0565] Biomarkers (blood / serum): Neurofilament light chain and glial fibrillary acidic protein levels. Optional for participants who relapse during the course of the trial.

[0566] The Principal Investigator must document the review of each laboratory safety report.

[0567] Example 2.8B - AE and SAE: Definitions and procedures for recording, evaluation, follow-up, reporting Definition of Example 2.8B1 - AE Definition of Example 2.8B1a - AE An AE is any adverse medical event in a patient or clinical trial participant that is temporally associated with the use of an investigational intervention, whether or not considered related to the investigational intervention.

[0568] Note: Thus, an AE can be any unfavorable unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally associated with the use of an investigational intervention.

[0569] Example 2.8B1b - Events Meeting the AE Definition Any abnormal clinical laboratory result (hematology, clinical chemistry, or urine test) or other safety assessment (e.g., ECG, radiologic scan, vital sign measurement), e.g., worsening from baseline that is considered clinically significant (i.e., not related to the progression of underlying disease) in the medical and scientific judgment of the treating investigator: · Leading to discontinuation or change in dosing of the IMP, or · Meeting the severity criteria, or · Defined as an AESI.

[0570] Worsening of a chronic or intermittent pre - existing condition, including an increase in the frequency or intensity of the condition.

[0571] A new condition detected or diagnosed after administration of the investigational intervention, which may have been present prior to the start of the trial.

[0572] Signs, symptoms, or clinical sequelae suggesting a drug - drug interaction.

[0573] Signs, symptoms, or clinical sequelae suggesting overdose of either the investigational intervention or a concomitant medication.

[0574] "Lack of efficacy" or "failure of an expected pharmacological effect" per se is not reported as an AE or SAE. Such examples are captured in the efficacy assessment. However, signs, symptoms, or clinical sequelae resulting from lack of efficacy are reported as an AE or SAE if they meet the definition of an AE or SAE.

[0575] Example 2.8B1c - Events that do not meet the AE definition Clinically significant abnormal test findings related to underlying diseases or other abnormal safety evaluations, unless judged by the principal investigator of the clinical trial to be more severe than expected for the participant's condition.

[0576] The disease / disorder being tested or the expected progression, signs, or symptoms of the disease / disorder being tested are those of the disease / disorder being tested or the expected progression, signs, or symptoms of the disease / disorder being tested, unless they are more severe than expected for the participant's condition.

[0577] Medical or surgical treatment (e.g., endoscopy, appendectomy): The conditions leading to the procedure are AEs.

[0578] Situations where no adverse medical events occurred (social or convenient hospitalization).

[0579] The predicted daily fluctuations of existing diseases or conditions are present or detected at the start of the trial and do not worsen.

[0580] Example 2.8B2 - Definition of SAE SAE is defined as any adverse event at any dose that results in the following.

[0581] Results in death.

[0582] Life - threatening: The term "life - threatening" in the definition of "severe" refers to an event where the participant was at risk of death at the time of the event. This does not refer to an event that hypothetically could have caused death if it were more severe.

[0583] Inpatients require hospitalization or an extension of an existing hospitalization. Generally, hospitalization means that a participant was admitted to a hospital or emergency ward (usually including at least an overnight stay) for observation or treatment that was not appropriate in a physician's clinic or outpatient setting. Complications that occur during hospitalization are AEs. If the complication prolongs the hospitalization or meets some other significant criterion, the event is serious. If there is any doubt as to whether "hospitalization" occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of an existing condition that did not deteriorate from the baseline is not considered an AE.

[0584] Result in a permanent or significant disability / incapacity. · The term "disability" means a substantial interference with the ability of a person to perform normal life functions. · This definition is not intended to include relatively minor medical significance experiences such as headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) without complications that interfere with or may interfere with daily living functions but do not constitute a substantial disruption.

[0585] Are congenital anomalies / birth defects.

[0586] Other situations: · When determining whether an SAE report is appropriate in other situations such as other significant medical events that may put the participant at risk or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, the principal investigator of the clinical trial should make a medical or scientific judgment. These events should generally be considered serious. · Note: The following list of medically important events is intended to serve as a guide for determining which conditions should be considered medically important events. This list is not intended to be exhaustive. · Intensive treatment in the emergency department or at home: - Allergic bronchospasm. - Blood disorders (i.e., agranulocytosis, aplastic anemia, myelodysplasia, myelodysplastic syndrome, pancytopenia, etc.). - Convulsions (seizures, epilepsy, epileptic seizures, syncope, etc.). · Occurrence of drug dependence or drug abuse. · ALT > 3xULN + total bilirubin > 2xULN or asymptomatic ALT increase > 10xULN. · Any event suggesting suicidal attempt or suicidal tendency. · Fainting, loss of consciousness (except when recorded as a result of blood sampling). · Vesicular skin rash. · Cancer diagnosed during the trial or deteriorated during the trial.

[0587] Example 2.8B3 - Evaluation and follow-up of AE and / or SAE Example 2.8B3a - Severity evaluation The principal investigator of the clinical trial will evaluate the severity of each AE and SAE using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, which was released on November 27, 2017. The list of MedDRA terms should first be referred to in NCI CTCAE to find the description of the severity grade of a specific AE. For AEs not listed in NCI CTCAE, the principal investigator of the clinical trial needs to evaluate the severity of the AE using general guidelines. · Grade 1 Mild; asymptomatic or mild symptoms; only clinical or diagnostic observations; no intervention is indicated. · Grade 2 Moderate; minimal local or non-invasive intervention indicated; limitation of instrumental ADL* according to age. · Grade 3 Severe or medically significant but not immediately life-threatening; indicated hospitalization or extension of hospitalization; invalidation; limitation of self-care ADL**. · Grade 4 Life-threatening outcome; indication for emergency intervention. · Grade 5 Death related to AE. Note: Activities of daily living (ADL) * Instrumental ADL refers to preparation of meals, shopping for groceries or clothes, use of the telephone, money management, etc. **Self-care ADLs refer to bathing, dressing and undressing, self-feeding, toilet use, drug intake, and not being bedridden.

[0588] Any Grade 4 or 5 event must be reported as an SAE. Grade 1-3 events are defined as "serious" if they meet at least one of the specified outcomes described in the definition of SAE.

[0589] Example 2.8B3b - Evaluation of Causality The investigator is obliged to evaluate the relationship between the study intervention and each occurrence of an AE / SAE.

[0590] "A reasonable possibility" of a relationship does not mean that the relationship cannot be excluded, but rather conveys that there are facts, evidence, or opinions that suggest a causal relationship.

[0591] The investigator uses clinical judgment to determine the relationship.

[0592] Alternative causes such as underlying diseases, concomitant therapies, and other risk factors, as well as the temporal relationship between the event and the administration of the study intervention, are considered and investigated.

[0593] The investigator also refers to the investigational medicinal product brochure (IB) or product information for the marketed product during the evaluation.

[0594] For each AE / SAE, the investigator must record in the medical notes that the investigator reviewed the AE / SAE and provided an assessment of causality.

[0595] The investigator can change their opinion on causality in light of follow-up information and send an SAE follow-up report with an updated causality assessment.

[0596] Causality assessment is one of the criteria used when determining regulatory reporting requirements.

[0597] Example 2.8B3c - Follow-up of AEs and SAEs The principal investigator of the clinical trial has the obligation to conduct or arrange for the implementation of supplementary measurements or evaluations as medically indicated in order to elucidate the nature or causal relationship of an AE or SAE as completely as possible. This may include additional tests or investigations, histopathological examinations, or consultations with other medical specialists.

[0598] Example 2.8C - Liver and Other Safety: Recommended Actions and Follow - up Evaluations These actions are described in Table 19 and Figures 2, 3, 4B, 5, and 6. For only ALT increases and thrombocytopenia events are required. For all other safety events described, these are suggested by the medical judgment of the principal investigator of the clinical trial.

[0599] Thrombocytopenia should be recorded as an AE only if at least one of the criteria listed in the general guidelines for reporting adverse events in Example 2.8B is met (Figure 3). Abbreviations in Figure 3: aPTT, activated partial thromboplastin time; EDTA, ethylenediaminetetraacetic acid; INR, international normalized ratio; PK, pharmacokinetics; PT, prothrombin time.

[0600] Neutropenia should be recorded as an AE only if at least one of the criteria listed in the general guidelines for reporting adverse events in Example 2.8B is met.

[0601] Abbreviations in Figure 4B: 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, investigational drug; INR, international normalized ratio; LFT, liver function test; LKM, liver - kidney microsomal antibody; PT, prothrombin time; ULN, upper limit of normal

[0602] Note: In Figure 4B, "baseline" refers to the ALT sampled at baseline visit, or the most recent ALT sampled before the baseline visit if the baseline value is not available. This algorithm is not applicable in case of an increase in ALT during screening.

[0603] In Figure 4B, normalization is defined as ≤ ULN or as the baseline value if the baseline value is > ULN.

[0604] Record an increase in serum creatinine as an AE only if at least one of the criteria listed in the general guidelines for reporting adverse events in Example 1.8B is met (Figure 5).

[0605] Abbreviations in Figure 5: ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, electrocardiogram; PK, pharmacokinetics.

[0606] An increase in CPK should be recorded as an AE only if at least one of the criteria of the general guidelines for reporting adverse events in Example 2.8B is met.

[0607] If either the clinical symptoms or the MRI features of the participant suggest PML, the following diagnostic and action algorithm is recommended (Figure 6).

[0608] Abbreviations in Figure 6: CSF, cerebrospinal fluid; Gd, gadolinium; IMP, investigational drug; JCV, John Cunningham virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy.

[0609] Abbreviations in Figure 8: CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetics; ULN, upper limit of normal.

[0610] Propose the characteristics of the clinical symptoms or MRI lesions suspected of PML in Table 19.

[0611]

Table 51

[0612] If PML is suspected based on the imaging results, the local radiologist will notify the principal investigator directly. The principal investigator will obtain additional plasma, urine, and CSF samples for John Cunningham virus (JCV) analysis. Samples will be analyzed upon receipt and the results will be provided directly to the study facility and the sponsor. Further management is delegated to the principal investigator. However, the next step includes discontinuation of the investigational treatment. Additional imaging is at the discretion of the principal investigator depending on post-diagnostic workup and treatment planning.

[0613] Detection of JCV DNA in the CSF of patients with clinical and MRI features suggestive of PML establishes the diagnosis of PML.

[0614] If JCV DNA is not detected in the CSF and the clinical suspicion of PML remains high, another lumbar puncture should be performed.

[0615] If the diagnosis remains uncertain and the suspicion of PML remains high, a brain biopsy can be considered to establish a definitive diagnosis.

[0616] Clinical or MRI features suggestive of PML should be recorded as AE / AESI / SAE according to the definitions and procedures of Example 1.8B.

[0617]

Table 52

[0618]

Table 53

[0619] Example 2.8D - Diagnostic Criteria for MOG Antibody Disease For the definitive diagnosis of MOG antibody disease, all of the following criteria must be met (Jarius et al. J Neuroinflammation 2018, 15, 134): · Monophasic or relapsing acute ON, myelitis, brainstem encephalitis, or encephalitis, or any combination of these syndromes. · MRI or electrophysiological (visual evoked potentials in patients with isolated ON) findings consistent with CNS demyelination. · Serum positivity rate of MOG-IgG detected by a cell-based assay using full-length human MOG as the target antigen.

[0620] Example 1.8E - Abbreviations Ab: Antibody ADL: Activities of daily living AE: Adverse event AESI: Adverse event of special interest ALT: Alanine aminotransferase aPTT: Activated partial thromboplastin time ARF: Acute renal failure ARR: Annual relapse rate BTK: Bruton tyrosine kinase CDP: Confirmed 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 study 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 (electrocardiogram), electrocardiography (electrocardiography) eCRF: Electronic Case Report Form EDSS: Expanded Disability Status Scale eGFR: Estimated Glomerular Filtration Rate EOS: End of Study 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: Investigator's Brochure ICF: Informed Consent Form ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use IEC: Independent Ethics Committee Ig: Immunoglobulin IL: Interleukin IMP: Investigational Medicinal Product INR: International Normalized Ratio IRB: Institutional Review Board ITT: Intention to Treat IUD: Intrauterine Device IUS: Intrauterine System IV: Intravenous IVIG: Intravenous Immunoglobulin JCV: John Cunningham Virus KM: Kaplan - Meier LFT: Liver Function Test LLN: Lower Limit of Normal MedDRA: Medical Dictionary for Regulatory Activities MOG: Myelin Oligodendrocyte Glycoprotein MOGAD: Myelin Oligodendrocyte Glycoprotein Antibody - Related 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 - Investigational Medicinal Product NMO: Neuromyelitis optica NSAID: Nonsteroidal anti-inflammatory drug NYHA: New York Heart Association OCT: Optical coherence tomography ON: Optic neuritis PBPK: Physiologically based pharmacokinetics PD: Pharmacodynamics PK: Pharmacokinetics PML: Progressive multifocal leukoencephalopathy PP: Per protocol PT: Prothrombin time QTcF: QTc interval corrected using Fridericia's formula RMS: Relapsing-remitting multiple sclerosis RNFL: Retinal nerve fiber layer SAE: Serious adverse event SAP: Statistical analysis plan 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), 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 recurrence in a subject having MOGAD, 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 the MOG antibody titer in a subject having MOGAD, 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 according to any one of claims 1 to 3, wherein the subject has at least one symptom of MOGAD before treatment.

5. The method according to claim 4, wherein the at least one MOGAD symptom is selected from loss of color vision, loss of vision or blurring, paralysis / paresis of the limbs, and loss of bladder / bowel control.

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

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

8. The method according to any one of claims 1 to 6, wherein the subject has had at least one confirmed recurrence in the past 12 months or two confirmed recurrences in the past 24 months at the time of screening.

9. The method according to claim 8, wherein the recurrent subject is administered a corticosteroid.

10. The method according to claim 9, wherein the corticosteroid is methylprednisolone.

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

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

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

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

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

16. The method according to any one of claims 1 to 15, wherein the dose is once a day.

17. The method according to any one of claims 1 to 16, wherein the dose is administered once a day with food.

18. The method according to any one of claims 1 to 11 or 15 to 17, wherein the dose is 60 mg and is administered once a day with food.

19. The method according to any one of claims 1 to 8 or 11 to 18, wherein the BTK inhibitor compound is administered as monotherapy.

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

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

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

23. The method according to claim 22, wherein the subject is a human subject in the range of 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 or 4 to 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 or 4 to 23 for use in a method of reducing the frequency of MOGAD relapse in a subject having MOGAD in need thereof.

26. For use in a method of reducing or eliminating the MOG antibody titer in a subject having MOGAD who requires reducing or eliminating the MOG antibody titer, 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 or 4 to 23.

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

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

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

30. (a) performing a liver function test in a patient; (b) detecting appropriate liver function in the patient; (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; comprising; the liver function test measures one or more of the levels of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total bilirubin and direct bilirubin, and total protein in the patient's blood; the patient having appropriate liver function has one or more of an ALT of 1.5x or less of the upper limit of normal value (ULN), an AST level of 1.5x or less of the ULN, an alkaline phosphatase of 2x or less of the ULN (except when caused by non-liver-related disorders or explained by stable chronic liver disorders), and a total bilirubin of 1.5x or less of the ULN (except in cases of Gilbert's syndrome or non-liver-related disorders); A method for treating MOGAD.

31. (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) measuring the level of alanine aminotransferase (ALT) in the patient; (c) detecting a level of ALT above 8x the upper limit of normal value (ULN); (d) stopping the administration of the compound to the patient, and optionally, (e) monitoring the ALT level of the patient; (f) restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN; A method for treating MOGAD, comprising.

32. (a) Administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) Measuring the level of alanine aminotransferase (ALT) in the patient; (c) Detecting a level of ALT that exceeds 5x the upper limit of normal (ULN) during a period of at least two weeks; (d) Discontinuing the administration of the compound to the patient; and optionally, (e) Monitoring the ALT level of the patient; (f) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x ULN; A method for treating MOGAD, comprising:

33. (a) Administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (b) Measuring the level of alanine aminotransferase (ALT) in the patient; (c) Detecting a level of ALT that exceeds 3x the upper limit of normal (ULN); (d) Measuring one or more of the patient's total bilirubin and international normalized ratio (INR); (e) Detecting one or more of a total bilirubin that exceeds 2x ULN and an INR that exceeds 1.5; (f) Discontinuing the administration of the compound to the patient; and optionally, (g) Monitoring the ALT level of the patient; (h) Resuming the administration of a therapeutically effective amount of the compound to the patient if it is determined that the ALT level of the patient is less than 1.5x ULN; A method for treating MOGAD, comprising:

34. (b) Administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (compound) to a patient in need thereof; (c) Measuring the level of alanine aminotransferase (ALT) in the patient; (d) Detecting a level of ALT that exceeds 3x the upper limit of normal (ULN); (e) If the patient experiences one or more of fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash, and eosinophilia greater than 5%, the step of discontinuing the administration of the compound to the patient, and optionally, (f) The step of monitoring the ALT level of the patient; (g) The step of restarting the administration of a therapeutically effective amount of the compound to the patient when it is determined that the ALT level of the patient is less than 1.5x the ULN; A method for treating MOGAD, comprising:

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 according to 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 for treating MOGAD in a patient in need of treatment for MOGAD, comprising administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient has not received a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 liver enzyme.

39. (a) Advising the patient to limit alcohol consumption during treatment; (b) Administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one; comprising: The patient is female and is advised to limit alcohol intake to 14 grams per day or less, or the patient is male and is advised to limit alcohol intake to 28 grams per day or less. A method for treating MOGAD in a patient in need of treatment for MOGAD.

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