Tyrosine kinase inhibitors for the treatment of multiple sclerosis

Abstract

The present disclosure relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton's tyrosine kinase (“BTK”) inhibitors for treating subjects with relapsing multiple sclerosis.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 415,027, filed October 11, 2022, and U.S. Provisional Patent Application No. 63 / 433,873, filed December 20, 2022, which are hereby incorporated by reference in their entireties for all purposes.

[0002] The present disclosure relates to the field of therapeutic tyrosine kinase inhibitors, particularly Bruton tyrosine kinase ("BTK") inhibitors for the treatment of relapsing multiple sclerosis (RMS). [Background technology]

[0003] Multiple sclerosis (MS) is a neurological disease affecting over one million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has a significant physical, psychological, social, and economic impact on patients and their families. MS involves an immune-mediated process in which an abnormal response of the body's immune system is directed against the central nervous system (CNS). During the progression of the disease, sclerosis, or lesions or scars, develop in the myelin sheath of nerve cells, interfering with the transmission of electrical signals. The sclerosis accumulates over time, resulting in the debilitating symptoms experienced by MS patients. MS patients generally experience one of four clinical courses: clinically isolated syndrome, relapsing-remitting, secondary progressive, or primary progressive, with mild, moderate, or severe disease. Approximately 85% of MS patients have the relapsing-remitting form of the disease, experiencing clearly defined relapses (also called exacerbations or exacerbations), which are episodes of acute deterioration of neurological function, followed by periods of partial or complete recovery (remission) without disease progression. Within the scope of this disclosure, "relapsing multiple sclerosis," "relapsing MS," or "RMS" can include clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and relapsing secondary progressive multiple sclerosis (R-SPMS). See, e.g., Lublin et al., "Defining the clinical course of multiple sclerosis; the 2013 revisions," Neurology 2014;83:278-286.

[0004] Immunomodulatory drugs are the mainstay of MS therapy. Recent results from clinical trials have demonstrated the efficacy of agents targeting B lymphocytes, particularly B cell-depleting agents such as ocrelizumab (anti-CD20) (Hauser et al., N Engl J Med. 2017;376(3):221-34). Targeting B cells demonstrates therapeutic benefit by modulating T cell activity and represents a departure from the prevailing dogma based on animal models that places B cells at the center of current MS drug development (Lehmann-Horn K et al., Int J Mol Sci. 2017;18(10):2048). The importance of immune cells present in the CNS is also well known and needs to be considered in MS pathogenesis (Hemmer B et al., Nat Clin Pract Neurol. 2006;2(4):201-11).

[0005] Despite these recent advances, there remains a significant unmet need for therapies that target neuroinflammation in the central nervous system to halt long-term disability and neurodegeneration in patients with relapsing multiple sclerosis (RMS) and progressive forms of multiple sclerosis (primary progressive multiple sclerosis (PPMS) and non-relapsing secondary progressive multiple sclerosis (NR-SPMS)) (Stys PK et al., Nat Rev Neurosci. 2012;13(7):507-14). Recent studies in progressive MS have demonstrated that even the most current, highly effective disease-modifying therapies, which primarily act on peripheral adaptive immunity to halt neuroinflammatory and neurodegenerative processes, have only a limited or temporary ability to halt disease progression (Montalban X et al, N Engl J Med. 2017;376(3):209-20; Kappos L et al, Lancet 2018;391(10127):1263-73).

[0006] In addition to existing strategies to modulate the cellular components of adaptive immunity, there is growing evidence that innate immunity mediated by myeloid cells (bone marrow-derived monocytes / macrophages and CNS-resident microglial cells) is involved in many of the neurodegenerative aspects of MS that persist despite the effectiveness of approved disease-modifying therapies in preventing acute relapses (Hemmer B et al., Lancet Neurol. 2015;14(4):406-19; Rahmanzadeh R et al.,Rev Neurosci.2018 Jun 8). Immunomodulation directed at innate immunity may suppress "smoldering neuroinflammation" and other symptoms of disease progression that remain unaddressed by currently approved therapies.

[0007] The Bruton's tyrosine kinase (BTK) pathway is important for signaling in myeloid cells, including B lymphocytes and CNS microglia. Each of these cell types is involved in the pathophysiology of multiple sclerosis (MS). Furthermore, because 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, inhibitors of BTK signaling provide a dual mechanism for targeting both aspects of the immune system.

[0008] Therefore, compounds that inhibit BTK, which can inhibit antigen-induced B cell activation involved in neuroinflammation and regulate maladaptive microglial cells associated with neuroinflammation in the brain and spinal cord, may be useful in the treatment of RMS and offer significant advantages over currently available treatments.

[0009] After discontinuing some disease-modifying therapies for MS, rebound disease activity, characterized by recurrence of neurological symptoms and brain lesions, has been reported. For example, for sphingosine-1-phosphate (S1P) receptor modulators, a mechanism has been proposed in which autoreactive lymphocytes are expelled from lymph nodes after treatment, resulting in recovery of disease activity. (Barry B, et al. Neurol Ther 2019;8(2):241-50; Gonzalez-Suarez I, et al. Brain Behav 2017;7:e00671) Therefore, new therapies that prevent rebound disease activity in RMS patients after treatment discontinuation are needed.

[0010] Drug-induced liver injury has been observed in ongoing phase 3 trials of trebrutinib. The reported events occurred within 2–3 months of initiating trebrutinib treatment, and elevated liver enzymes appear to be reversible after discontinuation of trebrutinib. Therefore, there is a need to mitigate the risk of liver injury and provide a safer treatment for patients with RMS. Summary of the Invention [Means for solving the problem]

[0011] Accordingly, the following embodiments are provided: In some embodiments, a method of reducing the incidence of multiple sclerosis (MS) relapse in a subject with relapsing multiple sclerosis (RMS) is provided, comprising: a) 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 for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the incidence of MS relapse in the subject after terminating administration of the BTK inhibitor is equal to or less than the incidence of MS relapse in the subject during the one year period prior to administration of the BTK inhibitor.

[0012] In some embodiments, the subject remains relapse-free for at least 4 weeks after stopping administration of the BTK inhibitor.

[0013] In some embodiments, the subject remains relapse-free for at least 6 weeks after stopping administration of the BTK inhibitor.

[0014] In some embodiments, the subject remains relapse-free for at least 21 weeks after completing administration of the BTK inhibitor.

[0015] In some embodiments, relapsing multiple sclerosis

[0003] Provided is a method for reducing the number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the number of new or enlarged T2 hyperintense lesions in a subject with recurrent myeloma (RMS), comprising: a) 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 for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or new or enlarged T2 hyperintense lesions measured in the subject after terminating administration of the BTK inhibitor is equal to or less than the baseline number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or new or enlarged T2 hyperintense lesions measured in the subject during the 4 weeks prior to administration of the BTK inhibitor.

[0016] In some embodiments, the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or the total number of new or enlarged T2 hyperintense lesions measured in a subject by 21 weeks after completing administration of the BTK inhibitor is 2 or less.

[0017] In some embodiments, the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks after administration of the BTK inhibitor is discontinued is 1 or less.

[0018] In some embodiments, the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or the total number of new or enlarged T2 hyperintense lesions measured in a subject by 4 weeks after completing administration of the BTK inhibitor is 1 or less.

[0019] In some embodiments, the total number of new or enlarged T2 hyperintense lesions measured in a subject by 21 weeks after administration of the BTK inhibitor has ended is 3 or less.

[0020] In some embodiments, the total number of new or enlarged T2 hyperintense lesions measured in a subject by 6 weeks after administration of the BTK inhibitor has ended is 1 or less.

[0021] In some embodiments, a method of reducing the number of gadolinium (Gd)-enhanced T1-hyperintense lesions in a subject with relapsing multiple sclerosis (RMS) is provided, comprising: a) 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 for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the total number of gadolinium (Gd)-enhanced T1-hyperintense lesions measured in the subject after terminating administration of the BTK inhibitor is equal to or less than the baseline number of gadolinium (Gd)-enhanced T1-hyperintense lesions measured in the subject before administration of the BTK inhibitor.

[0022] In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks after administration of the BTK inhibitor is discontinued is four or less.

[0023] In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks after administration of the BTK inhibitor is discontinued is 2 or less.

[0024] In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject from baseline by 4 weeks after completing administration of the BTK inhibitor is 1 or less.

[0025] In some embodiments, the dose of the BTK inhibitor is 60 mg daily.

[0026] In some embodiments, the lesion is measured by MRI.

[0027] In some embodiments, the subject is administered the BTK inhibitor for at least 16 weeks.

[0028] In some embodiments, the subject is administered the BTK inhibitor for at least 24 weeks.

[0029] In some embodiments, the subject is administered the BTK inhibitor for at least 48 weeks.

[0030] In some embodiments, the subject is administered the BTK inhibitor for at least 72 weeks.

[0031] In some embodiments, the subject is administered the BTK inhibitor for at least 96 weeks.

[0032] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) in a patient in need of treatment for RMS is provided, comprising determining whether the patient has elevated transferrin or ferritin levels if the patient is found not to have elevated transferrin or ferritin levels, and administering to the patient a therapeutically effective amount of a BTK inhibitor consisting of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0033] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided in a patient in need of treatment for RMS, comprising determining the patient's iron panel, and if the patient's iron panel is found to be adequate, 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.

[0034] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one in a patient in need of treatment for MS, wherein the patient does not exhibit elevated transferrin levels or elevated ferritin levels.

[0035] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) comprises the steps of: (a) performing an iron panel test on the patient's blood or serum; (b) detecting a level of the iron panel test that is within the normal range; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the iron panel test detects levels of iron, ferritin, transferrin, and / or erythrocyte sedimentation protein (ECF) in the blood or serum of the patient. A saturation and iron panel test is provided that includes measuring one or more levels of iron, ferritin, transferrin saturation, and total iron-binding capacity (TIBC) in a patient's blood or serum, and the normal range for the iron panel test includes one or more of: (i) an iron level of 60 to 170 μg / dL; (ii) a ferritin level of 500 μg / L or less; (iii) a transferrin saturation of 50% or less for male patients and 40% or less for female patients; and (iv) a TIBC of 240 to 450 μg / dL.

[0036] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: (a) detecting a transferrin saturation level in a patient's blood or serum that is within the normal range; and (b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the transferrin saturation level within the normal range in a male patient's blood or serum is a transferrin saturation level of 50% or less, and the transferrin saturation level within the normal range in a female patient's blood or serum is 40% or less.

[0037] In some embodiments, a method for treating relapsing multiple sclerosis (RMS) comprises: (a) detecting a ferritin level in a patient's blood or serum that is 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 patient's ferritin level within the normal range in the blood or serum is ≦500 μg / L. In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided that includes the steps of: (a) performing liver function tests in a patient; (b) detecting adequate liver function in the patient; and (c) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the liver function tests measure one or more of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein levels in the patient's blood, and wherein patients with adequate liver function have an ALT of ≦1.5 × upper limit of normal. normal (ULN), AST level ≦1.5×ULN, alkaline phosphatase ≦2×ULN (unless caused by non-liver-related disorders or explained by stable chronic liver damage), and total bilirubin ≦1.5×ULN (unless caused by Gilbert's syndrome or non-liver-related disorders).

[0038] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: (a) administering a therapeutically effective amount of a BTK inhibitor, including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (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 8× the upper limit of normal (ULN); (d) terminating administration of the compound to the patient; and optionally (e) monitoring the ALT level in the patient; and (f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be <1.5×ULN.

[0039] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: (a) administering a therapeutically effective amount of a BTK inhibitor, including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (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 5× the upper limit of normal (ULN) for at least two weeks; (d) terminating administration of the compound to the patient; and optionally (e) monitoring the ALT level in the patient; and (f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be <1.5×ULN.

[0040] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) comprises the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor, comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (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× the upper limit of normal (ULN); and (d) measuring the patient's total bilirubin and international normalized ratio (ILR). (e) detecting one or more of total bilirubin greater than 2×ULN and INR greater than 1.5; (f) terminating administration of the compound to the patient; and optionally (g) monitoring the patient's level of ALT; and (h) resuming administration of a therapeutically effective amount of the compound to the patient if the patient's level of ALT is determined to be <1.5×ULN.

[0041] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) comprises the steps of: (a) administering a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (the Compound) to a patient in need thereof; (b) measuring the level of alanine aminotransferase (ALT) in the patient; and (c) measuring 3 × upper limit of normal (ULM). (d) detecting ALT levels above 1.5xULN; (d) terminating administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally (e) monitoring the patient's ALT levels; and (f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT levels are determined to be <1.5xULN.

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

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

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

[0045] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) in a patient in need of treatment for MS is provided, comprising administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not receiving a strong, moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of CYP2C8 hepatic enzyme.

[0046] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: (a) advising the patient to limit alcohol intake during treatment; and b) administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is female and is advised to limit alcohol consumption to 14 grams / day or less, or wherein the patient is male and is advised to limit alcohol consumption to 28 grams / day or less.

[0047] In another embodiment, the dose of the BTK inhibitor is about 5 mg to about 60 mg. In another embodiment, the dose is 5 mg. In another embodiment, the dose is 15 mg. In another embodiment, the dose is 30 mg. In another embodiment, the dose is 60 mg. In another embodiment, the BTK inhibitor compound is administered as monotherapy. In some embodiments, the RMS is selected from clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and relapsing secondary progressive multiple sclerosis (R-SPMS). In another embodiment, the subject is human.

[0048] In some embodiments, the dose is once a day. In some embodiments, the dose is administered once a day with a meal. In some embodiments, a 15 mg dose is administered once a day with a meal. In some embodiments, a 30 mg dose is administered once a day with a meal. In some embodiments, a 60 mg dose is administered once a day with a meal. [Brief explanation of the drawings]

[0049] [Figure 1] FIG. 1 shows an exemplary overall design of the treatment. LTS = long-term safety study, R = randomization, S = screening, W = Week. [Figure 2A] Figure 1 shows the number of new Gd-enhancing T1-hyperintense lesions after 12 weeks of BTK inhibitor treatment after a 4-week placebo run-in (Cohort 2) and during a 4-week placebo run-out (Cohort 1). Data are means (SE). Gd: gadolinium; SE: standard error; W: week. [Figure 2B]Figure 1 shows the number of new / hypertrophic T2 lesions after 12 weeks of BTK inhibitor treatment after a 4-week placebo run-in (Cohort 2) and during a 4-week placebo run-out (Cohort 1). Data are means (SE). Gd: gadolinium; SE: standard error; W: week. [Figure 3] FIG. 1 shows B cell counts after the first BTK inhibitor administration and the end of the placebo run-out in Cohort 1. [Figure 4] This figure shows the number of new Gd-enhancing T1 hyperintense lesions after 12 weeks of BTK inhibitor administration up to the start of the long-term safety study. Data are means (standard error). DBP = double-blind period, W = week. [Figure 5] This figure shows the number of new / hypertrophic T2 lesions after 12 weeks of BTK inhibitor administration up to the start of the long-term safety study. Data are means (standard error). DBP = double-blind period, W = week. [Figure 6] This figure shows the change in T2 lesion volume from week 12 of BTK inhibitor administration to the start of the long-term safety study. Data are means (standard error). DBP = double-blind period, W = week. DETAILED DESCRIPTION OF THE INVENTION

[0050] Reference will now be made in detail to specific embodiments which are illustrated in the accompanying drawings. While this disclosure provides illustrated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of this disclosure as defined by the appended claims.

[0051] The section headings used herein are for organizational purposes only and should not be construed as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined herein, the present specification shall control. While the present teachings will be described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0052] I. Definition Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0053] As used herein, "BTK inhibitor," "BTK inhibitor compound," "trebrutinib," and "compound" refer to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one having the following structure: [ka] It has the following structure: [ka] 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one and / or a pharmaceutically acceptable salt thereof.

[0054] A "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 pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0055] "Treating" or "treatment" of a disease includes: (1) To prevent disease, e.g., to prevent the development of clinical symptoms of disease in a mammal that may be exposed to or predisposed to the disease but has not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, e.g., preventing or reducing the onset of the disease or its clinical symptoms; (3) Alleviating the disease, e.g., reversing the disease or its clinical symptoms.

[0056] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0057] A "therapeutically effective amount" means the amount of a BTK inhibitor compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0058] "Cease" or "termination" when used in reference to the administration of an active pharmaceutical ingredient (API) means that the API is no longer administered to a subject, either temporarily or permanently.

[0059] Before describing the present teachings in detail, it is to be understood that this disclosure is not limited to particular compositions or process steps, as such may vary.

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

[0061] Numerical ranges are inclusive of the numbers defining the range. Measurements and measurable values ​​are understood to be approximations, taking into account significant digits and error associated with the measurements. Also, the use of "comprise," "comprises," "comprising," "contain," "contains," "containing," and "include," "includes," "including" are not intended to be limiting. It is to be understood that both the foregoing general and detailed descriptions are exemplary and explanatory only and are not restrictive of the teachings.

[0062] Unless otherwise stated in the specification above, embodiments herein that recite various components as "comprising" are also contemplated as "consisting of" or "consisting essentially of" the recited components; embodiments herein that recite various components as "consisting of" are also contemplated as "comprising" or "consisting essentially of" the recited components; and embodiments herein that recite various components as "consisting essentially of" are also contemplated as "consisting of" or "comprising" the recited components (this interchangeability does not apply to the use of such terms in the claims).

[0063] As used herein, the terms "or combinations thereof" and "or combinations thereof" refer to any and all permutations and combinations of the listed terms preceding the term. 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 repeats of one or more items or terms, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. Those of skill in the art will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise clear from the context.

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

[0065] II. Administered BTK Inhibitor Compounds 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 relapsing multiple sclerosis (RMS) 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.

[0066] BTK inhibitor compounds can be prepared, for example, according to the methods and schemes described in U.S. Pat. No. 9,688,676 B2, particularly column 62, line 8 to column 65, line 32 and column 67, lines 28 to 69, which are incorporated herein by reference.

[0067] To enable one of ordinary skill in the art to prepare BTK inhibitor compounds, the preparation of the following compound, (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, is shown below. The synthetic routes should not be construed as limiting the scope of the present disclosure, but are merely illustrative and representative thereof.

[0068] Exemplary Synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one: [ka] In a 100 mL round-bottom flask, (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv.), DCM-CHOH (6 mL), and TEA (113 mg, 1.12 mmol, 3.00 equiv.) were added. Subsequently, prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv.) was added dropwise with stirring at 0° C. for 5 minutes. The resulting solution was stirred at 0° C. for 2 hours. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column using dichloromethane / methanol (30:1). The crude product (100 mg) was purified by Prep-HPLC under the following conditions (Column: XBridge Prep C). 18OBD Column, 5 μm, 19*150 mm; Mobile phase: Water containing 0.05% TFA and ACN (from 25.0% ACN to 45.0% in 8 min). 54.5 mg of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m / z: 465.2 (M+1).

[0069] III. Treatment method Provided herein are methods for reducing the incidence of multiple sclerosis (MS) relapses in a subject with relapsing multiple sclerosis (RMS), comprising: a) administering to a subject in need thereof a BTK inhibitor, including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the incidence of MS relapse in the subject after terminating the administration of the BTK inhibitor is equal to or less than the incidence of MS relapse in the subject during the one year period prior to the administration of the BTK inhibitor. Also provided herein are methods for reducing the incidence of MS relapses in a subject with relapsing multiple sclerosis (RMS), comprising: a) administering to a subject in need thereof a BTK inhibitor, including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the incidence of MS relapse in the subject after terminating the administration of the BTK inhibitor is equal to or less than the incidence of MS relapse in the subject during the one year period prior to the administration of the BTK inhibitor.

[0003] Provided is a method for reducing the number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the number of new or enlarged T2 hyperintense lesions in a subject with recurrent myeloma (RMS), comprising: a) 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 for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or new or enlarged T2 hyperintense lesions measured in the subject after terminating administration of the BTK inhibitor is equal to or less than the baseline number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or new or enlarged T2 hyperintense lesions measured in the subject during the 4 weeks prior to administration of the BTK inhibitor.Also provided herein is a method for reducing the number of gadolinium (Gd)-enhanced T1 hyperintense lesions in a subject with relapsing multiple sclerosis (RMS), comprising: (a) 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 for at least 12 weeks; and (b) terminating the administration of the BTK inhibitor, wherein the total number of gadolinium (Gd)-enhanced T1 hyperintense lesions measured in the subject after terminating administration of the BTK inhibitor is equal to or less than the baseline number of gadolinium (Gd)-enhanced T1 hyperintense lesions measured in the subject before administration of the BTK inhibitor. In some embodiments, the dose of the BTK inhibitor is about 5 to about 60 mg. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human. In some embodiments, the subject exhibits one or more symptoms of RMS prior to treatment, and treatment reduces or eliminates one or more symptoms. In some embodiments, the subject suffers from neuropathic pain, musculoskeletal pain, or spasticity caused by RMS.

[0070] In some embodiments, subjects with RMS have at least one documented relapse within the past year and / or more than two documented relapses within the past two years, and / or more than one active Gd-enhancing brain lesion in the past six months and on an MRI scan prior to screening.

[0071] In some embodiments, the subject remains relapse-free for at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, or at least 21 weeks after completing administration of the BTK inhibitor.

[0072] In some embodiments, a dose of about 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, or 55-60 mg is administered. In some embodiments, the dose is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg. In some embodiments, the dose is 5 mg. In some embodiments, the dose is 15 mg. In some embodiments, the dose is 30 mg. In some embodiments, the dose is 60 mg.

[0073] In some embodiments, the dose is administered daily. The daily dose can be administered as a single dose or in multiple doses. For example, in some embodiments, the dose is administered once a day (e.g., about every 24 hours). In some embodiments, the dose is administered twice a day. In some embodiments, the dose is subdivided into two portions that are administered twice a day (e.g., about every 12 hours). In some embodiments, the dose is subdivided into three portions that are administered three times a day (e.g., about every 8 hours). In some embodiments, the dose is subdivided into four portions that are administered four times a day (e.g., about every 6 hours).

[0074] In some embodiments, the dose is administered orally. In some embodiments, the dose is administered in the form of a tablet. In some embodiments, the dose is administered in the form of a pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0075] In some embodiments, the subject is administered the BTK inhibitor compound for a period of at least about 12, 16, 24, 48, 72, or 96 weeks. In some embodiments, the subject is administered the BTK inhibitor compound for a period of at least about 12 weeks. In some embodiments, the dose is once daily.

[0076] In some embodiments, the dose is administered with food. In some embodiments, the dose is administered once daily with a meal. In some embodiments, a 5 mg, 15 mg, 30 mg, or 60 mg dose is administered with a meal. In some embodiments, a 5 mg, 15 mg, 30 mg, or 60 mg dose is administered once daily with a meal. In some embodiments, a 60 mg dose is administered once daily with a meal. In some embodiments, the dose is administered in an oral solution or tablet. In some embodiments, the dose is administered in an oral solution or tablet with a meal. In some embodiments, the dose is administered once daily in an oral solution or tablet. In some embodiments, the dose is administered once daily in an oral solution or tablet with a meal. In some embodiments, a 60 mg dose is administered in an oral solution or tablet. In some embodiments, a 60 mg dose is administered in an oral solution or tablet with a meal. In some embodiments, a 60 mg dose is administered in an oral solution or tablet with a meal. In some embodiments, a 60 mg dose is administered in an oral solution or tablet once daily. In some embodiments, a 60 mg dose is administered once daily with a meal in an oral solution or tablet.

[0077] In some embodiments, administration of a BTK inhibitor reduces new active brain lesions. In some embodiments, administration of a BTK inhibitor reduces new active gadolinium (Gd)-enhancing T1 hyperintense lesions. In some embodiments, administration of a BTK inhibitor reduces new or enlarged T2 lesions.

[0078] In some embodiments, administration of a BTK inhibitor reduces the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as measured by MRI. In some embodiments, the number of new Gd-enhancing T1 hyperintense lesions is less than 1. In some embodiments, the number of Gd-enhancing T1 hyperintense lesions is less than or equal to 0.77, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1. In some embodiments, after 12 weeks of BTK inhibitor treatment, no new Gd-enhancing T1 hyperintense lesions form.

[0079] In some embodiments, administration of a BTK inhibitor reduces the number of new or hypertrophic T2 lesions as measured by MRI. In some embodiments, the number of new or hypertrophic T2 lesions is two or less. In some embodiments, the number of new or hypertrophic T2 lesions is less than or equal to 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1. In some embodiments, after 12 weeks of BTK inhibitor treatment, no new or hypertrophic T2 lesions form.

[0080] In some embodiments, administration of a BTK inhibitor reduces the total number of Gd-enhancing T1 hyperintense lesions after 12 weeks of BTK inhibitor treatment.

[0081] In some embodiments, the dose is 60 mg, and one or zero new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of BTK inhibitor treatment. In some embodiments, zero new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of BTK inhibitor treatment. In some embodiments, the number of new or hypertrophic T2 lesions is two or less. In some embodiments, the number of new or hypertrophic T2 lesions is less than or equal to 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1.

[0082] In some embodiments, administration of a BTK inhibitor reduces the total number of Gd-enhancing T1 hyperintense lesions after 12 weeks of BTK inhibitor treatment.

[0083] In some embodiments, the total number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the sum of the number of new or hypertrophic T2 hyperintense lesions measured in a subject up to 21 weeks after completion of administration of the BTK inhibitor is 2 or less, or 1 or less. In some embodiments, the total number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the sum of the number of new or hypertrophic T2 hyperintense lesions measured in a subject up to 21 weeks after completion of administration of the BTK inhibitor is zero. In some embodiments, the total number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the sum of the number of new or hypertrophic T2 hyperintense lesions measured in a subject up to 4 weeks after completion of administration of the BTK inhibitor is 1 or less. In some embodiments, the total number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the sum of the number of new or hypertrophic T2 hyperintense lesions measured in a subject up to 4 weeks after completion of administration of the BTK inhibitor is zero.

[0084] In some embodiments, the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is 2 or less. In some embodiments, the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is 1 or less. In some embodiments, the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is zero.

[0085] In some embodiments, the total number of new or hypertrophic T2 hyperintense lesions measured in a subject by 21 weeks after discontinuing administration of the BTK inhibitor is 3 or less, 2 or less, 1 or less, or zero. In some embodiments, the total number of new or hypertrophic T2 hyperintense lesions measured in a subject by 6 weeks after discontinuing administration of the BTK inhibitor is 3 or less, 2 or less, 1 or less, or zero.

[0086] In some embodiments, the total number of new or hypertrophic T2 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after administration of the BTK inhibitor is discontinued is no more than 3. In some embodiments, the total number of new or hypertrophic T2 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after administration of the BTK inhibitor is discontinued is no more than 2. In some embodiments, the total number of new or hypertrophic T2 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after administration of the BTK inhibitor is discontinued is less than or equal to 1. In some embodiments, the total number of new or hypertrophic T2 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after administration of the BTK inhibitor is discontinued is zero. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks after discontinuing administration of the BTK inhibitor is 4 or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks after discontinuing administration of the BTK inhibitor is 2 or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 4 weeks after discontinuing administration of the BTK inhibitor from baseline is 1 or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is four or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is 3 or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is 2 or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after discontinuing administration of the BTK inhibitor is 1 or less. In some embodiments, the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in a subject by 21 weeks, 20 weeks, 19 weeks, 18 weeks, 17 weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, or 4 weeks after administration of the BTK inhibitor is discontinued is zero.

[0087] In some embodiments, the present disclosure provides a method for treating multiple sclerosis (RMS) in a subject with relapsing multiple sclerosis (RMS) in need thereof. Provided is 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 incidence of relapse in MS (multiple sclerosis (MS)), the method comprising: a) administering to a subject in need thereof the BTK inhibitor, comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the incidence of MS relapse in the subject after terminating administration of the BTK inhibitor is equal to or less than the incidence of MS relapse in the subject during the one-year period prior to administration of the BTK inhibitor.In some embodiments, the present disclosure provides a method for treating relapsing multiple sclerosis, comprising administering to a patient a compound selected from the group consisting of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

[0003] Provided is a BTK inhibitor for use in a method for reducing the number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or the number of new or hypertrophic T2 hyperintense lesions in a subject with recurrent myeloablative sclerosis (RMS), the method comprising: a) 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 for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or new or hypertrophic T2 hyperintense lesions measured in the subject after terminating administration of the BTK inhibitor is equal to or less than the baseline number of new gadolinium (Gd)-enhanced T1 hyperintense lesions or new or hypertrophic T2 hyperintense lesions measured in the subject during the 4 weeks prior to administration of the BTK inhibitor.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, for use in treating relapsing multiple sclerosis in need thereof.

[0003] Provided is a method for reducing the total number of gadolinium (Gd)-enhanced T1-hyperintense lesions in a subject with recurrent myeloablative sclerosis (RMS), the method comprising: a) administering to a subject in need thereof a BTK inhibitor, including (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, for at least 12 weeks; and b) terminating the administration of the BTK inhibitor, wherein the total number of gadolinium (Gd)-enhanced T1-hyperintense lesions measured in the subject after terminating administration of the BTK inhibitor is equal to or less than the baseline number of gadolinium (Gd)-enhanced T1-hyperintense lesions measured in the subject before administration of the BTK inhibitor.

[0088] In some embodiments, the BTK inhibitor compound is administered as monotherapy. In some embodiments, the method comprises administering a BTK inhibitor compound and at least one additional therapeutic agent. The additional therapeutic agent may be administered simultaneously or sequentially with the BTK inhibitor compound.

[0089] The determination of the frequency of administration can be made by one skilled in the art, such as an attending physician, taking into consideration the condition being treated, the age of the subject being treated, the severity of the condition being treated, the general health of the subject being treated, etc. In some embodiments, the BTK inhibitor compound is administered in a therapeutically effective amount for the treatment of RMS. The therapeutically effective amount typically depends on the weight of the subject being treated, their physical or health condition, the extent of the condition being treated, or the age of the subject being treated, the pharmaceutical formulation method, and / or the method of administration (e.g., the time and route of administration).

[0090] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising administering to a subject in need thereof 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 and / or a pharmaceutically acceptable salt thereof. In some embodiments, administration of the inhibitor reduces the number of new active brain lesions. In some embodiments, the lesions are Gd-enhanced T1 hyperintense lesions. In some embodiments, the number of lesions is detected by magnetic resonance imaging (MRI).

[0091] In some embodiments, a method of treating RMS is provided, comprising administering to a subject in need thereof about 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, or 55-60 mg of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one and / or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating RMS is provided, 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 and / or a pharmaceutically acceptable salt thereof at a dose of about 5 mg. In some embodiments, a method of treating RMS is provided, 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 and / or a pharmaceutically acceptable salt thereof at a dose of about 15 mg. In some embodiments, a method of treating RMS is provided, 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 and / or a pharmaceutically acceptable salt thereof at a dose of about 30 mg. In some embodiments, a method of treating RMS is provided, 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 and / or a pharmaceutically acceptable salt thereof at a dose of about 60 mg.

[0092] IV. Treatment methods to reduce the risk of liver damage In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising administering an iron panel test to the patient's blood or serum, and, if the patient has an adequate 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, a suitable iron panel includes one or more of: (i) iron concentration between 60 μg / dL and 170 μg / dL; (ii) ferritin level less than or equal to 500 μg / L; (iii) transferrin saturation level less than or equal to 50% for male patients or less than or equal to 40% for female patients; and (iv) TIBC between 240 μg / dL and 450 μg / dL.

[0093] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising administering an iron panel test to a patient's blood or serum, detecting a level of the iron panel test within the normal range, and administering to the patient a pharmaceutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. 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 for an 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 for male patients or 40% or less for female patients; and (iv) a TIBC of 240-450 μg / dL.

[0094] In some embodiments, the present disclosure provides a BTK inhibitor, including (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 relapsing multiple sclerosis (RMS), the method comprising administering an iron panel test to the patient's blood or serum, detecting a level of the iron panel test that is within the normal range, and administering a pharmaceutically acceptable amount of the compound to the patient. 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 for an 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 for male patients or 40% or less for female patients; and (iv) a TIBC of 240-450 μg / dL.

[0095] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising determining a transferrin saturation level in a patient's blood or serum, and, if the transferrin saturation level is appropriate, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, an appropriate transferrin saturation level in a male patient's blood or serum is 50% or less. In some embodiments, an appropriate transferrin saturation level in a female patient's blood or serum is 40% or less.

[0096] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising detecting a transferrin saturation level in a patient's blood or serum that is 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, a transferrin saturation level within the normal range in a male patient's blood or serum is 50% or less transferrin saturation. In some embodiments, a transferrin saturation level within the normal range in a female patient's blood or serum is 40% or less transferrin saturation.

[0097] 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 relapsing multiple sclerosis (RMS), the method comprising detecting a transferrin saturation level in the patient's blood or serum that is within the normal range and administering a therapeutically effective amount of the compound to the patient. 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.

[0098] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising determining a level of ferritin in a patient's blood or serum; and, if the ferritin level is adequate, 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 adequate ferritin level in the patient's blood or serum is 500 μg / L or less.

[0099] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising detecting a ferritin level in a patient's blood or serum that is 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, the ferritin level within the normal range in the patient's blood or serum is 500 μg / L or less.

[0100] 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 relapsing multiple sclerosis (RMS), the method comprising detecting a ferritin level in the patient's blood or serum that is within the normal range and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the ferritin level within the normal range in the patient's blood or serum is 500 μg / L or less.

[0101] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: performing liver function tests in a patient; and, if the patient has adequate liver function, administering to the patient a pharmaceutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the liver function tests measure one or more of the following levels in the patient's blood: aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein. In some embodiments, a patient with adequate liver function has one or more of an ALT level of 1.5 times the upper limit of normal (ULN) or less, an AST level of 1.5x the ULN or less, an alkaline phosphatase of 2x the ULN or less (unless caused by a non-liver-related disorder or explained by stable chronic liver damage), and a total bilirubin of 1.5x the ULN or less (unless caused by Gilbert's syndrome or a non-liver-related disorder).

[0102] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: performing liver function tests in a patient; detecting adequate liver function; and administering to the patient a pharmaceutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the liver function tests measure one or more of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein levels in the patient's blood. In some embodiments, a patient with adequate liver function has one or more of an ALT level of 1.5 times the upper limit of normal (ULN) or less, an AST level of 1.5x the ULN or less, an alkaline phosphatase of 2x the ULN or less (unless caused by a non-liver-related disorder or explained by stable chronic liver damage), and a total bilirubin of 1.5x the ULN or less (unless caused by Gilbert's syndrome or a non-liver-related disorder).

[0103] 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 relapsing multiple sclerosis (RMS), the method comprising: performing liver function tests in a patient; detecting adequate liver function; and administering a therapeutically acceptable amount of the compound to the patient. In some embodiments, the liver function tests measure one or more of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein levels in the patient's blood. In some embodiments, a patient with adequate liver function has one or more of an ALT level of 1.5 times the upper limit of normal (ULN) or less, an AST level of 1.5x the ULN or less, an alkaline phosphatase of 2x the ULN or less (unless caused by a non-liver-related disorder or explained by stable chronic liver damage), and a total bilirubin of 1.5x the ULN or less (unless caused by Gilbert's syndrome or a non-liver-related disorder).

[0104] In some embodiments, liver function tests are performed at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about every month. In some embodiments, liver function tests are performed at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about every week.

[0105] In some embodiments, the method of treating relapsing multiple sclerosis (RMS) comprises: 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 patient's alanine amino transferase (ALT) level; c) ALT levels exceeding 8 times the upper limit of normal (ULN); d) terminating the administration of the compound to the patient; and optionally e) monitoring the patient's ALT level; f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be less than 1.5 x ULN.

[0106] 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 (a compound), for use in a method of treating relapsing multiple sclerosis (RMS), a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the patient's alanine amino transferase (ALT) level; c) ALT levels exceeding 8 times the upper limit of normal (ULN); d) terminating the administration of the compound to the patient; and optionally e) monitoring the patient's ALT level; f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be less than 1.5 x ULN.

[0107] In some embodiments, the method of treating relapsing multiple sclerosis (RMS) comprises: 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 patient's alanine amino transferase (ALT) level; c) detecting an ALT value greater than 5 times the upper limit of normal (ULN) for at least two weeks; d) terminating the administration of the compound to the patient; and optionally e) monitoring the patient's ALT level; f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be less than 1.5 x ULN.

[0108] 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 (a compound), for use in a method of treating relapsing multiple sclerosis (RMS), a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the patient's alanine amino transferase (ALT) level; c) detecting an ALT value greater than 5 times the upper limit of normal (ULN) for at least two weeks; d) terminating the administration of the compound to the patient; and optionally e) monitoring the patient's ALT level; f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be less than 1.5 x ULN.

[0109] In some embodiments, the method of treating relapsing multiple sclerosis (RMS) comprises: 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 patient's alanine amino transferase (ALT) level; c) ALT levels exceeding three 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 greater than 2×ULN and an INR greater than 1.5; f) terminating the administration of the compound to the patient; and optionally, g) monitoring the patient's ALT level; h) resuming administration of a therapeutically effective amount of the compound when the patient's ALT level is determined to be less than 1.5 x ULN.

[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 (a compound), for use in a method of treating relapsing multiple sclerosis (RMS), a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the patient's alanine amino transferase (ALT) level; c) ALT levels exceeding three 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 greater than 2×ULN and an INR greater than 1.5; f) terminating the administration of the compound to the patient; and optionally, g) monitoring the patient's ALT level; h) resuming administration of a therapeutically effective amount of the compound when the patient's ALT level is determined to be less than 1.5 x ULN.

[0111] In some embodiments, the method of treating relapsing multiple sclerosis (RMS) comprises: 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 patient's alanine amino transferase (ALT) level; c) ALT levels exceeding three times the upper limit of normal (ULN); d) terminating administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally, e) monitoring the patient's ALT level; f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be less than 1.5 x ULN.

[0112] 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 (a compound), for use in a method of treating relapsing multiple sclerosis (RMS), a) administering a therapeutically effective amount of a compound to a patient in need thereof; b) measuring the patient's alanine amino transferase (ALT) level; c) ALT levels exceeding three times the upper limit of normal (ULN); d) terminating administration of the compound to the patient if the patient experiences one or more of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia >5%; and optionally, e) monitoring the patient's ALT level; f) resuming administration of a therapeutically effective amount of the compound if the patient's ALT level is determined to be less than 1.5 x ULN.

[0113] In some embodiments, the patient's ALT levels are measured at least about every 6 months, at least about every 5 months, at least about every 4 months, at least about every 3 months, at least about every 2 months, or at least about every month. In some embodiments, the patient's ALT levels are measured at least about every 12 weeks, at least about every 11 weeks, at least about every 10 weeks, at least about every 9 weeks, at least about every 8 weeks, at least about every 7 weeks, at least about every 6 weeks, at least about every 5 weeks, at least about every 4 weeks, at least about every 3 weeks, at least about every 2 weeks, or at least about every week.

[0114] In some embodiments, after administration of the compound is discontinued, the patient's ALT levels are monitored about every 2-3 days, about every 3 days, about every 2 days, or about every day.

[0115] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising administering to a patient a therapeutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein the patient is not receiving a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 hepatic enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampin, carbamazepine, phenobarbital, St. John's wort extract, awasimibe, lumacaftor, rifapentine, rifabutin, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semagacestat, asunaprevir, beclabuvir, daclatasvir, cenobamate, nafcillin, lesinurad, modafinil, bosentan, telotristat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[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 (a compound) for use in a method for treating relapsing multiple sclerosis (RMS), the method comprising administering a pharmaceutically acceptable amount of the compound to a patient, wherein the patient is not receiving a strong or moderate inducer of cytochrome P450 3A (CYP3A) or a strong inhibitor of the CYP2C8 hepatic enzyme. In some embodiments, the strong CYP3A inducer is selected from rifampin, carbamazepine, phenobarbital, St. John's wort extract, awasimibe, lumacaftor, rifapentine, rifabutin, and phenytoin. In some embodiments, the moderate CYP3A inducer is selected from semagacestat, asunaprevir, beclabuvir, daclatasvir, cenobamate, nafcillin, lesinurad, modafinil, bosentan, telotristat ethyl, thioridazine, elagolix, and rifabutin. In some embodiments, the strong CYP2C8 inhibitor is selected from gemfibrozil and clopidogrel.

[0117] In some embodiments, a method of treating relapsing multiple sclerosis (RMS) is provided, comprising: advising a patient to limit alcohol intake 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 no more than one drink per day. In some embodiments, one alcoholic drink is about 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of distilled spirits). In some embodiments, the patient is male and is advised to limit alcohol intake to no more than two drinks per day. In some embodiments, two alcoholic drinks are equivalent to about 28 grams of alcohol.

[0118] 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 for use in a method of treating relapsing multiple sclerosis (RMS), comprising the steps of: advising the patient to limit alcohol consumption during treatment; and administering to the patient a pharmaceutically acceptable amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. In some embodiments, the patient is female and is advised to limit her alcohol intake to one drink or less per day. In some embodiments, one alcoholic drink is about 14 grams of alcohol (e.g., 350 mL of beer, 140 mL of wine, or 40 mL of distilled spirits). In some embodiments, the patient is male and is advised to limit alcohol intake to no more than two drinks per day. In some embodiments, two alcoholic drinks equal about 28 grams of alcohol.

[0119] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed specifically for drugs exhibiting low bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 nm to 1,000 nm, in which the active material is supported on a crosslinked polymer matrix. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation with significantly higher bioavailability by milling a drug substance into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersing the nanoparticles in a liquid medium. The bioavailability of drugs that degrade at gastric pH can be increased by administering such drugs in a formulation that releases the drug in the duodenum.

[0120] The compositions generally comprise a BTK inhibitor compound and / or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient, such as a binder, surfactant, diluent, buffer, anti-adherent, glidant, hydrophilic or hydrophobic polymer, retardant, stabilizer or stabilizer, disintegrant or super-disintegrant, antioxidant, anti-foaming agent, filler, flavor, colorant, lubricant, adsorbent, preservative, plasticizer, or sweetener, and / or mixtures thereof, to facilitate processing of the BTK inhibitor compound or a pharmaceutically acceptable salt thereof into a preparation that can be used pharmaceutically. Any of the well-known techniques and excipients may be used as suitable and as understood in the art; see, e.g., 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).

[0121] In certain embodiments, the formulation may contain one or more pH adjusters or buffers, such as acids such as acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such buffers used as bases may have counterions other than sodium, such as potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0122] In certain embodiments, the formulation may also include one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0123] In certain embodiments, the formulation may also include one or more antifoaming agents to reduce foaming during processing, which can result in coagulation of the aqueous dispersion, air bubbles in the finished film, or generally impair processing. Exemplary antifoaming agents include silicone emulsion or sorbitan sesquioleate.

[0124] In certain embodiments, the formulation may also include one or more antioxidants, such as non-thiol antioxidants, such as 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 salts or EDTA, may also be added to retard oxidation.

[0125] In certain embodiments, the formulation may also contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0126] In certain embodiments, the formulation may also include one or more binders. Binders impart cohesiveness and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonite; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; alginate; cellulose acetate ... sugars such as tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; natural or synthetic gums such as acacia, tragacanth, gum ghatti mucilage from isapol husk, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegun®, polyethylene glycol, polyethylene oxide, waxes, and sodium alginate.

[0127] In certain embodiments, the formulation may also include a dispersing agent and / or viscosity modifier. Dispersing agents or viscosity modifiers include materials that control the diffusion and uniformity of the drug through the liquid medium and / or the granulation or blending process. In some embodiments, these agents also promote the effectiveness of the coating or erosion matrix. Exemplary diffusion enhancers / dispersing agents include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially available as Plasdone®), and carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose (e.g., HPC, H-PC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, RPMC K4M, HPMC K15M, and HPMC K100M). K100M), 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 with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68®, F88®, F10®8, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, are tetrafondiamine block copolymers derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ).), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol, for example, the polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, for example Examples include tragacanth gum and acacia gum, guar gum, xanthans including xanthan gum, sugars, celluloses such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomer, polyvinyl alcohol (PVA), alginates, chitosan, and combinations thereof. Plasticizers such as cellulose or triethylcellulose can also be used as dispersing agents. Particularly useful dispersing agents for liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol, and isopropyl myristate. Generally, binder levels of about 10 to about 70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary with either direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that can themselves act as moderate binders. While those skilled in the art can determine binder levels for their formulations, binder usage levels of up to 90%, and more typically up to 70%, are common in tablet formulations.

[0128] In certain embodiments, the formulation may also contain one or more diluents, which refer to chemical compounds used to dilute the compound of interest before delivery. Diluents can also be used to stabilize the compound because they can provide a more stable environment (which can also provide pH control or maintenance). Salts dissolved in buffer solutions are used as diluents in the art, including, but not limited to, phosphate buffered saline. 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, calcium diphosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, confectioners' sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed grain solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, mannitol, sodium chloride, inositol, bentonite, and the like.

[0129] In certain embodiments, the formulation may also include one or more disintegrants, which both dissolve and disperse the dosage form when it comes into contact with gastrointestinal fluids. Disintegrants or disintegrants facilitate the disintegration or breakup of a substance. Examples of disintegrants include starches, such as natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methylcrystalline celluloses, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked celluloses, such as cross-linked celluloses. Cross-linked celluloses such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, 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 salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, and tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, and sodium lauryl sulfate complex starch.

[0130] In certain embodiments, the formulation may also include an erosion enhancer. Erosion enhancers include materials that control the erosion of a particular material in gastrointestinal fluids. Erosion enhancers are generally known to those skilled in the art. Exemplary erosion enhancers include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0131] 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, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0132] In certain embodiments, the formulation may also contain one or more flavoring agents and / or sweeteners, such as acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavaro 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, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhizinate, glycyrrhizic acid (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate, maltol, mannitol, maple, menthol, mint cream, mixed berry, neohesperidin DC, neo The flavoring ingredients may include tame, 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, talc, xylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol-menthol, sherry anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0133] In certain embodiments, the formulation may also include one or more lubricants and glidants, which are compounds that prevent, reduce, or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl cellulose, hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil, higher fatty acids and their alkali metal salts 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 lauryl sulfate or sodium lauryl sulfate, colloidal silica such as Syloid® or Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, etc.

[0134] In certain embodiments, the formulation may also include one or more plasticizers, which are compounds used to soften and reduce the brittleness of enteric or delayed-release coatings.Suitable plasticizers include, for example, polyethylene glycols, such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethyl citrate, dibutyl sebacate, triethylcellulose, and triacetin.In some embodiments, the plasticizer can also function as a dispersing agent or wetting agent.

[0135] In certain embodiments, the formulation may also include one or more solubilizing agents, including compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium dodecanoate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, such as Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, trans-cutol, propylene glycol, dimethyl isosorbide, etc. In one embodiment, the solubilizing agent is vitamin E TPGS and / or Captisol® or β-hydroxypropyl cyclodextrin.

[0136] In certain embodiments, the formulation also contains polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K112, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate The emulsion may contain one or more suspending agents including compounds such as polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum arabic, guar gum, xanthan including xanthan gum, xanthan gum, sugars, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monooleate, povidone, and the like.

[0137] In certain embodiments, the formulation may also include one or more surfactants, including compounds such as sodium lauryl sulfate, docusate sodium, Tween 20, 60, or 80, triacetin, vitamin ETPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbate, polaxomer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF). Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., Octoxynol 10, Octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[0138] In certain embodiments, the formulation may also include one or more thickening agents, including, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, hydroxypropyl methylcellulose phthalate, carbomer, polyvinyl alcohol alginate, acacia, chitosan, and combinations thereof.

[0139] In certain embodiments, the formulation may also include one or more wetting agents, including compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, docusate sodium, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, vitamin ETPGS, ammonium salts, and the like.

[0140] The pharmaceutical formulations disclosed herein can be obtained by mixing one or more solid excipients such as carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof, with one or more of the compounds described herein, optionally milling the resulting mixture, and processing the granular mixture to obtain tablets after adding suitable excipients as needed.

[0141] The pharmaceutical formulations disclosed herein also include capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules may also be made of polymers such as hypromellose. Capsules may contain the active ingredient mixed with a binder such as lactose or starch, and / 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 oils, liquid paraffin, lipids, solubilizers, or liquid polyethylene glycol. Additionally, stabilizers may be added. All formulations intended for oral administration must be in a dosage form suitable for such administration.

[0142] These formulations can be manufactured by conventional pharmaceutical techniques, including, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, (6) fusion, or (7) extrusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy, 3 rd ed. (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tabletting, extrusion, extrusion / spheronization, and the like.

[0143] It should be recognized that there is considerable overlap between the excipients used in the solid dosage forms described herein. Therefore, the additives listed above should be construed as merely exemplary and not limiting of the types of excipients that can be included in the solid dosage forms described herein. The types and amounts of such excipients can be easily determined by those skilled in the art according to the specific properties desired.

[0144] In some embodiments, the solid dosage forms described herein are enterically coated oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions described herein that utilize an enteric coating to affect the release of the compound in the intestines of the gastrointestinal tract. An "enterically coated" drug and / or tablet refers to a drug and / or tablet that is coated with a substance that remains intact in the stomach but dissolves and releases the drug upon reaching the intestine (in one embodiment, the small intestine). As used herein, an "enteric coating" is a material, such as one or more polymeric materials, that encases a therapeutically active agent core, either as a dosage form or particle. Typically, to achieve delayed dissolution of the therapeutically active agent core or particle in the small intestine and / or large intestine, a substantial amount or all of the enteric coating material is dissolved before the therapeutically active agent is released from the dosage form. 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 for applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, U.S. Patent Application Publication No. 2006 / 0045822.

[0145] An enteric-coated dosage form can be a compressed, molded, or extruded tablet (coated or uncoated) containing granules, powders, pellets, beads, or particles of the BTK inhibitor compound and / or its pharmaceutically acceptable salts and / or other excipients, which may themselves be coated or uncoated, provided that at least one of the tablets or BTK inhibitor compounds is coated. An enteric-coated oral dosage form can also be a capsule (coated or uncoated) containing pellets, beads, or granules of the BTK inhibitor compound and / or its pharmaceutically acceptable salts and / or other excipients, which may themselves be coated or uncoated, provided that at least one of the capsules is coated. Some examples of coatings originally 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. Pat. No. 2,809,918); polyvinyl acetate and ethyl cellulose (see U.S. Pat. No. 3,835,221). More recently, coatings used have been neutral copolymers of polymethacrylic acid esters (Eudragit L30D) (F.W. Goodhart et al., Pharm. Tech., pp. 64-71, April 1984), copolymers of methacrylic acid and methacrylic acid methyl ester (Eudragit S), or neutral copolymers of polymethacrylic acid esters containing metal stearates (Mehta et al., U.S. Pat. Nos. 4,728,512 and 4,794,001), cellulose acetate succinate, and hypromellose phthalate.

[0146] Any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve intestinal delivery. In one embodiment, delivery can be to the small intestine. In another embodiment, delivery can be to the duodenum. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and their compatible mixtures, as well as some of their properties, include, but are not limited to:

[0147] Shellac: Also known as purified lac, this is a purified product obtained from the resin secretions of insects. This coating dissolves in media with a pH greater than 7.

[0148] Acrylic polymers: The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series L, S, and RS (manufactured by RohmPharma, known as Evonik®) are available solubilized in organic solvents, aqueous dispersions, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and are primarily used for colonic targeting. The Eudragit series L, L-30D, and S are insoluble in the stomach and can be selected and formulated to dissolve in the intestine at pH values ​​above 5.5, as low as above 5, or as high as above 7.

[0149] Cellulose derivatives: Examples of suitable cellulose derivatives are ethyl cellulose and reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. Performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH >6. Aquateric (FMC) is a water-based system and is a spray-dried CAP pseudolatex with particles <1 μm. Other components of Aquateric may include Pluronics, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate tritonelate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g., AQOAT (Shin-Etsu)). Performance can vary based on the degree and type of substitution. For example, HPMCP grades such as HP-50, HP-55, HP-55S, and HP-55F are suitable. Performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG(LF), which dissolves at pH 5, AS-MG(MF), which dissolves at pH 5.5, and AS-HG(HF), which dissolves at higher pHs. These polymers are provided as granules or as fine powders for aqueous dispersion.

[0150] Polyvinyl Acetate Phthalate (PVAP): PVAP dissolves at pH >5 and is much less permeable to water vapor and gastric fluids. For a detailed description of the above polymers and their pH-dependent solubility, see the article entitled "Enteric coated hard gelatin capsules" by Professor Karl Thoma and Karoline Bechtold (http: / / pop.www.capsugel.com / media / library / enteric-coated-hard-gelatin-capsules.pdf). In some embodiments, the coating can, and typically does, include a plasticizer and, optionally, other coating excipients such as colorants, talc, and / or magnesium stearate, as are known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. Anionic carboxylic acrylic polymers typically contain 10-25% by weight of plasticizers, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as fluidized bed or Wurster coaters, 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 the desired site of topical delivery in the intestinal tract is reached.

[0151] In addition to plasticizers, colorants, surfactants, anti-adherents, anti-foaming agents, lubricants (e.g., carnauba wax or PEG), and other additives may be added to the coating to solubilize or disperse the coating materials and improve application performance and the coated product.

[0152] To promote dissolution of the enteric coat, a double coat of half-thickness enteric polymer (e.g., Eudragit L30D-55) may be applied, with the inner enteric coat buffered 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 two layers of enteric coats that were half the thickness of a typical enteric coat, were able to promote dissolution of the enteric coat 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).

[0153] 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 functionality.

[0154] 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 disclosed compounds 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).

[0155] Alternatively, a multiple unit dosage form comprising enteric coated pellets which can be incorporated into a tablet or capsule can be prepared as follows.

[0156] Core Material: The core material of the individual enteric-coated layered pellets can be constructed according to different principles. The core layered with the active agent (i.e., the BTK inhibitor compound and / or its pharmaceutically acceptable salt) can be optionally mixed with an alkaline substance or buffer and used as the core material for further processing. The core layered with the active agent can be a water-insoluble core containing different oxides, cellulose, organic polymers, and other materials, alone or in mixtures, or a water-soluble core containing different inorganic salts, sugars, nonpareils, and other materials, alone or in mixtures. Furthermore, the core may contain the active agent in the form of crystals, aggregates, compacts, etc. The size of the core is not essential to the present disclosure, but may be in the size range of about 0.1 to 2 mm. The core layered with the active agent can be manufactured by either powder or solution / suspension layering, for example, using a granulation or spray coating layering device.

[0157] Before layering the core, the active agent may be mixed with additional ingredients. Such ingredients may be binders, surfactants, fillers, disintegrants, alkali additives, or other and / or pharmaceutically acceptable ingredients, either alone or in mixture. Binders are, for example, polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), or sugars, starches, or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants can be found in the group of pharmaceutically acceptable nonionic or ionic surfactants, such as sodium lauryl sulfate.

[0158] Alternatively, the active agent can be optionally mixed with suitable ingredients and then incorporated into a core material. The core material may be manufactured by extrusion / spheronization, ball-ring, or compression using conventional processing equipment. The size of the incorporated core material is between about 0.1 and 4 mm, for example, between 0.1 and 2 mm. The manufactured core material can be further layered with additional ingredients, including the active agent, and / or used for further processing.

[0159] The active agent is mixed with pharmaceutical ingredients to obtain favorable handling and processing properties 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 excipients can be used.

[0160] Alternatively, the core materials described above can be prepared using spray drying or spray congealing techniques.

[0161] Enteric coating layer: Before the enteric coating layer is applied onto the core material in the form of individual pellets, the pellets may optionally be covered with one or more separating layers containing pharmaceutical excipients, optionally including alkaline compounds such as pH buffering compounds. This / these separating layers separate the core material from the outer layer, which is the enteric coating layer. This / these separating layers, which protect the active agent core material, must be water-soluble or rapidly disintegrate in water.

[0162] The separating layer can be optionally applied to the core material by coating or laminating procedures in suitable equipment such as a coating pan, a coating granulator, or a fluidized bed equipment using water and / or organic solvents for the coating process. Alternatively, the separating layer can be applied to the core material by using powder coating techniques. The separating layer material is a pharmaceutically acceptable compound, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, water-soluble salts of enteric coating polymers, etc., used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-blocking agents, and anti-static agents, such as magnesium stearate, titanium dioxide, talc, and other additives, can also be included in the separating layer.

[0163] When an optional separating layer is applied to the core material, it may be of variable thickness. The maximum thickness of the separating layer is usually limited only by processing conditions. The separating layer can function as a diffusion barrier and can act as a pH buffer zone. The optional separating layer is not required for the embodiments of the present disclosure. However, the separating layer can improve the chemical stability of the active substance and / or the physical properties of the novel multi-unit tablet dosage form.

[0164] Alternatively, the separating layer may be formed in situ by reaction between an enteric coating polymer layer applied onto the core material and an alkali-reactive compound in the core material, such that the separating layer formed comprises a water-soluble salt formed between the enteric coating layer polymer and the alkali-reactive compound in a salt-forming position.

[0165] One or more enteric coating layers are applied to the core material or the core material covered with the separating layer by using a suitable coating technique. The enteric coating layer material can be dispersed or dissolved in either water or a suitable organic solvent. As the enteric coating layer polymer, for example, one or more of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, shellac, or other suitable enteric coating polymer solutions or dispersions can be used, either separately or in combination.

[0166] The enteric coating layer contains a pharmaceutically acceptable plasticizer to obtain desired mechanical properties such as flexibility and hardness of the enteric coating layer, such as, but not limited to, triacetin, citrate esters, phthalate esters, dibutyl sebacate, cetyl alcohol, polyethylene glycol, polysorbate, or other plasticizers.

[0167] The amount of plasticizer is optimized for each enteric coating layer formulation in relation to the selected enteric coating layer polymer, the selected plasticizer, and the amount of polymer applied, so that the mechanical properties, i.e., flexibility and hardness of the enteric coating layer (e.g., Vickers hardness), are adjusted so that the acid resistance of the enteric coating layer-covered pellets, if desired, is not significantly reduced during compression of the pellets into tablets. The amount of plasticizer is typically greater than 5% by weight of the enteric coating layer polymer, e.g., 15-50%, and even more preferably, 20-50%. Additives such as dispersants, colorants, pigmented polymers (e.g., poly(ethyl acrylate, methyl methacrylate)), anti-adherents, and anti-foaming agents can also be included in the enteric coating layer. Other compounds may be added to increase film thickness and reduce diffusion of acidic gastric juices into the acid-sensitive material. The maximum thickness of the applied enteric coating is typically limited only by processing conditions and the desired dissolution profile.

[0168] Overcoat layer: The enteric-coated pellets may optionally be further coated with one or more overcoating layers. The overcoating layer should be water-soluble or rapidly disintegrate in water. The overcoating layer can be applied to the enteric-coated layered pellets by coating or layering procedures in suitable equipment such as a coating pan, a coating granulator, or a fluidized bed equipment using water and / or organic solvents for the coating or layering process. The material for the overcoating layer is selected from pharmaceutically acceptable compounds, such as sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc., used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-adherents, and antistatic agents, such as magnesium stearate, titanium dioxide, talc, and other additives, may also be included in the overcoating layer. The overcoating layer can further prevent potential aggregation of the enteric-coated pellets and further protect the enteric coating layer from cracking during the compression process, enhancing the tableting process. The maximum thickness of the applied overcoating layer is usually limited by processing conditions and the desired dissolution profile. The overcoat layer can also be used as a tablet film coating layer.

[0169] Enteric coatings for soft gelatin capsules can include emulsions, oils, microemulsions, self-emulsifying systems, lipids, triglycerides, polyethylene glycols, surfactants, other solubilizers, and the like, and combinations thereof, to solubilize the active agent. The flexibility of soft gelatin capsules is maintained by residual water and plasticizers. Furthermore, for gelatin capsules, the gelatin must be dissolved in water and sprayed at a rate of relatively low relative humidity, such as can be achieved in a fluidized bed or Wurster process. Furthermore, drying must be achieved without removing residual water or plasticizers, causing the capsule shell to crack. Commercially available blends optimized for enteric coating of soft gelatin capsules, such as Instamodel EPD (enteric polymer dispersion), are available from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a laboratory scale, enteric coated capsules can be prepared by a) rolling the capsules in a flask or immersing them in a gently heated solution of enteric coating material containing a plasticizer at the lowest possible temperature, or b) rolling the capsules in a laboratory scale atomizer / fluid bed and then drying.

[0170] For aqueous active agents, it may be particularly desirable to incorporate the drug into the aqueous phase of emulsion.Such "water-in-oil" emulsion can provide a suitable biophysical environment for the drug and provide an oil-water interface that can protect the drug from the adverse effects of pH or enzymes that can decompose the drug.In addition, such water-in-oil formulations can provide a lipid layer that can favorably interact with the lipids in the body's cells, and can increase the distribution of the formulation on the membrane of the cell.Such distribution can increase the absorption of the drug in such formulation into circulation, and therefore increase the bioavailability of the drug.

[0171] In some embodiments, the water-in-oil emulsion contains an oil phase composed of a medium or long chain carboxylic acid or its ester or alcohol, a surfactant or surface-active agent, and an aqueous phase containing primarily water and the active agent.

[0172] Medium and long chain carboxylic acids are C8-C with up to three unsaturated bonds (or branches). 22 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 (polyolefin-based) straight-chain monocarboxylic acids are also useful. Examples of these are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid, and behenolic acid. Useful branched acids include, for example, diacetyltartaric acid. The unsaturated olefin chains may also be hydroxylated or ethoxylated to prevent oxidation or to modify surface properties.

[0173] 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 monolinoleate; glyceryl monooleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, and glyceryl monolinoleate; glyceryl monolinolenate; glyceryl monogadoleate; a mixture of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinolenate, and glyceryl monogadoleate; acetylated glycerides such as distilled acetylated monoglyceride; propylene glycol monoesters, distilled monoglycerides, sodium steroyl lactylate. and silicon dioxide mixture; d-alpha tocopherol polyethylene glycol 1000 succinate; mixtures 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 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 monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of wax; stearyl octanoate; C8-C 30Cholesterol / labosterol esters; and sucrose long-chain carboxylic acid esters. Self-emulsifying long-chain carboxylic acid esters include, for example, stearic acid esters, palmitic acid esters, ricinoleic acid esters, oleic acid esters, behenic acid esters, ricinoleic acid esters, myristic acid esters, lauric acid esters, caprylic acid esters, caproic acid esters, etc. In some embodiments, the oily phase may contain a combination of two or more long-chain carboxylic acids or their esters or alcohols. In some embodiments, medium-chain surfactants may be used, and the oily phase may be a C8 / C10 surfactant such as caprylic / capric triglyceride and caprylic acid, glyceryl caprylate, or propylene glycol monocaprylate. 10 It may also comprise a mixture of mono- / di-glycerides or mixtures thereof.

[0174] Alcohols that can be used are also exemplified by the hydroxyl forms of the carboxylic acids exemplified above and stearyl alcohol.

[0175] Surface active agents, or surfactants, are long-chain molecules that can accumulate at hydrophilic / hydrophobic (water / oil) interfaces and reduce interfacial surface tension, thereby stabilizing emulsions. In some embodiments, surfactants can include the Tween® (polyoxyethylene sorbate) 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® (polyglycolized glyceride) families 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 triglycerides, and mixtures thereof or mixtures of two or more of the above. In some embodiments, the surfactant phase may comprise a mixture of polyoxyethylene (20) sorbitan monooleate (Tween 80®) and sorbitan monooleate (Span 80®).

[0176] The aqueous phase may optionally contain an active agent and a buffer suspended in water.

[0177] In some embodiments, such emulsions are coarse emulsions, microemulsions, and liquid crystal emulsions. In other embodiments, such emulsions may optionally contain permeation enhancers. In other embodiments, spray-dried dispersions or microparticles or nanoparticles containing encapsulated microemulsions, coarse emulsions, or liquid crystals may be used.

[0178] In some embodiments, the solid dosage forms described herein are non-enteric-coated, time-delayed release dosage forms. As used herein, the term "non-enteric-coated, time-delayed release" refers to delivery in which drug release can be achieved at some generally predictable location in the intestinal tract further distally than would be achieved without the delayed-release modification. In some embodiments, the method for delayed release is a coating that becomes permeable, dissolves, ruptures, and / or is no longer intact after a designed duration. The coating in a time-delayed release dosage form can have a certain period of time to erode, after which the drug is released (suitable coatings include polymer coatings such as HPMC or PEO), or has a core composed of a superdisintegrant or osmotic agent, or a salt, a hydrophilic polymer, typically a water-attracting agent such as polyethylene oxide or alkylcellulose, a salt such as sodium chloride, magnesium chloride, sodium acetate, sodium citrate, a sugar such as glucose, lactose, or sucrose, or an acid such as citric acid or a gas-generating agent such as citric acid and sodium bicarbonate that draws water through the semipermeable membrane, with or without any of the aforementioned acids incorporated into the dosage form. The semipermeable membrane is almost impermeable to neither the drug nor the osmotic agent, but allows water to permeate at a nearly constant rate, which enters the dosage form, increasing the pressure, and bursts after the swelling pressure exceeds a certain threshold for a desired delay time.The drug permeability through this membrane should be less than 1 / 10 of that of water, and in one embodiment, less than 1 / 100 of that of water.Alternatively, the membrane can be made porous by allowing the extractable aqueous solution to permeate for a desired delay time.

[0179] Osmotic dosage forms are described in U.S. Patent No. 3,760,984 to Theeuwes, and osmotic burst dosage forms are described in U.S. Patent No. 3,952,741 to Baker. This osmotic burst dosage form can provide a single release pulse or multiple pulses, if 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 rupture point, and the drug is then released. Alternatively, specific rupture areas can be created in the membrane by having thinner, weaker areas of the membrane or by adding a weaker material to the coating membrane area. Some preferred polymers with high water permeability that can be used as semipermeable membranes are cellulose acetate, cellulose acetate butyrate, cellulose nitrate, cross-linked polyvinyl alcohol, polyurethane, nylon 6, nylon 6.6, and aromatic nylon. Cellulose acetate is a particularly preferred polymer.

[0180] In another embodiment, the time-delay coating, which begins to delay drug release after the enteric coating has at least partially dissolved, is composed of a hydrophilic erodible polymer that gradually begins to erode over time upon contact with water. Examples of such polymers include cellulose polymers and their derivatives, including, but not limited to, hydroxyalkylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, microcrystalline cellulose; polysaccharides and their derivatives; polyalkylene oxides, such as polyethylene oxide or polyethylene glycol, especially high molecular weight polyethylene glycol; chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly(vinylpyrrolidone); starch and starch-based polymers; maltodextrin; poly(2-ethyl-2-oxazoline); poly(ethyleneimine); polyurethanes; hydrogels; cross-linked polyacrylic acid; and combinations or blends of any of the above.

[0181] Some preferred erodible hydrophilic polymers suitable for forming erodible coatings are poly(ethylene oxide), hydroxypropyl methylcellulose, and a combination 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 poly(ethylene oxide) polymers is about 10 5 Dalton ~ approx. 10 7 The preferred molecular weight range for poly(ethylene oxide) polymers is about 2x10 Daltons. 5 ~2x10 6 Daltons and is commercially available from The Dow Chemical Company, Midland, Mich., called SENTRYR POLYOX™ Water-Soluble Resin, NF (National Formulary) Grade. When higher molecular weight polyethylene oxides are used, other hydrophilic agents, such as salts or sugars, such as glucose, sucrose, or lactose, which promote erosion or disintegration of the coating, are also included.

[0182] The time-delay dosage form can be a mechanical pill such as an Enterion® capsule or a pH-sensitive capsule that can release the drug after a preprogrammed time, or upon receiving a transmissible signal, or upon exiting the stomach.

[0183] The amount of a compound of the present disclosure in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation contains about 0.01 to 99.99% by weight of the BTK inhibitor compound, based on the total formulation, on a weight percent (wt%) basis, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80% by weight.

[0184] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It is therefore to be understood that the foregoing description is intended to be illustrative and not limiting. The scope of the present disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. [Example]

[0185] The following examples are provided to illustrate certain disclosed embodiments and should not be construed as limiting the scope of the present disclosure in any way. In the examples discussed below, the BTK inhibitors defined above may be referred to interchangeably as "compounds" or "drugs."

[0186] Example 1 - Dose-finding study of a BTK inhibitor in relapsing multiple sclerosis Example 1.1 - Introduction and Summary The purpose of this Phase 2b study is to determine the safe and optimal dose of a BTK inhibitor. The proposed mechanism of action of BTK inhibitors is the inhibition of the formation of new active brain lesions in MS, as measured by MRI, which predicts clinical efficacy in further clinical trials in MS patients. In this study, dose-response was assessed by measuring changes in the number of gadolinium (Gd)-enhanced T1 hyperintense lesions associated with inflammation. This radiographic outcome has been established as a reliable predictive biomarker of clinical benefit in pivotal MS clinical trials and has also been demonstrated to be a predictive biomarker of clinical benefit (reduction in ARR) in Phase 3 registration trials (Sormani et al., Ann Neurol. 2009;65(3):268-75; Sormani et al., Neurology, 2010;75(4):302-9). The dose-response of lesion inhibition was evaluated using a two-stage statistical approach based on four dose levels and a short placebo period. The efficacy of the BTK inhibitor compared to placebo will be assessed by assessing the inhibition of new active brain lesion formation as measured by MRI. The study will also evaluate the safety and tolerability of the BTK inhibitor in patients with RMS.

[0187] The study uses a number of secondary outcome measures to gather additional data on the potential utility of BTK inhibitors in neuroinflammation.

[0188] Exploratory evaluations, including analysis of serum NfL (neurofilament light) levels and advanced imaging modalities, are expected to begin to build evidence regarding the activity of BTK inhibitors against neuroinflammation and neurodegeneration, as well as their potential effects on remyelination and tissue preservation. Figure 1 shows the overall study design, and Table 1 shows the Schedule of Activities (SOA).

[0189] [Table 1]

[0190] [Table 2]

[0191] [Table 3]

[0192] [Table 4]

[0193] [Table 5]

[0194] [Table 6]

[0195] [Table 7]

[0196] [Table 8]

[0197] [Table 9]

[0198] [Table 10]

[0199] [Table 11]

[0200] The treatment objectives and endpoints are shown in Table 2.

[0201] [Table 12]

[0202] [Table 13]

[0203] [Table 14]

[0204] Measurement validity As with most RMS clinical trials, magnetic resonance imaging (MRI) markers of inflammatory activity in the brain will be collected. The number of new Gd-enhanced T1 hyperintense lesions will be used as the primary endpoint to evaluate the efficacy of BTK inhibitors. Because MS results in blood-brain barrier leakage, accumulation of Gd contrast agent in brain tissue is associated with inflammatory activity in MS patients. This radiographic finding has been established as a reliable predictive biomarker of clinical benefit in pivotal MS trials. A central review will identify new Gd-enhanced T1 hyperintense lesions not seen on previous MRIs. The total number of Gd-enhanced T1 hyperintense lesions will also be used as a secondary endpoint to detect the impact on existing inflammatory foci. The number of new and enlarging T2 lesions, a marker of inflammatory activity and brain tissue destruction in RMS, will also be assessed by central review to gather additional data on the efficacy of BTK inhibitors. The total volume of T2 lesions (MS burden) and the number of T1 hyperintense lesions (black holes) will also be evaluated as supportive efficacy data.

[0205] Magnetic resonance imaging (MRI) measurements include changes in brain volume, which is considered a marker of CNS degeneration but is also associated with inflammatory events in RMS patients. Some MS medications are known to slow brain atrophy.

[0206] Clinical relapse is the main clinical symptom of RMS. The relapse-related endpoint (ARR, the proportion of participants without relapse) is widely used as an endpoint in clinical trials. Due to the short duration of this study, a significant difference in the occurrence of relapse between treatment groups cannot be expected, and relapses are considered rare in PPMS. However, due to its clinical importance, we evaluated it and attempted to collect additional data on efficacy.

[0207] The EDSS is widely used to measure neurological impairment in clinical trials and in daily life (Kurtzke JF, Neurology. 1983;33(11):1444-52). Although significant changes are not expected during the course of this study, it will be used as supporting data for efficacy.

[0208] Example 1.2 - Study Design Overall Design: A phase 2b, randomized, double-blind, placebo-controlled, crossover, dose-ranging study to investigate the efficacy and safety of 12-week administration of a BTK inhibitor on MRI. Individuals diagnosed with RMS were eligible to enroll as long as they met all inclusion criteria and no exclusion criteria.

[0209] All participants will be centrally assigned to one of eight arms (two cohorts, four treatment arms each, starting with the BTK inhibitor (Cohort 1) or placebo (Cohort 2)) using an interactive voice / web response system (IVRS / IWRS) prior to crossover. Within each cohort, participants will be equally randomized in a blinded manner to receive one of four BTK inhibitor doses: 5, 15, 30, or 60 mg once daily. Cohort 1: Participants will receive one dose of the BTK inhibitor for the first 12 weeks, then cross over to placebo for four weeks. Cohort 2: Participants will receive a placebo for the first four weeks, then cross over to one of the doses of the BTK inhibitor for 12 weeks.

[0210] After the double-blind treatment period, participants will have the option to enroll in a long-term safety (LTS) follow-up study to evaluate the safety and tolerability of the BTK inhibitor.

[0211] Approximately 160 participants will be screened, approximately 120 will be randomized to the study intervention (based on a 25% screening failure rate), and approximately 105 evaluable participants (based on a 15% dropout rate, providing at least 26 participants for each BTK inhibitor dose level) will complete 12 weeks of BTK inhibitor treatment. Cohort 2 participants (n = 60) will receive 4 weeks of placebo treatment before transitioning to the BTK inhibitor, providing data that can be used to estimate dose-response curves and compare with placebo. This approach is based on the assumption that the incidence of new Gd-enhancing T1-hyperintense lesions over 12 weeks under placebo treatment is theoretically constant. This approach minimizes placebo exposure for study participants. A brief description of the handling of placebo data and analysis, along with additional details including sample size determination, is provided in Example 1.14.

[0212] Intervention Groups and Duration: A 4-week placebo treatment period will be introduced after or before 12 weeks of treatment with the BTK inhibitor (Cohorts 1 and 2, respectively). Participants will be randomized equally into 8 groups (4 treatment groups per 2 cohorts). See Table 5 for a summary of study interventions.

[0213] Rationale: This study is blinded to dose and administration sequence. While the focus is on dose selection, it also takes into account the need to minimize participant exposure to placebo. Therefore, a dose range will be evaluated using four doses: 5 mg, 15 mg, 30 mg, and 60 mg administered once daily. Furthermore, to minimize placebo exposure while maintaining investigator and participant blinding, each participant will be assigned to a 4-week placebo period during either the first or last 4 weeks of the study. The 4-week placebo treatment period will be introduced after or before 12 weeks of treatment with the BTK inhibitor (Cohorts 1 and 2, respectively). Participants will be randomly assigned to one of eight groups (four treatment arms in equal proportions in each of the two cohorts). To minimize placebo exposure, the placebo treatment period will be limited to 4 weeks. The crossover design will allow all participants to receive treatment with the BTK inhibitor. This crossover design allows for blinding of treatment interventions and more objective assessment of baseline safety events and efficacy endpoints. A 12-week treatment period with a BTK inhibitor should enable detection of the inhibitor's ability to suppress the formation of new Gd-enhancing T1 lesions. A recent study of evobrutinib in patients with RMS confirmed that a significant reduction in these lesions was observed as early as week 12 (Merck Press Release - Merck KGaA, Darmstadt, Germany, Announces Positive Phase IIB Results for Evobrutinib in Relapsing Multiple Sclerosis. 7 Mar 2018).

[0214] Dosing Regimen: The dose range selected for this study was based on several assessments. First, non-proportional modeling aimed at translating BTK inhibitor occupancy in preclinical animal models (mice, rats, and dogs) predicted an optimal human dose range of 1–100 mg once daily. Second, phase 1 multiple ascending dose measurements of BTK occupancy in human peripheral blood mononuclear cells (PBMCs) demonstrated receptor saturation with the BTK inhibitor at a dose of 7.5 mg once daily, with saturation approaching more rapidly at higher doses. Finally, absolute CD19+ B cell counts were measured and showed a dose-dependent increase (maximum observed on day 4) of up to 80% over baseline. The BTK-induced increase in circulating B cells is predicted by literature, as BTK inhibition alters the expression of cell surface adhesion molecules, leading to lymph node egress (Burger JA et al., Nat Rev Cancer. 2018;18(3):148-67). The dose-response relationship for this effect is maximized at approximately 30 mg once daily. Taking all these factors into consideration, the dose range of 5 to 60 mg once daily was established as the range most likely to capture the optimal dose of BTK inhibitors in RMS.

[0215] Definition of Study Completion: Participants are considered to have completed the study if they have completed all phases of the study, including the final visit. The end of the study is defined as the date of the study participant's last visit.

[0216] Example 1.3 - Study Population Example 1.3A - Inclusion Criteria Participants could be included in the study only if they met all of the following criteria, as shown in Table 3:

[0217] [Table 15]

[0218] [Table 16]

[0219] Example 1.3B - Exclusion Criteria Participants will be excluded from the study if any of the following criteria apply as shown in Table 4:

[0220] [Table 17]

[0221] [Table 18]

[0222] [Table 19]

[0223] [Table 20]

[0224] [Table 21]

[0225] [Table 22]

[0226] Example 1.4 - Study Intervention A study intervention is defined as an investigational intervention, commercially available product, placebo, or medical device intended to be administered to study participants according to the study protocol.

[0227] Example 1.4A - Study Interventions Administered The study interventions included an IMP and a non-investigational medicinal product (NIMP). To maintain blinding, participants received four tablets of the BTK inhibitor and / or placebo once daily in a blinded manner. Details of the interventions are shown in Table 5.

[0228] [Table 23]

[0229] NIMP:T1 contrast-enhanced MRI sequences use intravenous contrast agents that enhance the radiological signal. Use locally approved vehicles.

[0230] Example 1.4A1 - Measures to Minimize Bias: Randomization and Blinding All participants will be centrally assigned to one of eight arms (initiating BTK inhibitor (Cohort 1) or placebo (Cohort 2) treatment in equal proportions across four treatment arms in each of the two cohorts) using the IVRS / IWRS prior to crossover. Participants cannot be randomly assigned multiple times. Prior to the start of the study, each site will be provided with the IVRS phone number and instructions, and / or IWRS login information and instructions. Study intervention medications will be dispensed at study visits summarized in the Activity Schedule (Table 1). Returned study intervention medications should not be re-prescribed to participants.

[0231] Blind Break (IVRS / IWRS): The IVRS / IWRS is programmed with instructions for blind breaking. In an emergency, the investigator has sole responsibility for determining whether unblinding of a participant's treatment assignment is justified. When making such a decision, the participant's safety must always be the primary consideration. If the investigator determines that unblinding is necessary, the investigator must make every effort to contact the sponsor before unblinding the participant's treatment assignment, unless this would delay the participant's emergency treatment. If a participant's treatment assignment will not be blinded, the sponsor must be notified within 24 hours of unblinding. The date and reason for unblinding, if applicable, must be recorded in the documentation and case report form.

[0232] This study was blinded to the dose and order of BTK inhibitor-placebo administration. The placebo was administered in the same tablet form at different dose levels. Due to ethical considerations, the placebo administration period was limited to 4 weeks. This allowed for a more objective evaluation of safety events at the start of the study period and increased objectivity in the evaluation of clinical endpoints.

[0233] The investigator will not have access to MRI data, except for non-MS-related findings that will be communicated to assess participant safety. Any non-MS findings on MRI will be reported to the investigator in a timely manner by the local radiology department.

[0234] An Independent Data Monitoring Committee (IDMC) will regularly monitor safety in this study. Unblinded data will be provided to the IDMC for review by an unblinded independent statistician. Study team members, investigators, and study participants will not have access to unblinded data.

[0235] Example 1.4B - Combination Therapy Any medications or vaccines (including over-the-counter, prescription, vitamin, and / or herbal supplements) that participants were receiving at the time of enrollment or during the study will be recorded, along with administration information including reason for use, dates of administration including start and end dates, dose, and frequency.

[0236] The same data will be collected on all previous medications administered in the 4 weeks prior to enrollment, as well as on MS treatment history and any other medications deemed clinically important for assessing MS and comorbidities. Standard treatment of MS relapses with high-dose glucocorticoids is permitted. Local guidance regarding such treatment should be followed.

[0237] In addition to the drugs excluded in Table 4, the following drugs are prohibited during the study: - Other disease-modifying treatments for MS -Acetylsalicylic acid (aspirin) -Antiplatelet drugs (e.g., clopidogrel) -Anticoagulants: including warfarin, heparin (including low molecular weight heparin), dabigatran, apixaban, edoxaban, and rivaroxaban.

[0238] Paracetamol / acetaminophen at doses up to 3 grams / day will be permitted at any time during the study. NSAIDs (other than acetylsalicylic acid) at recommended doses may be administered for short periods (up to 5 days) during the study if clinically necessary for the treatment of existing conditions or new events. The investigator will record the use of NSAIDs (and other medications) on the CRF.

[0239] In vitro experiments and in silico modeling have demonstrated that gastric acid-reducing agents may decrease the plasma exposure of BTK inhibitors. Proton pump inhibitors (e.g., omeprazole) should be avoided. Antacids (e.g., calcium carbonate) should be staggered with respect to BTK inhibitor administration, with administration occurring at least 2 hours before or 2 hours after BTK inhibitor administration. H2 receptor antagonists (e.g., ranitidine) should also be staggered with respect to BTK inhibitor administration, with administration occurring at least 10 hours before or 2 hours after BTK inhibitor administration. See Table 13 for examples of agents that may affect BTK inhibitor plasma exposure via gastric acid reduction.

[0240] Based on preclinical drug metabolism studies, BTK inhibitors are substrates of CYP3A and CYP2C8 isoenzymes and therefore plasma exposure of BTK inhibitors may be altered when coadministered with other drugs that induce or inhibit CYP3A and / or CYP2C8 metabolism. This has not been studied in humans; therefore, drugs that strongly inhibit or induce CYP3A or CYP2C8 should be avoided, if possible. See Table 12 for a list of drugs not to be used.

[0241] Example 1.4C - Dose Modification Dose reductions are not anticipated in this study. Participants, investigators, and the sponsor team are blinded to the assigned dose level. Treatment may need to be interrupted or permanently discontinued if deemed necessary by AEs (Example 1.4E and Example 1.8).

[0242] Example 1.4D - Post-Study Intervention Participants in this study who complete week 16 will be offered a separate open-label LTS study. Upon completion of the double-blind treatment period, participants already enrolled in the DRI study and subsequent participants will have the option to enroll in an LTS follow-up study to evaluate the safety and tolerability of the BTK inhibitor.

[0243] Example 1.4E - Discontinuation of Study Intervention and Participant Withdrawal / Withdrawal A distinction should be made between withdrawal of consent for treatment, withdrawal of (additional) consent for follow-up, and withdrawal of consent for follow-up of non-participant contact (e.g., medical record checks). Institutions should document withdrawal of consent, if any.

[0244] Example 1.4E1 - Discontinuation of Study Intervention Definitive Discontinuation: The IMP should be continued whenever possible. If the IMP is discontinued, a determination should be made as to whether temporary discontinuation is possible. Definitive discontinuation of the IMP should be a last resort. Discontinuation of the IMP is fully documented in the eCRF. Regardless, participants should remain in the study for as long as possible. Definitive intervention discontinuation is an intervention discontinuation that accompanies a definitive decision by the investigator not to re-expose the participant to the IMP at any time during the study or that the participant will not be re-exposed to the IMP for any reason. Discontinuation of the study intervention due to abnormal liver function should be considered by the investigator if the participant meets any of the conditions outlined in Section 10.6 or if the investigator determines it is in the participant's best interest. If a clinically significant finding is identified on the ECG (including, but not limited to, a change from baseline in the QT interval corrected using the Fridericia formula [QTcF]) after enrollment, the investigator or qualified designee will determine whether the participant can continue in the study and whether any changes in the participant's management are necessary. Cardiologist review of ECG findings should be considered to determine definitive discontinuation of study intervention due to ECG changes. This review of printed ECGs at the time of collection will be documented. Any new clinically relevant findings will be reported as AEs.

[0245] See the SoA (Table 1) for data to be collected at the time of intervention discontinuation (end of treatment) and follow-up, as well as the assessments that must be completed. Any abnormalities in laboratory values ​​or ECG parameters will be confirmed by immediate retesting after 24 hours, prior to a decision to discontinue the intervention for that participant. If the intervention is discontinued early, an end-of-treatment visit will be conducted.

[0246] Participants will be followed according to the study procedures specified in this protocol until the end of the study or until resolution or stabilization of any adverse events requiring follow-up as specified in this protocol, whichever occurs later. If possible, after definitively discontinuing the intervention, participants will be evaluated with their routinely scheduled procedures on the last day of treatment with the IMP, including PK samples. Details are provided in the SoA (Table 1). All definitive intervention discontinuations will be recorded by the investigator on the appropriate page of the eCRF once they are considered definitive.

[0247] If abnormal laboratory values ​​and / or ECG are suspected, the investigator may consider temporary discontinuation. For all temporary discontinuations, the investigator must record the duration of the discontinuation on the appropriate page of the eCRF. An investigator-determined temporary discontinuation corresponds to more than one missed dose to a participant.

[0248] If the investigator, based on their best medical judgment, believes that IMP is unlikely to have contributed to the occurrence of the event and the patient still meets the study inclusion criteria (see Table 3), the IMP intervention will be resumed under close and appropriate clinical and laboratory monitoring.

[0249] Example 1.4E2 - Participant Withdrawal / Withdrawal: Participants may withdraw from the study at any time for safety, behavioral, compliance, or administrative reasons at their own request or at the discretion of the investigator. -If a participant withdraws consent for future disclosures, the Organizer may retain and continue to use the data collected prior to such withdrawal of consent. - If a participant withdraws from the study, the participant may request that any samples collected but not tested be destroyed, and the investigator must document this in the site's study records. -See the SoA (Table 1) for data to be collected at study discontinuation and follow-up, as well as assessments to be completed. If the participant no longer wishes to receive IMP, they will be encouraged to continue participating in the study.

[0250] Investigators should discuss important visits with participants and emphasize that the value of all study data is important to the public health value of the study.

[0251] Participants withdrawing from the trial intervention should be explicitly asked about adverse events that may affect their decision, and any adverse event information elicited should be recorded.

[0252] All study withdrawals must be documented by the investigator in the appropriate section of the eCRF and in the participant's medical record, which must record at least the date and reason for withdrawal.

[0253] Furthermore, participants can withdraw their consent to participate in a study. A distinction needs to be made between withdrawal of consent for the intervention, withdrawal of consent for follow-up visits, and withdrawal of consent for follow-up contact other than the participant, for example, medical record checks. Institutions should record withdrawal of consent when it occurs.

[0254] Participants who withdraw from this study cannot be reassigned (treated) to this study. Participant numbers and kit numbers will not be reused.

[0255] Example 1.4E3 - Untraceable Participants are considered lost to follow-up if they repeatedly fail to show up for scheduled visits and cannot be contacted by the study site.

[0256] If a participant fails to return to the clinic for a required study visit, the following actions will be taken: - The site should contact the participant and attempt to reschedule any missed visits as soon as possible, advise the participant on the importance of maintaining the designated visit schedule, and confirm whether the participant wishes and / or should continue in the study. Before a participant is considered lost to follow-up, the investigator or designee must make every effort to re-establish contact with the participant (three telephone calls, if possible, and, if necessary, a certified letter to the participant's last known mailing address or local equivalent). Such contact attempts must be documented in the participant's medical record. -Participants who continue to be unable to be contacted will be considered to have withdrawn from the study.

[0257] Example 1.5 - Testing Evaluations and Procedures Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers or waivers will not be permitted. Procedures performed as part of the potential participant's routine clinical management (e.g., blood count) and prior to signing the Informed Consent Form (ICF) may be utilized for screening or baseline purposes if they meet the criteria specified in the protocol and were performed within the time period defined in the SoA (Table 1). In the event of early discontinuation of the study intervention, an end-of-treatment visit will be conducted. Participants will return to the clinic 2–4 weeks after early treatment termination.

[0258] Example 1.6 - Efficacy Evaluation Example 1.6A - Magnetic Resonance Imaging Assessment Cranial (brain) MRI will be performed with and without Gd-enhanced contrast. Baseline MRI, consisting of T2- and T1-weighted sequences without and with Gd-enhanced contrast, will be performed for all participants at all study sites. Because of potential safety risks associated with brain deposition of certain intravenous Gd-enhanced contrast agents, these agents should be used in accordance with local recommendations / regulations (Fischer JS et al. "The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment," National MS Society Clinical Outcomes Assessment Task Force. Mult Scler. 1999;5(4):244-50).

[0259] New Gd-enhancing T1 hyperintense lesions and new and enlarged T2 lesions will be assessed at each visit according to the System of Assessment (SoA) (Table 1), comparing the number of lesions with the previous MRI scan. Unless otherwise noted, the baseline brain MRI will be used as the reference for assessing all MRI-derived endpoints. The baseline MRI will be the last MRI before randomization. Standardized endpoint assessment will be ensured by central review of brain MRI scans. Blinded central review will be performed for all MRI-derived endpoints. Reviewers of magnetic resonance images will be blinded to treatment assignment and other participant data. If the investigator suspects spinal MS lesions, a spinal MRI may be required. Spinal MRIs will be assessed locally and reported on the eCRF. No central review will be performed for spinal MRIs.

[0260] Magnetic resonance imaging for exploratory efficacy assessment will include regional and whole-brain volume assessment, additional analysis of T1 and T2 images, and sequences such as magnetic transfer ratio and susceptibility weighted images.

[0261] Example 1.6B - Multiple Sclerosis Relapse Unscheduled Assessment Visit for Suspected Multiple Sclerosis Relapse: Participants are instructed to immediately report any new neurological symptoms and any recurrence or worsening of previous symptoms to the investigator. All reported symptoms will be collected. If a participant reports symptoms that may be consistent with a relapse, an unscheduled assessment visit with the investigator will be scheduled as soon as possible (preferably within 7 days of symptom onset). The investigator will assess whether the reported episode is consistent with the definition of an MS relapse (see Example 1.6B). If the episode is consistent with the definition of an MS relapse, or if there is doubt and relapse cannot be ruled out, an EDSS assessment should be performed. Unscheduled visits are detailed in the SoA (Table 1) and should be accommodated if additional testing or laboratory investigations are required for conditions other than MS to determine safe follow-up and optimal treatment.

[0262] Multiple Sclerosis Relapse: For the purposes of this study, a relapse of MS is defined as an acute new neurological symptom or worsening of a previous neurological symptom accompanied by objective changes on neurological examination. Symptoms must meet the following: MS-related -Continues for more than 24 hours, and · Have a normal body temperature (i.e., no infection, excessive exercise, or excessive fever).

[0263] Note: Worsening or recurrence of symptoms or signs that can reasonably be attributed to drug-induced transient conduction disturbances of demyelinating pathways (such as may occur rarely several hours after interferon beta injection), elevated core body temperature (Uhthoff phenomenon), or systemic cytokine release (such as may occur with alemtuzumab administration) is not considered a relapse.

[0264] Example 1.6C - Comprehensive Disability Scale Assessment The investigator will perform the Expanded Disability Status Scale (EDSS) assessment (Kurtzke JF, Neurology. 1983;33(11):1444-52) as indicated in the SoA (Table 1).

[0265] The investigator will assess the functional system against a standard neurological examination and report these assessments according to the EDSS reporting instructions, along with information on the participant's motor skills, ambulation, and use of assistive devices. Standard EDSS assessments of neurological symptoms will be conducted for each of seven functional domains (visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and bowel / bladder). Gait will also be scored as part of the assessment. Fatigue may be assessed optionally but does not contribute to the EDSS score.

[0266] Example 1.7 - Safety Assessment All safety assessment timepoints are described in the SoA (Table 1). Definitions of AEs and SAEs are described in Example 1.8B. For purposes of this protocol, MS relapses (Example 1.6B) are exempt from reporting as AEs unless they meet the criteria for an SAE. Non-severe MS relapses will be collected on a special eCRF page and analyzed as an efficacy endpoint. After MS relapse assessment (Example 1.6B), events determined not to meet the criteria for MS relapse will be reported as AEs.

[0267] Example 1.7A - Physical Examination A complete physical examination should, at a minimum, include evaluation of the general appearance, head and neck, abdomen, lymph nodes, skin (signs of bleeding include bruising, petechial rash), circulatory system, respiratory system, gastrointestinal system, musculoskeletal system, and nervous system. Height and weight should also be measured and recorded. A brief physical examination should, at a minimum, include evaluation of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Investigators should pay particular attention to clinical signs associated with previous serious illness. Any new findings or worsening of previous findings should be reported as a new AE. The SoA (Table 1) provides a schedule for the physical examination.

[0268] Example 1.7B - Vital Signs Body temperature, pulse rate, respiratory rate, and blood pressure will be measured. Temperature measurements should be made using the same method throughout the study. Blood pressure and pulse measurements will be assessed in the seated or supine position using fully automated equipment. The same measurements should be taken for the same participant throughout the study. Manual techniques will only be used if automated equipment is not available. Caffeinated drinks should be avoided before blood pressure measurements. Before blood pressure and heart rate measurements, participants should be given at least 5 minutes of rest in a quiet environment without distractions (e.g., television, mobile phone). Vital signs (measured before blood is drawn for clinical testing) will consist of one pulse, three blood pressure measurements (record three consecutive blood pressure measurements at least one minute apart), and respiratory rate. The average of the three blood pressure measurements will be recorded.

[0269] Example 1.7C - Electrocardiogram A single 12-lead electrocardiogram will be obtained as outlined in the SOA (Table 1) using an ECG device that automatically calculates heart rate and measures PR, QRS, QT, and QTc intervals. Each ECG should be followed by at least one longer heart rate monitoring recording. ECGs will be reviewed for abnormalities and clinically evaluated by a cardiologist. See Example 1.4E for QTc withdrawal criteria and any additional QTc measurements that may be necessary.

[0270] Example 1.7D - Clinical Safety Laboratory Evaluation See Example 1.16 for a list of laboratory tests to be performed and the System of Assessment (SoA) (Table 1) for timing and frequency. The investigator will review laboratory test reports, document this review, and record any clinically relevant changes that occur during the study in the AE section of the eCRF. Clinically significant abnormal laboratory findings are those not related to an underlying disease unless the investigator determines that the findings are more severe than expected for the participant's condition. All laboratory tests with values ​​considered clinically significant abnormal during study participation or within 4 weeks after the last dose of study intervention must be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor. If the values ​​do not return to normal or baseline within a time period deemed reasonable by the investigator, the etiology must be identified and the sponsor notified. All laboratory evaluations required by the protocol, as defined in Example 1.16, will be performed in accordance with the laboratory manual and System of Assessment (SoA) (Table 1). - If a laboratory value from a non-protocol-specified laboratory evaluation performed at the site's local laboratory requires a change in the participant's management or is deemed clinically significant by the investigator (e.g., SAE or AE or dose modification), the result will be recorded on the eCRF.

[0271] Example 1.7E - Suicide Risk Monitoring Because BTK inhibitors are believed to act on the central nervous system, regular suicide risk monitoring is performed. Suicide risk assessment will involve the Columbia Suicide Severity Rating Scale (C-SSRS) and a thorough clinical assessment of symptomatic complaints. Clinically significant observations or events will be reported as AEs. The C-SSRS is a tool used to assess participants' lifetime suicidality and track suicidal events throughout the study. A structured interview will prompt participants to recount suicidal ideation, including the intensity of ideation, behavior, and actual / potentially fatal attempts. This scale will be administered by the investigator or a qualified designee at the time points indicated in the SoA (Table 1).

[0272] Example 1.8 - Adverse Events and Serious Adverse Events Example 1.8A - Adverse Events of Special Interest An AESI is an AE (serious or non-serious) of scientific or medical concern specific to the sponsor's product or program that requires ongoing monitoring and prompt notification to the sponsor by the investigator. Such events may require further investigation to characterize and understand them. Adverse events of special interest may be added, modified, or removed by protocol amendment during the trial. - Acute hypersensitivity / anaphylaxis - Pregnancy of female participants in the study and pregnancy of the female partner of male participants in the study with IMP / NIMP. o If a female participant in a clinical trial or the female partner of a male participant in a clinical trial becomes pregnant. An SAE will only be recognized if one of the severity criteria is met (see Example 1.8B). If a female participant becomes pregnant, the IMP must be discontinued. Pregnancy follow-up in the female participant or the female partner of the male participant is mandatory until the outcome is confirmed (see Example 1.17). Symptomatic IMP / NIMP overdose (serious or non-serious): An IMP / NIMP overdose (accidental or intentional) is defined as an investigator-suspected event or a participant-sponsored event (not based on systematic pill counts) in which at least twice the intended dose was administered within the intended treatment interval, adjusted for study drug. Of note, asymptomatic overdose is reported as a standard AE. -ALT Elevation: Any increase in ALT >3 x ULN.

[0273] Other project-specific AESI ECG findings of QTc ≥ 500 ms or clinically significant arrhythmias confirmed by a cardiologist (e.g., atrial fibrillation, atrial flutter, etc.), serious infections (especially opportunistic infections), serious bleeding events including symptomatic bleeding in critical areas or organs that could lead to an SAE, such as central nervous system bleeding or intraocular bleeding, platelet count < 100 × 10 9 / L.

[0274] AEs will be reported by the participant (or, where appropriate, by the caregiver, surrogate, or legally authorized representative of the participant).

[0275] The investigator and qualified designee will be responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE, and for tracking serious AEs that are considered related to the study intervention or study procedures, or that cause a participant to discontinue the study intervention (see Example 1.4E).

[0276] The definition of AE or SAE is provided in Example 1.8B.

[0277] Example 1.8B - Adverse Events: Definitions and Procedures for Recording, Evaluation, Follow-up, and Reporting Adverse Event (AE): An AE is any untoward medical occurrence in a patient or clinical trial participant temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) temporally associated with the use of the study intervention.

[0278] Events that meet the AE definition: Any abnormal clinical laboratory results (e.g., hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiology scan, vital sign measurements), including, for example, any deterioration from baseline that, in the investigator's medical and scientific judgment, is considered clinically significant (i.e., not related to progression of the underlying disease): -Aggravation of a chronic and / or intermittent pre-existing condition, including an increase in the frequency or intensity of the condition. - A new condition is detected or diagnosed after administration of the study intervention, although it may have been present before the start of the study. -Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction. - Signs, symptoms, or clinical sequelae suggestive of overdose of either the study intervention or concomitant medication.

[0279] Lack of efficacy or failure of the expected pharmacological effect per se is reported as an AE or SAE, but is captured in the efficacy evaluation.

[0280] Events that do not meet the definition of AE: - Clinically significant laboratory or other safety abnormalities related to the underlying disease, unless the investigator determines that the condition is more severe than expected for the participant. - The disease / disorder being studied or the expected progression, signs, or symptoms of the disease / disorder being studied (unless more severe than expected for the participant's condition). - Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition leading to the procedure is an AE. - Situations in which an unforeseen medical incident did not occur (social admission and / or admission for convenience). - Pre-existing medical conditions or conditions present or detected at study entry have expected day-to-day fluctuations and do not worsen.

[0281] If an event is not an AE according to the above definition, it cannot be an SAE, even if it meets the serious criteria (e.g., hospitalization due to signs / symptoms of the study disease, death due to disease progression).

[0282] Serious Adverse Events (SAEs): SAEs occurred at any dose: a) Causes death. b) Life-threatening (the term "life-threatening" refers to an event / reaction in which the participant was at risk of dying at the time of the event / reaction, not an event / reaction in which death could have occurred if the event / reaction had been more severe). c) Requires hospitalization or results in an extension of an existing hospitalization (generally, hospitalization means that the participant is admitted to a hospital or emergency room (usually involving at least an overnight stay) for observation and / or treatment that was not appropriate in a physician's office or outpatient clinic). A complication occurring during hospitalization is an AE. If the complication extends the hospitalization or meets some other significant criterion, the event is serious. If there is doubt as to whether a "hospitalization" occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. d) Result in a persistent impairment / incapacity (the term impairment means a substantial interference with a person's ability to perform normal life functions). This definition is not intended to include experiences of relatively minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, flu, and accidental trauma (e.g., a sprained ankle), which interfere or may interfere with daily life functioning but do not constitute a substantial disruption. e) Congenital anomalies / birth defects. f) Other circumstances, such as significant medical events that are not immediately life-threatening or result in death or hospitalization, but may endanger the participant or require medical or surgical intervention to prevent any of the other outcomes listed in the definition above. These events should generally be considered serious. Examples of such events include invasive or malignant cancer, intensive care in the emergency room or at home for allergic bronchospasm, blood abnormalities or seizures that do not result in hospitalization, and the development of drug dependence or abuse.

[0283] Recording and follow-up of AEs and / or SAEs Recording AEs and SAEs: If an AE / SAE occurs, all documentation related to the event (e.g., hospital progress notes, laboratory reports, diagnostic reports) will be reviewed, and all relevant AE / SAE information will be recorded in the eCRF. Investigators are not permitted to send copies of the participant's medical records to the sponsor's representative instead of completing the AE / SAE eCRF page. Medical records may be required as additional data for SAE and AESI reporting. In such cases, the participant's name and initials will be anonymized by replacing them with the study participant number. In certain cases, sponsors may request copies of medical records. In this case, all participant identifiers, except for the participant number, will be redacted from the copies of the medical records before submitting them to the sponsor. The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and / or other clinical information. Whenever possible, the diagnosis (not individual signs / symptoms) will be recorded as the AE / SAE.

[0284] Severity Assessment: AEs / SAEs reported during the study will be assessed for severity and assigned to one of the following categories: -Mild: An event that causes minimal discomfort, does not interfere with daily activities, and is easily tolerated by the participant. - Moderate: An event that causes sufficient discomfort to interfere with normal daily activities. -Severe: An event that interferes with normal daily activities. AEs rated as severe should not be confused with SAEs. Severity is a category used to rate the intensity of an event; both AESs and SAEs can be rated as severe.

[0285] An event was defined as "serious" if it met at least one of the predefined outcomes as described in the SAE definition, and not "serious" if it was assessed as severe.

[0286] Assessment of causality: The investigator is obligated to assess the relationship between the study intervention and each occurrence of each AE / SAE. A "reasonable possibility" of relationship means that there is fact, evidence, and / or reason to suggest a causal relationship, rather than that a relationship cannot be ruled out. The investigator will use clinical judgment to determine the relationship. Alternative causes, such as underlying disease, concomitant therapy, and other risk factors, will be investigated, taking into consideration the temporal relationship between the event and administration of the study intervention. The investigator will also refer to the Investigator Brochure (IB) and / or product information for marketed products during the assessment.

[0287] For each AE / SAE, the investigator will document in the medical note that the investigator reviewed the AE / SAE and provided a causality assessment. There may be situations where an SAE occurs and the investigator has minimal information to include in the initial report to the sponsor. However, it is very important that the investigator always assesses the causality of every event before the initial submission of SAE data to the sponsor. The investigator may change his or her opinion of causality in light of follow-up information and submit an SAE follow-up report with an updated causality assessment. The causality assessment is one of the criteria used in determining regulatory reporting requirements.

[0288] Follow-up of AEs and SAEs: The investigator is obligated to perform or arrange for supplementary measurements and / or evaluations, if medically indicated or at the request of a representative of the monitoring team, to clarify as completely as possible the nature and / or causality of the AE or SAE. This may include additional tests or investigations, histopathological examination, or consultation with other medical professionals. New or updated information will be recorded in the originally completed eCRF. If a participant dies during study participation or the permitted follow-up period, the investigator will provide a copy of the post-mortem findings, including histopathological examination, to the sponsor's representative. New or updated information will be recorded in the originally completed eCRF. The investigator will submit updated SAE data to the sponsor within 24 hours of receiving the information.

[0289] Reporting SAEs: Reporting SAEs to the Sponsor via Electronic Data Collection Tools. The primary method for reporting SAEs to the sponsor is via the electronic data collection tool. If the electronic system is unavailable for more than 24 hours, sites will use the paper SAE data collection tool (see this document). Sites will enter SAE data into the electronic system as soon as it becomes available. When a study is completed at a site, the electronic data collection tool will be taken offline to prevent the entry of new data or changes to existing data. After the electronic data collection tool is taken offline, if a site receives a new SAE from a study participant or an update to a previously reported SAE, the site can report this information to the sponsor via a paper SAE form (see Example 1.8C) or by telephone.

[0290] Reporting SAEs to the Sponsor via Case Report Forms (CRFs): The preferred method of transmitting this information to the sponsor is to facsimile the SAE CRF. In the rare event that a facsimile machine is not available, sending a copy of the SAE data collection tool by overnight mail or courier followed by telephone notification is acceptable. Initial notification by telephone does not replace the need for the investigator to complete and sign the SAE CRF page within the designated reporting period.

[0291] Example 1.8 Duration and Frequency of Collecting C-AE and SAE Information All AEs (including SAEs) will be collected at the time specified in the SOA, from ICF signature through EOT (Table 1). All SAEs and AESIs will be recorded and reported to the sponsor or designee within 24 hours, as described in Example 1.8B. The investigator will submit updated SAE data to the sponsor within 24 hours of its availability. The investigator is under no obligation to actively investigate AEs or SAEs after study participation ends. However, if the investigator learns of an SAE, including death, at any time after a participant has been discharged from the study and determines that the event is reasonably related to the study intervention or participation, the investigator will promptly notify the sponsor. The procedures for recording, evaluating, and assessing causality of AEs and SAEs, as well as the procedures for completing and submitting the SAE report, are described in Example 1.8B.

[0292] Example 1.8 Method for detecting D-AE and SAE Care should be taken to avoid bias when detecting AEs and / or SAEs. Open-ended, non-leading verbal questions are preferred when inquiring about the occurrence of AEs.

[0293] Example 1.8E-AE and SAE Follow-up After the first AE / SAE report, investigators are expected to actively follow up each participant at subsequent visits / contacts. At the pre-specified study end date, all SAEs and non-serious AESIs (as defined in Example 1.8B) will be followed until they resolve, stabilize, the event is explained, or the participant is lost to follow-up (as defined in Example 1.4E3).

[0294] Example 1.8F-Pregnant Details of all pregnancies in female participants and female partners of male participants will be collected from the start of the study intervention until the final study visit. If a pregnancy is reported, the investigator will notify the sponsor within 24 hours of learning of the pregnancy and will take action as described in Example 1.17. An adverse pregnancy outcome (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) will be considered an SAE.

[0295] Example 1.8G - Cardiovascular and Mortality Events Observation of atrial fibrillation, atrial flutter, QTc ≥ 500 ms, or other clinically significant arrhythmias is an AESI in this study and is subject to expedited reporting to the sponsor. All other cardiovascular events will be reported according to standard safety reporting and safety monitoring practices (including data review by the IDMC). A central ECG review will be conducted to ensure consistency of ECG evaluation. Fatal events will be reported according to standard SAE reporting rules, with the cause of death clarified and the diagnosis of the fatal event reported as an SAE.

[0296] Example 1.8H - Multiple Sclerosis Relapse Report Multiple sclerosis relapses, as determined by the assessments described in Example 1.6B, as well as all efficacy endpoints, will be exempt from reporting as AEs unless they meet the definition of an SAE. Hospitalizations for MS relapses, if routinely performed at the institution (e.g., for high-dose intravenous methylprednisolone), will not be considered as severity criteria for this study. Other neurological worsening symptoms that do not meet the definition of an MS relapse will be reported as AEs in accordance with general safety reporting rules.

[0297] Example 1.8I - Reporting of Magnetic Resonance Imaging Safety Findings Magnetic resonance imaging should be performed to focally confirm the absence of pathology other than MS. If such findings are present, the MRI report should be submitted to the investigator for appropriate safety reporting. If available, a diagnosis of pathology as the cause of such MRI findings or the findings themselves will be reported as an AE until a diagnosis is made. Multiple sclerosis findings on MRI do not need to be reported unless they are determined to be abnormal and therefore a definite safety finding.

[0298] Example 1.9 - Overdose Treatment The sponsor does not recommend any specific treatment for overdose. If an overdose occurs, the investigator should: - Immediately contact the medical monitor. Participants will be closely monitored for AEs / SAEs and laboratory abnormalities until the study intervention is no longer detectable systemically and activity is terminated (for at least 9 days). - Plasma samples for PK analysis will be collected within one day of the last dose of study drug, if possible, or later if requested by the medical monitor (on a case-by-case basis). -Record the overdose amount and duration on the eCRF.

[0299] Decisions regarding dose interruptions or changes will be made by the investigator in consultation with the medical monitor based on the participant's clinical evaluation.

[0300] Example 1.10 - Pharmacokinetics Example 1.10A - Sampling Time Samples for BTK inhibitor PK analysis will be collected 1 hour (±0.5 hours) post-dose for all participants in both cohorts at visits at weeks 1, 4, 8, 12, and 16. Additional 3-hour (±0.5 hours) post-dose PK samples will be collected for all participants in both cohorts at visits at weeks 4 and 12. Data from the most recent meal prior to PK sampling will be included in the eCRF.

[0301] Example 1.10B - Pharmacokinetics Handling Procedure Each PK sample will require a total of 2 mL of blood. The total volume of PK blood per participant and the total number of samples collected in this study are shown in Table 6.

[0302] [Table 24]

[0303] Example 1.10C - Bioanalytical Methods BTK inhibitors are assayed by a validated LC / MS method.

[0304] Example 1.10D-PK parameters BTK inhibitor concentrations at specific time points after IMP ingestion are reported using descriptive statistics. max , t max Additional PK parameters, such as AUC, are estimated using population PK methods.

[0305] Example 1.11 - Pharmacodynamics Example 1.11A - Sampling Time Venous blood samples collected for PBMCs will be used to measure lymphocyte subset analysis BTK occupancy at baseline (pre-dose) and 1 hour (±0.5 hours) after BTK inhibitor administration at the week 12 and week 16 visits (as part of a biomarker substudy).

[0306] Example 1.11B - Bioanalytical Methods for Pharmacodynamic Parameters Peripheral blood mononuclear cells are prepared from whole blood and BTK occupancy is measured. Descriptive statistics are used to report BTK occupancy at specific time points.

[0307] Example 1.12 - Pharmacogenetics Participants who consent to participate in the genetic analysis of this study will be given a 6 mL blood sample for DNA isolation. Participants who do not wish to participate in the genetic study will also be accepted. Samples will be collected to investigate allelic variants of drug-metabolizing enzymes and / or drug transporters as intrinsic factors associated with PK or PD variability of BTK inhibitors (Example 1.18).

[0308] If DNA extraction fails, participants can be asked to provide a replacement genetic blood sample.

[0309] Example 1.13 - Biomarkers Plasma and serum samples for biomarker studies will be collected from all study participants as specified in the Study Assessment (Table 1). All participant samples will be used to test neurofilament light chain, chitinase 3-like protein 1, and immunoglobulin levels to assess correlation with observed clinical responses. Blood samples for PBMC isolation will also be collected from all participants at selected facilities that can rapidly send them to a central laboratory for processing. Peripheral blood mononuclear cell samples will be used to assess BTK receptor occupancy (Example 1.11B), analyze selected lymphocyte subsets throughout the study, and analyze other potential biomarkers. Approximately 50 mL of blood will be collected for all of these samples.

[0310] Example 1.14 - Statistical Considerations Example 1.14A - Statistical Analysis The primary objective of this study is to evaluate the dose-response relationship based on the primary endpoint (number of new Gd-enhancing T1 hyperintense lesions detected by brain MRI) at the end of 12 weeks of BTK inhibitor treatment. The null hypothesis is a flat, absent dose-response curve for the primary endpoint, and the alternative hypothesis is a dose-response signal.

[0311] Example 1.14B - Sample Size Determination In this study, 120 participants were divided into two cohorts (60 participants each in Cohort 1 and Cohort 2) and randomly assigned to one of four BTK inhibitor doses. Cohorts 1 and 2 represented different treatment sequences, and each participant was crossed over to either the BTK inhibitor or placebo in a blinded manner.

[0312] Sixty participants in Cohort 2 will begin with a 4-week placebo run-in and will be used as placebo data in the analysis of the primary endpoint, based on the assumption that the monthly mean incidence of new Gd-enhanced T1 hyperintense lesions remains constant over the 12-week placebo period. Assuming that 15% of participants are free of the primary endpoint at the end of 12 weeks of BTK inhibitor treatment, 105 participants (26 per BTK inhibitor dose) will be included in the six dose-response curves (two E maxUsing a two-stage MCP-Mod model with predefined parameters (quadratic, quadratic, linear, logistic, and exponential), we have at least 83% power to detect a maximum 85% reduction. This calculation assumes a variance parameter of 2, a within-subject correlation between 4-week placebo and 12-week BTK inhibitor measurements in Cohort 2 ranging from -0.9 to 0.9, and a placebo mean number of new Gd-enhancing T1 hyperintensity lesions after 4 weeks of treatment of ≥1. This power was calculated using the DoseFinding package (Bornkamp B, Pinheiro J, Bretz F. Package 'DoseFinding', January 4, 2018) from the Comprehensive R Archive Network (CRAN) using six candidate curves considered for dose-response modeling in a negative binomial regression framework.

[0313] Example 1.14C - Population for Analysis For the purposes of analysis, the following populations are defined as shown in Table 7:

[0314] [Table 25]

[0315] Example 1.14D - Statistical Analysis Efficacy analysis Primary Analysis: The primary endpoint, the dose-response relationship of BTK inhibitors to the number of new Gd-enhancing T1-hyperintense lesions detected on brain MRI at the end of 12 weeks of BTK inhibitor treatment, was assessed in the modified intention-to-treat (mITT) population using a two-stage multiple comparison procedure (MCP-Mod) using modeling techniques. The first step of this procedure tests the efficacy signal (compared to the null hypothesis of a flat, non-existent dose-response curve) in a procedure that controls for type 1 error. To account for uncertainty in the dose-response shape, six candidate models were considered, encompassing diverse potential dose-response profiles: two E max Model (ED 50 = 10 mg, ED 50= 30 mg), linear model, quadratic model, logistic model, exponential model. The second step is dose estimation of the dose-response curve if an efficacy signal has been established in the first step.

[0316] A negative binomial regression model with baseline Gd-enhanced T1-hyperintense lesion counts, treatment, and cohort (Cohort 1 or Cohort 2) as covariates was used to evaluate the mean number of new Gd-enhanced T1-hyperintense lesions in each of the four treatment groups at the end of 12 weeks of BTK inhibitor treatment and at the end of 4 weeks of placebo treatment. Cohort 2 placebo data from 4 weeks after randomization (i.e., Cohort 2 Week 4 data) served as the Week 12 placebo data in the analysis, assuming a constant rate of Gd-enhanced T1-hyperintense lesion formation as participants received placebo over the 12 weeks. Cohort 2 participants contributed data for placebo (Week 4) and BTK inhibitor dose 4 (Week 16). Therefore, to account for potential correlation between measurements during the 4-week placebo period and the subsequent 12-week BTK inhibitor treatment period in Cohort 2, a generalized estimating equation (GEE) approach was used to fit a negative binomial model that accounted for within-participant correlation using an iterative procedure in SAS PROC GENMOD. The mean lesion counts were negative-log transformed and entered into MCP-Mod. The null hypothesis that the dose-response curve for the primary endpoint at the end of 12 weeks of BTK inhibitor treatment was flat (i.e., there was no dose-response relationship) was jointly evaluated for each of the six candidate dose-response models using a two-sided contrast test with a family mean error rate of 0.05. If significant results were obtained in Step 1, the best-fitting model was selected from the six predefined candidate models using the generalized Akaike information criterion (AIC).

[0317] The primary analysis was based on pooled data from Cohorts 1 and 2 for each BTK inhibitor dose (i.e., data on the number of new Gd-enhancing T1-hyperintense lesions at week 12 for Cohort 1 and week 16 for Cohort 2). Data from Cohorts 1 and 2 may also be examined separately if necessary.

[0318] Secondary Analysis: For the secondary endpoint of Gd-enhanced T1-hyperintense lesion counts at the end of 12 weeks of BTK inhibitor treatment, a similar negative binomial model and MCP-Mod method were used. For the total number of Gd-enhanced T1-hyperintense lesions, the same method as for the primary endpoint was used, using the week 4 data from Cohort 2 as the week 12 placebo data, while taking into account intraparticipant correlation, because it is reasonable to assume a constant lesion formation rate over 12 weeks under placebo treatment. Descriptive summary statistics over time are presented for each of the four BTK inhibitor doses.

[0319] Descriptive summary statistics for the number of new or enlarged T2 lesions are presented for each of the four BTK inhibitor doses over time (weeks 4, 8, 12, and 16). Additionally, if extrapolation of the week 4 data from Cohort 2 to the week 12 placebo data is deemed appropriate, a similar MCP-Mod approach will be considered.

[0320] The primary efficacy analysis was based on the mITT population. For endpoints assessed as change from baseline, baseline was defined as the last measurement collected on or before the randomization visit (Day 1) before the start of the first dose of study intervention.

[0321] Data from Cohorts 1 and 2 will be combined for the primary analysis (i.e., number of new Gd-enhancing T1-hyperintense lesions at week 12 for Cohort 1 and week 16 for Cohort 2). For each cohort, descriptive statistics will be summarized over time (weeks 4, 8, 12, and 16), as appropriate. The Cohort 1 summary includes descriptive statistics for the 4-week placebo period after 12 weeks of BTK inhibitor treatment. Other efficacy analyses are described in the SAP.

[0322] [Table 26]

[0323] [Table 27]

[0324] Safety analysis All safety analyses will be performed on the safety analysis population. All safety summaries will be narrative. No statistical significance tests will be performed on safety data. Safety endpoints are listed in Table 9.

[0325] Baseline values ​​are generally defined as the last available value before the first dose of the randomized trial intervention. Safety data for the first 4 weeks after randomization (participants in Cohort 2 received placebo) are summarized separately for BTK inhibitor and placebo. Safety data for the 4-week placebo period (i.e., 4 weeks) in Cohort 1 are summarized and presented separately by BTK inhibitor treatment group and overall. Safety data for BTK inhibitor treatment are summarized by treatment group, duration of BTK inhibitor treatment, and overall.

[0326] For safety variables, the following observation periods are defined and will be used to classify AEs, determine on-treatment PCSA values, and final on-treatment values ​​of clinical laboratory and vital sign parameters: The pre-treatment period is defined as the period from signing the ICF to the first administration of the randomized study intervention. For the purposes of defining "treatment initiation," the treatment period is defined as the period from the first administration of the randomized study intervention to the last study visit. The treatment period is further defined as follows: - "Week 1 to Week 4" is defined as the time from the first randomized dose of study treatment to the dose of study treatment at Week 4. Cohort 1 received 4 weeks of BTK inhibitor treatment, and Cohort 2 received 4 weeks of placebo treatment. - "BTK inhibitor treatment period" refers to weeks 1 through 12 for Cohort 1 and weeks 4 through 16 for Cohort 2. Note: Participants in weeks 1 through 4 of Cohort 1 are included in the 12-week BTK inhibitor treatment period. - The "post-placebo / BTK inhibitor period" is defined as weeks 12 to 16 in Cohort 1, which is 12 weeks of BTK inhibitor treatment followed by 4 weeks of placebo treatment.

[0327] The analysis of AEs focused on treatment-emergent adverse events (TEAEs). Treatment-emergent AEs are defined as AEs that occurred, worsened, or became severe during the pretreatment period. Treatment-emergent AEs (TEAEs) are defined as AEs that occurred, worsened, or became severe during the treatment period.

[0328] The following definitions apply to laboratory parameters, ECG, and vital sign results: - Potentially clinically significant abnormalities (PCSA) are abnormal values ​​that the sponsor determines to be medically important according to predefined criteria / thresholds based on literature review, and are defined by the sponsor for laboratory values ​​and vital signs. The potentially clinically significant abnormality criteria consider all assessments performed during the treatment period, including unscheduled and repeat assessments, and determine participants who had at least one PCSA during the treatment period. The number of such participants will form the numerator of the on-treatment PCSA rate.

[0329] [Table 28]

[0330] [Table 29]

[0331] [Table 30]

[0332] Individual PK concentrations are summarized narratively by visit. Additional PK parameters described in Example 1.10D, and population PK and PD analyses are described in separate documents.

[0333] Example 1.15 - Interim Analysis If deemed necessary due to slower-than-expected recruitment, one interim analysis will be conducted once at least 44 participants have completed the 16-week trial (12 weeks of BTK inhibitor treatment and 4 weeks of placebo). Interim analyses are not conducted if the trial is recruiting too quickly because they are too close to the final analysis (i.e., within 3–4 months) to be of value. The purpose of the interim analysis is to explore efficacy signals and optimize the Phase 3 trial design. The operating document specifies the criteria for conducting an interim analysis (e.g., recruitment rate), and the decision to conduct an interim analysis will be made before the SAP is finalized. If an interim analysis is conducted, it will examine the reduction in the number of new Gd-enhanced T1-hyperintense lesions compared with placebo (60 mg alone or the 60 mg and 30 mg combination groups) (using placebo data from 4 weeks after randomization in Cohort 2) and the potential for a dose-response curve. The interim analysis will be conducted by an unblinded, independent statistician. Because the study will not be stopped early due to an efficacy claim based on this potential exploratory interim analysis, no alpha adjustment will be performed in the final analysis, even if an interim analysis is performed. The SAP will provide details of any planned interim analyses, if any.

[0334] The IDMC will be used to monitor the safety of the trial.

[0335] Example 1.16 - Clinical Testing Details of the clinical tests are shown in Table 10. Additional tests will be performed at any time during the study if deemed necessary by the investigator or if required by local regulations.

[0336] [Table 31]

[0337] [Table 32]

[0338] Example 1.17 - Contraception guidance and pregnancy information collection Woman of childbearing potential (WOCBP): A woman is considered capable of becoming pregnant from the time she reaches menarche until she reaches postmenopause, unless she is permanently infertile.

[0339] The following categories of women are not considered WOCBP: 1) Premenarche 2) Premenopausal women who have undergone any of the following: hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. 3) Postmenopausal women -Postmenopausal status is defined as the absence of menstruation for 12 months without any other medical cause. In women not using hormonal contraception or hormone replacement therapy (HRT), elevated FSH levels in the postmenopausal range can confirm postmenopausal status. However, if there is no 12-month period of amenorrhea, a single FSH measurement is insufficient. -Women receiving HRT and whose menopausal status is in doubt will be required to use one of the non-estrogenic, highly effective methods of contraception if they wish to continue HRT during the study, otherwise they must discontinue HRT so that their postmenopausal status can be confirmed prior to study enrollment.

[0340] Contraception Guidance ·Male participants Male participants with a female partner of childbearing potential are eligible to participate if they agree to one of the following from enrollment through 3 months after the final dose of study intervention: Agree to abstain from penile-vaginal intercourse (long-term, sustained abstinence) and remain abstinent as part of your normal, desirable lifestyle. If I engage in penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant, I agree to use a male condom and to have my partner use a contraceptive method listed in Table 11 that has an annual failure rate of less than 1%. Additionally, male participants must refrain from donating sperm during the study and for 6 months after the final dose of study intervention. Male participants with a pregnant or breastfeeding partner must agree to abstain from penile-vaginal intercourse for 3 months after their final dose or use a male condom with each penile penetration. ·Female participants Because definitive reproductive toxicity studies with BTK inhibitors have not yet been conducted, investigators are instructed to take appropriate precautions during exposure of WOCBPs in this clinical trial. Female participants of childbearing potential are eligible to participate if they agree to consistently and correctly use a dual contraceptive method, including a highly effective method, as listed in Table 9, from the time of enrollment until two months after the final study dose. Additionally, WOCBPs must refrain from donating eggs during the study period and for two months after the final dose of study intervention.

[0341] [Table 33]

[0342] Pregnancy Testing: WOCBP will be enrolled only if menstruation is confirmed and a high-sensitivity serum pregnancy test is negative. Additional pregnancy tests will be performed at monthly intervals during the intervention period, one month after the last dose of study intervention, and as needed locally. Pregnancy tests will be performed if menstrual cycle is late or pregnancy is suspected.

[0343] Pregnancy information collection: Male participants with pregnant partners - The investigator will endeavor to collect pregnancy information from female partners of male participants who become pregnant while the male participant is participating in this study. This applies only to male participants receiving a BTK inhibitor. After obtaining the required signed informed consent directly from the pregnant female partner, the investigator will record the pregnancy information on the appropriate form and submit it to the sponsor within 24 hours of learning of the partner's pregnancy. The female partner will also be followed up to determine the outcome of the pregnancy. Information regarding the status of the mother and baby will be forwarded to the sponsor. Follow-up is generally within 6-8 weeks of the expected date of delivery. Termination of pregnancy will be reported regardless of the fetal status (presence or absence of abnormalities) or indication for treatment.

[0344] Pregnant Female Participants - The investigator will collect pregnancy information for female participants who become pregnant while participating in this study. Information will be recorded on appropriate forms and submitted to the sponsor within 24 hours of the participant's pregnancy being identified. Participants will be followed to determine pregnancy outcomes. The investigator will collect follow-up information for the participant and newborn, which will be forwarded to the sponsor. Generally, follow-up is not required beyond 6-8 weeks from the expected date of delivery. Termination of pregnancy will be reported regardless of fetal status (absence or absence of abnormalities) or indication for treatment. All pregnancy complications or elective terminations will be reported as AEs or SAEs. Spontaneous abortions are always considered SAEs and will be reported as such. Pregnancy-related serious adverse events after the end of the study that the investigator determines are reasonably related to study treatment will be reported to the sponsor. The investigator is under no obligation to proactively solicit this information from former study participants, although investigators may learn of SAEs through voluntary reporting. Female participants who become pregnant while participating in this study will discontinue the study intervention and be withdrawn from the study.

[0345] Example 1.18 - Genetics DNA Uses / Analysis Genetic variation may influence participants' response to study interventions, susceptibility to disease, and disease severity and progression. Variability in response to study interventions may result from genetic determinants affecting drug absorption, distribution, metabolism, and excretion; drug mechanism of action; disease etiology; and / or molecular subtype of the disease being treated. Therefore, where local regulations and the IRB / IEC permit, blood samples for DNA analysis will be collected from consenting participants.

[0346] DNA samples will be used in trials related to the investigational intervention or MS and related disorders. They may also be used to develop tests / assays, including diagnostic tests, related to the investigational intervention or indication. Genetic studies consist of analysis of one or more candidate genes or genome-wide genetic markers (as appropriate). DNA samples will be analyzed to investigate allelic variants in drug-metabolizing enzymes and / or drug transporters as intrinsic factors associated with PK or PD variability of BTK inhibitors. Additional analyses may be performed if hypothesized to help further understand clinical data. The samples may be analyzed as part of a multi-trial evaluation of genetic factors involved in response to BTK inhibitors or this class of investigational intervention to understand the investigational disease and related pathologies.

[0347] Example 1.19 - Illustrative List of Prohibited Drugs The following drugs are strong inducers or inhibitors of CYP3A or CYP2C8 hepatic enzymes and may alter the disposition of BTK inhibitors through interactions with P450-mediated metabolism and therefore should not be taken during the study (listed by the University of Washington's Drug Interaction Database Program (www.druginteractioninfo.org)). Please note that this list is not exhaustive and product information for the intended concomitant drug should be consulted.

[0348] [Table 34]

[0349] [Table 35]

[0350] [Table 36]

[0351] [Table 37]

[0352] [Table 38]

[0353] Example 2: Results of dose-finding and safety studies of BTK inhibitors in relapsing multiple sclerosis Herein, we present the results of the dose-finding and safety study described in Example 1. We determined the dose-response relationship of BTK inhibitors to reduce the number of new active brain lesions, including gadolinium (Gd)-enhancing T1 hyperintense lesions. The efficacy of BTK inhibitors on disease activity was also assessed by imaging, measuring the number of new or enlarged T2 lesions and the total number of Gd-enhancing T1 hyperintense lesions. We also evaluated the safety and tolerability of the dose-response BTK inhibitors.

[0354] As described in Example 1, this was a multicenter study involving a total of 40 active sites in Europe and North America. All participants were centrally assigned to one of eight groups (two cohorts, each with equal proportions of four treatment arms, starting with the BTK inhibitor (Cohort 1) or placebo (Cohort 2)) prior to crossover using an interactive voice / web response system.

[0355] Within each cohort, participants were randomly and equally assigned in a blinded manner to one of four BTK inhibitor doses: 5 mg, 15 mg, 30 mg, or 60 mg once daily.

[0356] Cohort 1: Participants will receive one dose of a BTK inhibitor for the first 12 weeks, then cross over to placebo for four weeks.

[0357] Cohort 2: Participants will receive a placebo for the first four weeks, then cross over to one of the doses of the BTK inhibitor for 12 weeks.

[0358] All brain scans were reviewed and interpreted by one or more blinded radiologists at an independent central center blinded to treatment, which avoided bias and ensured standardized endpoint assessment.

[0359] Diagnosis and inclusion criteria: Participants were aged 18–55 years, diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria, and had at least one documented relapse within the past year, or two or more documented relapses within the past two years, or one or more active Gd-enhancing brain lesions on MRI in the six months prior to screening.

[0360] Primary and key secondary endpoints Efficacy: Primary endpoint: Number of new gadolinium (Gd)-enhanced T1 hyperintense lesions detected by brain MRI at the end of 12 weeks of BTK inhibitor treatment.

[0361] Secondary endpoints: Number of new or enlarged T2 lesions at the end of 12 weeks of BTK inhibitor treatment Number of Gd-enhanced T1 hyperintense lesions at the end of 12 weeks of BTK inhibitor treatment

[0362] Safety: Adverse events (AEs), serious adverse events (SAEs), and potentially clinically significant laboratory, electrocardiogram (ECG), or vital sign abnormalities during the study.

[0363] Statistical method: Primary endpoint analysis: The primary analysis was based on pooled data from Cohorts 1 and 2 for each BTK inhibitor dose (i.e., data on the number of new Gd-enhancing T1-hyperintense lesions at week 12 in Cohort 1 and week 16 in Cohort 2).

[0364] The primary endpoint, the dose-response relationship of BTK inhibitors to the number of new Gd-enhancing T1-hyperintense lesions detected on brain MRI at the end of 12 weeks of BTK inhibitor treatment, was assessed in a modified intention-to-treat (mITT) population using a two-stage multiple comparison procedure (MCP-Mod) using modeling techniques. The first step of this procedure tests the efficacy signal (compared to the null hypothesis of a flat dose-response curve) in a procedure that controls for type 1 error. To account for uncertainty in the dose-response shape, six candidate models were considered, encompassing a variety of potential dose-response profiles: two E max Model (ED 50 = 10 mg, ED 50 = 30 mg), linear model, quadratic model, logistic model, and exponential model. In the second step, a dose-response curve was estimated, as an efficacy signal was established in the first step.

[0365] In MCP-Mod step 1, a negative binomial regression model with baseline Gd-enhanced T1-hyperintense lesion activity (presence or absence) and treatment as covariates was used to evaluate the mean number of new Gd-enhanced T1-hyperintense lesions in each of the four treatment groups at the end of 12 weeks of BTK inhibitor treatment and at the end of 4 weeks of placebo treatment. MRI assessments were excluded from the analysis if participants had received systemic corticosteroids within 30 days prior to the MRI assessment date. Cohort 2 placebo data from 4 weeks after randomization (i.e., week 4 data for Cohort 2) were used as week 12 placebo data in the analysis, assuming a constant rate of Gd-enhanced T1-hyperintense lesion formation if participants received placebo over the 12 weeks. Cohort 2 participants contributed placebo data (week 4) and data for the four BTK inhibitor doses (week 16). Cohort 1's 4-week placebo runout data were not included in the analysis. Therefore, to account for potential correlation between measurements from the 4-week placebo period and the subsequent 12-week BTK inhibitor treatment period in Cohort 2, a generalized estimating equation (GEE) approach was used to fit a negative binomial model that accounted for within-participant correlation using the "iterative" statement in SAS PROC GENMOD. The mean lesion counts were negative-log transformed and entered into MCP-Mod. The null hypothesis that the dose-response curve for the primary endpoint at the end of 12 weeks of BTK inhibitor treatment was flat (i.e., there was no dose-response relationship) was jointly evaluated for each of the six candidate dose-response models using a two-sided contrast test with a family mean error rate control at α = 0.05. Test statistics and adjusted p-values ​​were provided for all six candidate models.

[0366] In MCP-Mod step 2, all candidate models with adjusted p-values ​​less than 0.05 in step 1 were applied. The generalized Akaike information criterion (AIC) and model parameters were provided. The best-fitting model was selected as the one with the smallest generalized AIC. The dose for the phase 3 program was then estimated from the final selected model.

[0367] Furthermore, based on the negative binomial regression model described above, the relative reduction in the mean number of new Gd-enhancing T1-hyperintense lesions for each of the four BTK inhibitor treatment groups versus the placebo group, along with the corresponding 95% confidence intervals (CIs), was demonstrated.

[0368] Descriptive statistics for the number of new Gd-enhancing T1-hyperintense lesions observed over time (weeks 4 / 8, 8 / 12, and 12 / 16 for Cohort 1 / Cohort 2) and in the placebo group (week 4 / Cohort 2) are also presented for the four BTK inhibitor treatment groups.

[0369] Secondary endpoint analysis: For each secondary endpoint, a similar negative binomial model and MCP-Mod method were used. Because it is reasonable to assume that the lesion formation rate under placebo treatment is constant over 12 weeks, we used the same method as for the primary endpoint, i.e., we used the week 4 data from Cohort 2 as the placebo data at week 12 to account for within-participant correlation. Descriptive summary statistics over time are presented for each of the four BTK inhibitor treatment groups.

[0370] All safety summaries were narrative and performed on the safety analysis population. Safety data for the first 4 weeks after randomization (Cohort 2 participants received placebo) were summarized by BTK inhibitor and placebo treatment. Safety data during the BTK inhibitor treatment period (from the first BTK inhibitor dose) were summarized by BTK inhibitor treatment group and overall.

[0371] Population characteristics: 130 patients were randomized.

[0372] Baseline participant demographics and characteristics were generally balanced across the eight treatment groups (two cohorts of four treatment groups). The median age of participants was 36.3 years (range: 19-55 years). The majority of participants were women (91, 70.0%). Of note, 119 of the 130 participants (91.5%) were white.

[0373] All 130 participants were diagnosed with RMS (128 with relapsing RMS and 2 with secondary progressive MS). The mean EDSS score was 2.50, the median time since first diagnosis was 3.5 years, and the median time since first MS symptom onset was 4.9 years. 127 participants (97.7%) had at least one relapse in the year before screening, and 61 participants (46.9%) had highly active disease (HAD), defined as one relapse in the year before screening and one or more Gd-enhancing lesions on MRI within 6 months before screening, nine or more T2 lesions at baseline, or two or more relapses in the year before screening.

[0374] 129 of 130 patients completed the treatment period. One participant permanently discontinued treatment after week 12 due to failure to meet contraceptive requirements.

[0375] Table 15 provides details of patient status. Tables 16A-16B summarize patient demographic and baseline characteristics. Table 17 provides details of exposure duration for each group, and Table 18 provides details of exposure duration by dose for each group.

[0376] Efficacy Results: Primary Efficacy Endpoint: The study achieved its primary objective and demonstrated a dose-response relationship for the BTK inhibitor, as evidenced by a reduction in the number of new active Gd-enhancing T1-hyperintense brain lesions detected by brain MRI after 12 weeks of treatment.

[0377] Table 19 summarizes the relative reduction in new Gd-enhancing T1-hyperintense brain lesions after 12 weeks of treatment compared to placebo. Table 20 shows the MCP-Mod of new Gd-enhancing T1-hyperintense brain lesions after 12 weeks of treatment. MCP-Mod evaluation was performed as described in the statistical methods section above.

[0378] MCP-Mod step 2 was used to assess the estimated dose-response curve for novel Gd-enhancing T1-hyperintense brain lesions. To account for potential correlation between measurements during the run-in and treatment periods in Cohort 2, a model was fitted using generalized estimating equations (GEE) to account for within-subject correlation. The mean lesion counts in the BTK inhibitor group at week 12 and the placebo group at week 4 were estimated using a negative binomial regression model to account for potential correlation between measurements during the 4-week placebo treatment period and the subsequent 12-week BTK inhibitor treatment period in Cohort 2. MRI evaluations were excluded from the analysis if participants had received systemic corticosteroids within 30 days prior to the MRI evaluation date.

[0379] As shown in Table 19, the observed mean (SD) number of new Gd-enhanced T1-hyperintense lesions at 12 weeks post-treatment was 1.03 (2.50) in the placebo group, 1.39 (3.20) in the BTK inhibitor 5 mg group, 0.77 (1.48) in the BTK inhibitor 15 mg group, 0.76 (3.31) in the BTK inhibitor 30 mg group, and 0.13 (0.43) in the BTK inhibitor 60 mg group. The relative reduction in lesions at 12 weeks compared with placebo using a negative binomial regression model adjusted for baseline Gd-enhanced T1-hyperintense lesion activity was statistically significant in the 60 mg group (85.02%; 95% CI [28.02%, 96.88%]; nominal p-value = 0.0178) but not in the lower dose groups. Of note, 90.30% (28 of 31) of participants in the BTK inhibitor 60 mg group with evaluable MRI data had no new Gd-enhanced T1-hyperintense lesions at the end of 12 weeks of treatment. An exponential model was selected as the best-fitting dose-response curve.

[0380] Key secondary efficacy endpoints: Table 21 summarizes the relative reduction in the number of new or enlarged T2 lesions after 12 weeks of treatment compared to placebo. Table 22 shows the MCP-Mod for the number of new and enlarged T2 lesions after 12 weeks of treatment. Table 23 summarizes the relative reduction in the total number of T2 Gd-enhanced T1 hyperintense lesions after 12 weeks of treatment compared to placebo. Table 24 shows the MCP-Mod for the total number of Gd-enhanced T1 hyperintense lesions after 12 weeks of treatment. The 12 weeks after initiation of treatment were week 12 of BTK inhibitor treatment in Cohort 1, week 16 of BTK inhibitor treatment in Cohort 2, and week 4 of placebo treatment in Cohort 2. MRI evaluations were excluded from the analysis if participants had received systemic corticosteroids within 30 days prior to the MRI evaluation date. MCP-Mod1 did not demonstrate significance.

[0381] As shown in Table 21, for the secondary endpoint of the number of new and enlarged T2 lesions at the end of 12 weeks of BTK inhibitor treatment, the observed mean (SD) values ​​were 2.12 (5.16) in the placebo group, 1.90 (3.97) in the 5 mg BTK inhibitor group, 1.32 (1.83) in the 15 mg BTK inhibitor group, 1.30 (4.90) in the 30 mg BTK inhibitor group, and 0.23 (0.62) in the 60 mg BTK inhibitor group. Unlike the other treatment groups, the 60 mg group showed a statistically significant reduction in the number of new and enlarged T2 lesions compared to the placebo group (89.34%; 95% CI: [68.39%, 96.41%], nominal p = 0.0001). 87.1% (27 of 31) of patients in the BTK inhibitor 60 mg group with evaluable MRI data had no new enlarged T2 lesions at the end of 12 weeks of treatment. A linear model was selected as the best-fitting dose-response curve.

[0382] As shown in Table 23, the observed mean (SD) number of Gd-enhanced T1-hyperintense lesions (a secondary endpoint) after 12 weeks of BTK inhibitor treatment was 1.36 (3.52) in the placebo group, 1.77 (4.10) in the 5 mg BTK inhibitor group, 0.87 (1.59) in the 15 mg BTK inhibitor group, 1.18 (4.87) in the 30 mg BTK inhibitor group, and 0.29 (0.86) in the 60 mg BTK inhibitor group. No statistically significant reduction in lesion number was observed with any dose of BTK inhibitor compared with placebo. However, a higher proportion of participants in the 60 mg BTK inhibitor group had evaluable MRI data (87.1%, 27 of 31 patients) compared with the placebo group (74.6%, 44 of 59 patients), and no Gd-enhanced T1-hyperintense lesions were observed at the end of 12 weeks of treatment.

[0383] Safety Results: The BTK inhibitor was well tolerated during the 12-week treatment period. Table 25A summarizes treatment-emergent adverse events during weeks 1 through 4. Table 25B summarizes adverse events over 4 weeks. Table 25C summarizes adverse events over 12 weeks. Table 26 summarizes treatment-emergent adverse events during BTK inhibitor treatment. Table 27 summarizes treatment-emergent serious adverse reactions during BTK inhibitor treatment. Table 28 summarizes treatment-emergent adverse reactions of particular note during weeks 1 through 4. Table 29 summarizes treatment-emergent adverse events of particular note during BTK inhibitor treatment. Table 30 summarizes adverse events occurring in two or more patients during the 12-week treatment period.

[0384] As shown in Table 17, the mean duration of exposure to the BTK inhibitor during the first 16 weeks was 82.1 days, 81.5 days, 83.6 days, and 82.1 days for the 5 mg, 15 mg, 30 mg, and 60 mg BTK inhibitor groups, respectively, and 28.0 days for the placebo group. The mean duration of exposure to the BTK inhibitor across treatment groups was 82 days.

[0385] No deaths were reported in this study. One treatment-emergent SAE was reported in a participant in Cohort 1 who received the BTK inhibitor 60 mg. This event was an MS relapse in a 32-year-old female participant, occurring approximately 8 weeks after initiating BTK inhibitor treatment. The participant had difficulty speaking and was unable to drink liquids without drooling. No swallowing problems were reported in the hospital records. The patient was admitted 2 days after the onset of symptoms to rule out the possibility of a stroke. The event was assessed as severe by the investigator. Despite the confirmed MS relapse, treatment continued without interruption, and the participant completed the study and was successfully enrolled in a long-term extension study.

[0386] With the exception of one severe TEAE reported in the BTK inhibitor 60 mg group, the aforementioned SAE of severe MS relapse, all reported TEAEs were mild or moderate.

[0387] No TEAEs leading to permanent treatment discontinuation were observed. The proportions of participants experiencing TEAEs during weeks 1-4 were 34.8%, 31.3%, 18.8%, 12.5%, and 31.3% in the placebo, 5 mg, 15 mg, 30 mg, and 60 mg groups, respectively. The proportions of participants experiencing TEAEs were similar across the four BTK inhibitor groups during treatment (57.6%, 53.1%, 54.5%, and 50.0% in the 5, 15, 30, and 60 mg BTK inhibitor groups, respectively).

[0388] The most frequently reported TEAEs (>3 events total) in the primary SOC during weeks 1 to 4 (placebo-controlled) were headache (4 cases in the placebo group, 3 cases in the BTK inhibitor 5 mg group, 2 cases in the BTK inhibitor 15 mg group, and 1 case in the BTK inhibitor 60 mg group), upper respiratory tract infection (1 case in each treatment group, including placebo), and nausea (1 case in the placebo group, 2 cases in the BTK inhibitor 5 mg group, and 1 case in the BTK inhibitor 30 mg group).

[0389] As shown in Table 30, during the 12-week BTK inhibitor treatment period, the most frequently reported TEAEs by major SOC were as follows: headache (1 case in the BTK inhibitor 5 mg group, 3 cases in the BTK inhibitor 15 mg group, 1 case in the BTK inhibitor 30 mg group, and 4 cases in the BTK inhibitor 60 mg group), upper respiratory tract infection (2 cases in the BTK inhibitor 5 mg group, 2 cases in the BTK inhibitor 15 mg group, 1 case in the BTK inhibitor 30 mg group, and 1 case in the BTK inhibitor 60 mg group), nasopharyngitis (1 case in the BTK inhibitor 5 mg group, 1 case in the BTK inhibitor 30 mg group, and 3 cases in the BTK inhibitor 60 mg group), back pain (1 case in the BTK inhibitor 5 mg group, 1 case in the BTK inhibitor 15 mg group, and 2 cases in the BTK inhibitor 30 mg group), peripheral edema (2 cases in the BTK inhibitor 5 mg group, 1 case in the BTK inhibitor 60 mg group), and urinary tract infection (1 case in the BTK inhibitor 5 mg group, 1 case in the BTK inhibitor 15 mg group, and 2 cases in the BTK inhibitor 30 mg group). The following adverse events were observed: gastroenteritis (1 patient in the 5 mg BTK inhibitor group, 2 in the 60 mg BTK inhibitor group), respiratory infection (1 patient in the 15 mg BTK inhibitor group, 1 patient in the 30 mg BTK inhibitor group, and 1 patient in the 60 mg BTK inhibitor group), muscle spasms (1 patient in the 30 mg BTK inhibitor group, and 2 patients in the 60 mg BTK inhibitor group), oropharyngeal pain (1 patient in the 5 mg BTK inhibitor group, 1 patient in the 30 mg BTK inhibitor group, and 1 patient in the 60 mg BTK inhibitor group), alopecia (1 patient in the 5 mg BTK inhibitor group, 1 patient in the 15 mg BTK inhibitor group, and 1 patient in the 60 mg BTK inhibitor group), increased alanine aminotransferase (1 patient in the 5 mg BTK inhibitor group, 1 patient in the 30 mg BTK inhibitor group, and 1 patient in the 60 mg BTK inhibitor group), and accidental overdose (3 patients in the 60 mg BTK inhibitor group). Each of the three participants who experienced alopecia had a medical history that could have contributed to the alopecia.

[0390] As shown in Table 29, two AESIs (alanine aminotransferase elevations >3 × ULN) were reported in this study: one during the 30 mg BTK inhibitor treatment period and one during the 60 mg BTK inhibitor treatment period. In both cases, the liver enzyme elevations were transient, IMP was not discontinued, liver enzymes returned to normal, and the participant completed the study. The event in the participant receiving the 60 mg dose was assessed by the investigator as mild and accompanied by pruritus. The other participant was assessed as moderate and accompanied by symptoms. One participant (60 mg group) had ALT levels above the ULN (34 U / L) at screening and randomization (48 U / L and 50 U / L, respectively), and at the Week 4 visit, they exceeded 3 × ULN (107 U / L). ALT levels gradually decreased, reaching normal levels (28 U / L) by Week 12. Another participant (30 mg group) had an ALT level above 3 × ULN (105 U / L) at the week 8 visit, but returned to normal (32 U / L) within 4 days. Both participants were female.

[0391] Vital signs (systolic blood pressure, weight), laboratory values ​​(hemoglobin ≤115 g / L [men]; ≤95 g / L [women], hematocrit ≤0.37 v / v [men]; ≤0.32 v / v [women], ALT >3 × ULN, bilirubin >1.5 × ULN), and electrocardiogram (e.g., heart rate <50 beats / min, heart rate >90 beats / min, heart rate >100 beats / min, PR >200 msec, QRS >110 msec, QTc Bazett >450 msec, QTc Fridericia >450 msec) were reported across treatment groups and no dose-related relationship was observed.

[0392] conclusion This study achieved its primary objective and demonstrated a dose-response relationship for BTK inhibitors, with a statistically significant reduction in the number of new, active, Gd-enhanced T1-hyperintense brain lesions detected by brain MRI after 12 weeks of treatment in the 60 mg BTK inhibitor group compared with the placebo group. Differences between the other BTK inhibitor groups were not statistically significant compared with the placebo group. Consistently, efficacy on disease activity was also demonstrated by a reduction in the number of new and enlarged T2-hyperintense lesions detected by brain MRI after 12 weeks of treatment with the 60 mg BTK inhibitor, but not with the 5 mg, 15 mg, or 30 mg BTK inhibitor doses. However, the data did not demonstrate a statistically significant reduction in the total number of Gd-enhanced T1-hyperintense lesions after 12 weeks of BTK inhibitor treatment, regardless of the dose tested.

[0393] There was no direct correlation between the dose of BTK inhibitor and the number of TEAEs. The most common events (preferred terms) observed in participants in the BTK inhibitor treatment group were headache, upper respiratory tract infection, and nasopharyngitis. The number of AESIs and PCSAs was lower in the multidrug group. No new risks were identified in this study.

[0394] These findings indicate that a range of BTK inhibitor doses is well tolerated and effective in reducing MRI lesions in patients with relapsing MS.

[0395] [Table 39]

[0396] [Table 40]

[0397] [Table 41]

[0398] [Table 42]

[0399] Table 43

[0400] Table 44

[0401] Table 45

[0402] Table 46

[0403] Table 47

[0404] Table 48

[0405] Table 49

[0406]

Table 50

[0407] Table 51

[0408] Table 52

[0409] [Table 53]

[0410] [Table 54]

[0411] [Table 55]

[0412] [Table 56]

[0413] [Table 57]

[0414] [Table 58]

[0415] [Table 59]

[0416] [Table 60]

[0417] Example 3 - MRI Results of a Long-Term Extension Study of a BTK Inhibitor in Patients with Relapsing Multiple Sclerosis: 2-Year Results The long-term safety of BTK inhibitors was also measured.

[0418] Objective: To report MRI treatment outcomes at 96 weeks (year 2) in a long-term safety (LTS) extension study of a phase 2b trial of a BTK inhibitor in patients with relapsing multiple sclerosis.

[0419] Background: BTK inhibitors are brain-penetrant inhibitors of Bruton's tyrosine kinase currently being evaluated for the treatment of multiple sclerosis. In the double-blind phase (DBP) of a phase 2b study (NCT03889639), BTK inhibitors were well tolerated over 12 weeks and demonstrated dose-dependent reductions in gadolinium (Gd)-enhancing T1 lesions and new / enlarged T2 lesions. LTS16004 (NCT03996291) is an LTS extension study of BTK inhibitors in patients who completed the phase 2b study.

[0420] Design / Methods: After the last DBP dose of the BTK inhibitor, followed by a treatment gap (mean ± SD, 7 ± 7.3 weeks; range, 0-21 weeks), patients began LTS extension Part A and continued receiving DBP doses (5, 15, 30, or 60 mg / day) in a double-blind manner until a Phase 3 dose was selected. In this open-label extension Part B, all patients will receive 60 mg / day. MRI outcomes included the number of new Gd-enhancing and new / enlarging T2 lesions, T2 lesion volume change from baseline, slowly evolving lesions (SELs), and paramagnetic rim lesions (PRLs).

[0421] Results: Of 125 patients receiving LTS extension, 124 completed Part A and entered Part B. 114 patients (90.5%) were still on the study as of February 18, 2022 (W96 cutoff). The mean ± SD age of enrolled patients at baseline was 37.7 ± 9.6 years (range, 19-56 years), and 69% were women. The number of new Gd-enhancing lesions remained low through week 96 in the 60 / 60 mg group and decreased from week 48 to week 96 in the other groups (mean ± SD at week 96: 0.85 ± 2.5, 0.41 ± 0.91, 0.90 ± 2.16, and 0.31 ± 0.66 for the 5 / 60 mg, 15 / 60 mg, 30 / 60 mg, and 60 / 60 mg groups, respectively). The number of new / hypertrophic T2 lesions remained low in the 60 / 60 mg group. The change in T2 lesion volume remained low with the 60 / 60 mg group (week 96 vs. baseline [mean ± SD]: +0.38 ± 2.11 cm3). The median (IQR) SEL volume at week 96 was 247.5 (84-420) mm3, 258 (66-906) mm3, 570 (133.5-1011) mm3, and 244.5 (87-939) mm3 for the 5 / 60 mg, 15 / 60 mg, 30 / 60 mg, and 60 / 60 mg groups, respectively. The number of PRLs remained unchanged in 18 patients; two patients had one PRL at baseline but none at week 96; and three patients experienced an increase of one to three PRLs at week 96 compared to baseline (none in the 60 / 60 mg group).

[0422] Conclusions: The number of new Gd-enhancing lesions in the 60 / 60 mg BTK inhibitor group remained low and decreased in the low-dose group from week 48 to week 96 of the LTS, when all patients were switched to 60 mg. As of March 7, 2022, 90.5% of MS patients enrolled in the BTK inhibitor LTS extension study remained on the study. The number of new Gd-enhancing lesions remained low through week 96 in the 60 / 60 mg BTK inhibitor group and decreased in the low-dose group from week 48 to week 96 of the LTS. Changes in T2 lesion volume remained low in the 60 / 60 mg group. Long-term follow-up in the ongoing extension study and data from phase 3 trials will continue to define the safety and efficacy profile of BTK inhibitors in MS patients.

[0423] Table 31 summarizes the number of new GD-enhanced T1 hyperintense lesion data.

[0424] [Table 61]

[0425] Note: MRI assessments were excluded from analysis if participants had received systemic corticosteroids within 30 days prior to the MRI assessment date.

[0426] Table 32 summarizes the number of new or enlarged T2 lesion data.

[0427] [Table 62]

[0428] Table 33 summarizes the data on new or enlarged T2 lesion volumes.

[0429] [Table 63]

[0430] Table 34 summarizes the number of new T1 non-weighted (hypointense) lesion data.

[0431] [Table 64]

[0432] In Tables 15-18, Week 12 does not represent a clinic visit but rather the 12 weeks of BTK inhibitor administration during the dose-finding study. Week 0 values ​​are the last MRI values ​​obtained in the dose-finding study if performed within 6 weeks prior to Day 1 of the long-term safety study. For some patients, Week 0 values ​​began after a gap period from Week 0 to Week 21. For patients with a gap period of 0 weeks, Week 0 values ​​began immediately after the end of Week 16 of the dose-finding study. For patients with a gap period of more than 6 weeks, a new MRI was obtained before Day 1 of the long-term safety study.

[0433] If starting from week 16 of the dose-finding study (Cohort 2), this also includes week 12. If starting from week 16 of the dose-finding study (Cohort 1), the placebo will run out after 4 weeks.

[0434] Example 4 - Lack of recovery of disease activity in patients with relapsing multiple sclerosis after completion of the placebo run-out in a trebrutinib Phase 2b trial The absence of rebound was also investigated.

[0435] Background: Relapsing disease activity, characterized by recurrence of neurological symptoms and brain lesions, has been reported after discontinuing disease-modifying treatments for multiple sclerosis (MS). (Barry B, et al. Neurol Ther 2019;8(2):241-50; Gonzalez-Suarez I, et al. Brain Behav 2017;7:e00671) A 16-week phase 2b trial (NCT03889639) of trebrutinib, a brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor, in patients with relapsing MS (RMS) demonstrated dose-dependent reductions in new gadolinium-enhancing (Gd+) T1 lesions and new / enlarging T2 lesions. The unique crossover study design, which included a 4-week placebo run-in and run-out period to minimize placebo exposure, allowed for evaluation of potential rebound disease after trebrutinib discontinuation, which may inform treatment sequencing.

[0436] Objective: To assess the likelihood of relapse in patients with RMS after placebo run-out of a phase 2b trial of trebrutinib.

[0437] Methods: As described in Examples 1 and 2, a 16-week, double-blind, crossover study randomized 130 patients with RMS (1:1:1:1) to receive trebrutinib at 5, 15, 30, or 60 mg / day. Magnetic resonance imaging (MRI) was performed at screening and every 4 weeks for 16 weeks. Cohort 1 (n=64) received trebrutinib for 12 weeks followed by a 4-week placebo run-out, while Cohort 2 (n=66) received trebrutinib for 12 weeks followed by a 4-week placebo run-in. The study design is shown in Figure 1.

[0438] Outcomes: Outcomes evaluated in this example included measurement of the incidence of relapse during the 4-week placebo run-in and run-out periods, the number of new Gd-enhancing T1 lesions detected by magnetic resonance imaging (MRI) at weeks 4, 8, and 16, the number of new or enlarged T2 lesions measured at weeks 4, 8, and 16, and plasma CD19+ B cell counts measured at baseline, 1 hour after the first dose, and then at weeks 12 and 16 in the placebo run-out cohort (Figure 3).

[0439] Results: Table 35 summarizes the baseline characteristics of patients in Cohort 1 and Cohort 2.

[0440] [Table 65]

[0441] Table 36 summarizes the status of patients in cohorts 1 and 2.

[0442] [Table 66]

[0443] [Table 67]

[0444] [Table 68]

[0445] Table 37 summarizes the number of new GD-enhancing T1 hyperintense lesion data in Cohort 1.

[0446] [Table 69]

[0447] [Table 70]

[0448] [Table 71]

[0449] [Table 72]

[0450] Table 38 summarizes the number of new / enlarged T2 lesion data in Cohort 1.

[0451] [Table 73]

[0452] [Table 74]

[0453] [Table 75]

[0454] [Table 76]

[0455] [Table 77]

[0456] Table 39 summarizes the number of GD-enhanced T1 hyperintense lesion data in Cohort 1.

[0457] [Table 78]

[0458] [Table 79]

[0459] [Table 80]

[0460] [Table 81]

[0461] Cohort 1 placebo run-out (98.4% relapse-free) had one relapse, while cohort 2 placebo run-in (93.9% relapse-free) had four relapses. After 12 weeks of trebrutinib treatment (cohort 1), 83.3% of patients had no new Gd-enhanced T1 lesions; 4 weeks after trebrutinib discontinuation (placebo run-out), 85.2% had no new Gd-enhanced T1 lesions. In cohort 1, the mean (SD) number of Gd-enhanced T1 lesions after 12 weeks of trebrutinib treatment was 0.37 (0.99), and the number of Gd-enhanced T1 lesions after 4 weeks of placebo run-out was 0.44 (1.70). In Cohort 1, who received trebrutinib 60 mg / day, the dose used in the phase 3 trial, the mean (SD) number of Gd+ lesions after 12 weeks of trebrutinib treatment was 0.20 (0.56), and the mean (SD) number of Gd+ lesions after a 4-week placebo run-out was 0.31 (0.70). After a 4-week placebo run-in (Cohort 2), the mean (SD) number of Gd+ lesions was 1.03 (2.50). In Cohort 1, the mean (SD) number of new / enlarged T2 lesions at week 12 was 0.58 (1.27) after a 4-week placebo run-out and 0.95 (2.72), respectively, compared with 2.12 (5.16) after a 4-week placebo run-in (Cohort 2).

[0462] All 130 enrolled patients completed the assigned placebo period. As shown in Table 35, baseline characteristics were similar between Cohort 1 (placebo run-out) and Cohort 2 (placebo run-in). The mean age ± SD of enrollees was 37 ± 10 years, and 70% were women. There was one relapse during the placebo run-out period and four during the placebo run-in period.

[0463] The number of new Gd-enhanced T1 lesions and new / enlarged T2 lesions decreased after 12 weeks of trebrutinib treatment, especially in the 60 mg group, and increased only slightly after placebo run-out. In cohort 1 (placebo run-out), the proportion of participants without new Gd-enhanced T1 lesions after 12 weeks of trebrutinib treatment (83.3%) was similar to the proportion 4 weeks after treatment discontinuation (85.2%).

[0464] Conclusions: These preliminary findings suggest that discontinuation of trebrutinib in patients with RMS does not induce a rebound in disease activity. A longer observation period is needed to validate this finding. Crossover to placebo after 12 weeks of trebrutinib treatment was not associated with an increased risk of relapse during the 4-week run-out period. Local inflammation, as evidenced by new lesion formation, decreased after 12 weeks of trebrutinib treatment, particularly in the 60 mg group, and remained low during the 4-week placebo run-out period. Circulating B-cell counts increased within 1 hour after the first trebrutinib dose and returned to baseline levels after the 4-week placebo run-out period.

[0465] Therefore, treatment with trebrutinib does not cause a rebound of RMS. Thus, this embodiment provides a method for preventing the rebound of MS flare-ups (sometimes called "relapses" or episodes). In this case, patients are administered trebrutinib for at least 12 weeks, followed by at least 4 weeks of placebo. It has been shown that there is no additional risk of relapse during the 4 weeks of placebo treatment. Therefore, a treatment method can be designed in which patients are administered trebrutinib for, for example, 12 weeks, 1 year, 96 weeks, 2 years (or any other period), followed by 4 weeks of placebo, and then the patient is re-administered with trebrutinib.

Claims

1. 1. A method of reducing the incidence of relapses of multiple sclerosis (MS) in a subject with relapsing multiple sclerosis (RMS) in need thereof, comprising: a) administering a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a subject in need thereof for at least 12 weeks; b) terminating the administration of the BTK inhibitor; Including, the incidence of MS relapse in the subject after administration of the BTK inhibitor has ended is equal to or less than the incidence of MS relapse in the subject during the one year period prior to administration of the BTK inhibitor. method.

2. 10. The method of claim 1, wherein the subject remains relapse-free for at least 4 weeks after stopping administration of the BTK inhibitor.

3. 3. The method of claim 1 or 2, wherein the subject remains relapse-free for at least 6 weeks after stopping administration of the BTK inhibitor.

4. 4. The method of any one of claims 1-3, wherein the subject remains relapse-free for at least 21 weeks after stopping administration of the BTK inhibitor.

5. 1. A method of reducing the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or the number of new or enlarged T2 hyperintense lesions in a subject with relapsing multiple sclerosis (RMS) in need thereof, comprising: a) administering a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a subject in need thereof for at least 12 weeks; b) terminating the administration of the BTK inhibitor; Including, the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or new or enlarged T2 hyperintense lesions measured in the subject after administration of the BTK inhibitor has ended is equal to or less than the baseline number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or new or enlarged T2 hyperintense lesions measured in the subject during the 4 weeks prior to administration of the BTK inhibitor; method.

6. 6. The method of claim 5, wherein the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or the number of new or enlarged T2 hyperintense lesions measured in the subject up to 21 weeks after administration of the BTK inhibitor is discontinued is 2 or less.

7. 7. The method of claim 6, wherein the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions measured in the subject by 21 weeks after administration of the BTK inhibitor is terminated is one or less.

8. 8. The method of any one of claims 5 to 7, wherein the total number of new gadolinium (Gd)-enhancing T1 hyperintense lesions or the number of new or enlarged T2 hyperintense lesions measured in the subject up to 4 weeks after administration of the BTK inhibitor is completed is 1 or less.

9. 6. The method of claim 5, wherein the total number of new or enlarged T2 hyperintense lesions measured in the subject by 21 weeks after administration of the BTK inhibitor has ended is 3 or less.

10. 6. The method of claim 5, wherein the total number of new or enlarged T2 hyperintense lesions measured in the subject by 6 weeks after administration of the BTK inhibitor has ended is 1 or less.

11. 1. A method of reducing the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions in a subject with relapsing multiple sclerosis (RMS) in need thereof, comprising: a) administering a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one to a subject in need thereof for at least 12 weeks; b) terminating the administration of the BTK inhibitor; Including, the total number of gadolinium (Gd)-enhancing T1-hyperintense lesions measured in the subject after administration of the BTK inhibitor has ceased is equal to or less than the baseline number of gadolinium (Gd)-enhancing T1-hyperintense lesions measured in the subject before administration of the BTK inhibitor; method.

12. 12. The method of claim 11, wherein the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in the subject up to 21 weeks after administration of the BTK inhibitor is completed is four or less.

13. 13. The method of claim 11 or 12, wherein the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in the subject by 21 weeks after administration of the BTK inhibitor is completed is 2 or less.

14. 14. The method of any one of claims 11-13, wherein the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions measured in the subject from baseline through 4 weeks after administration of the BTK inhibitor is 1 or less.

15. 15. The method of any one of claims 1 to 14, wherein the dose of the BTK inhibitor is 60 mg daily.

16. The method of any one of claims 5 to 15, wherein the lesions are measured by MRI.

17. 17. The method of any one of claims 1-16, wherein the subject is administered the BTK inhibitor for at least 16 weeks.

18. 18. The method of any one of claims 1-17, wherein the subject is administered the BTK inhibitor for at least 24 weeks.

19. 19. The method of any one of claims 1-18, wherein the subject is administered the BTK inhibitor for at least 48 weeks.

20. 20. The method of any one of claims 1-19, wherein the subject is administered the BTK inhibitor for at least 72 weeks.

21. 21. The method of any one of claims 1-20, wherein the subject is administered the BTK inhibitor for at least 96 weeks.

22. 1. A method for treating relapsing multiple sclerosis (RMS) in a patient in need thereof, comprising: determining whether the patient has elevated transferrin levels or elevated ferritin levels; 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 if the patient is found not to have elevated transferrin or ferritin levels.

23. 1. A method for treating relapsing multiple sclerosis (RMS) in a patient in need of treatment, comprising: determining an iron panel for the patient; and, if the patient is found to have an adequate iron panel, administering to the patient a therapeutically effective amount of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

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

25. 1. A method for treating relapsing multiple sclerosis (RMS), comprising: (a) performing an iron panel test on the patient's blood or serum; (b) detecting a level of said iron panel test that is 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; Including, 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, and the normal range for 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. Treatment method.

26. 1. A method for treating relapsing multiple sclerosis (RMS), comprising: (a) detecting a transferrin saturation level in the patient's blood or serum that is within a 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; Including, the transferrin saturation level within the normal range in the blood or serum of a male patient is the transferrin saturation of 50% or less, and the transferrin saturation level within the normal range in the blood or serum of a female patient is the transferrin saturation of 40% or less. Treatment method.

27. 1. A method for treating relapsing multiple sclerosis (RMS), comprising: (a) detecting a level of ferritin in the patient's blood or serum that is 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; Including, the patient's blood or serum ferritin level within the normal range is 500 μg / L or less; Treatment method.

28. 1. A method for treating relapsing multiple sclerosis (RMS), comprising: (a) performing liver function tests in the patient; (b) detecting adequate liver function in said 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; Including, the liver function tests measure one or more of aspartate transaminase (AST), alanine transaminase (ALT), albumin, alkaline phosphatase, total and direct bilirubin, and total protein levels in the patient's blood; The patient with adequate liver function has one or more of the following: ALT less than or equal to 1.5x the upper limit of normal (ULN), AST level less than or equal to 1.5x the ULN, alkaline phosphatase less than or equal to 2x the ULN (unless caused by a non-liver-related disorder or explained by stable chronic liver damage), and total bilirubin less than or equal to 1.5x the ULN (unless caused by Gilbert's syndrome or a non-liver-related disorder). Treatment method.

29. 1. A method for treating relapsing multiple sclerosis (RMS), 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 (the compound) to a patient in need thereof; (b) measuring the patient's alanine aminotransferase (ALT) level; (c) detecting an ALT value greater than 8 times the upper limit of normal (ULN); (d) terminating the administration of said compound to said patient; and optionally (e) monitoring the ALT level in the patient; (f) resuming administration of a therapeutically effective amount of the compound to the patient if the patient's ALT level is determined to be less than 1.5 x ULN; A method of treatment comprising:

30. 1. A method for treating relapsing multiple sclerosis (RMS), 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 (the compound) to a patient in need thereof; (b) measuring the patient's alanine aminotransferase (ALT) level; (c) detecting ALT levels greater than 5 times the upper limit of normal (ULN) for at least two weeks; (d) terminating the administration of said compound to said patient; and optionally (e) monitoring the ALT level in the patient; (f) resuming administration of a therapeutically effective amount of the compound to the patient if the patient's ALT level is determined to be less than 1.5 x ULN; A method of treatment comprising:

31. 1. A method for treating relapsing multiple sclerosis (RMS), 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 (the compound) to a patient in need thereof; (b) measuring the patient's alanine aminotransferase (ALT) level; (c) detecting an ALT value greater than three 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 values ​​of total bilirubin greater than 2×ULN and INR greater than 1.5; (f) terminating the administration of said compound to said patient; and optionally, (g) monitoring the ALT level in the patient; (h) resuming administration of a therapeutically effective amount of the compound to the patient upon determining that the patient's ALT level is less than 1.5 x ULN; A method of treatment comprising:

32. 1. A method for treating relapsing multiple sclerosis (RMS), 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 (the compound) to a patient in need thereof; (b) measuring the patient's alanine aminotransferase (ALT) level; (c) detecting an ALT value greater than three times the upper limit of normal (ULN); (d) terminating administration of the compound to the patient if the patient experiences one or more of the following: fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and eosinophilia greater than 5%; and optionally, (e) monitoring the ALT level in the patient; (f) resuming administration of a therapeutically effective amount of the compound to the patient if the patient's ALT level is determined to be less than 1.5 x ULN; A method of treatment comprising:

33. 33. The method of any one of claims 29 to 32, wherein the ALT value in step (b) is determined at least monthly.

34. 33. The method of any one of claims 29 to 32, wherein the ALT level in step (d) is monitored at least weekly.

35. 33. The method of any one of claims 29 to 32, wherein the ALT level in step (d) is monitored every 2 to 3 days.

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

37. 1. A method for treating relapsing forms of multiple sclerosis (RMS) in a patient in need thereof, comprising: (a) advising said 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; Including, the patient is female and is advised to limit alcohol intake to 14 grams / day or less, or the patient is male and is advised to limit alcohol intake to 28 grams / day or less; Treatment method.

Images