Treatment methods for relapsing-relapsing multiple sclerosis using Bruton's tyrosine kinase inhibitors

Abstract

A method for treating relapsing-remitting multiple sclerosis (RMS) using fenebrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), is provided herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 502,460 filed on 16 May 2023, U.S. Provisional Application No. 63 / 505,747 filed on 2 June 2023, and U.S. Provisional Application No. 63 / 588,389 filed on 6 October 2023, the disclosures of each of these applications being incorporated herein by reference in their entirety.

[0002] field This disclosure relates to a method for treating relapsing-remitting multiple sclerosis (RMS) using a Bruton's tyrosine kinase (BTK) inhibitor. [Background technology]

[0003] background Bruton's tyrosine kinase (BTK) is essential for the development of the immune system and for the differentiation and activation of B cells during normal adaptive immune responses. BTK is activated by phosphatidylinositol 3-kinase-dependent plasma membrane mobilization and phosphorylation of tyrosine Y551 by the Src family kinase Lyn. Autophosphorylation and activation also occur on tyrosine Y223 in a BTK-specific manner. Once activated, BTK is involved in PLCγ2-dependent signaling and Ca 2+ It induces NF-κB-dependent signaling, which leads to activation of the NF-κB-dependent and NFAT-dependent pathways, and subsequently to cell activation and differentiation (Niiro H, Clark EA, Nat Rev Immunol 2002, 2:945-56). BTK is a key mediator of B cell receptor (BCR) signaling in B cells and Fcγ receptor signaling in myeloid cells. Fenebrutinib, as a BTK inhibitor, effectively blocks B cell activation and proliferation as well as myeloid effector function.

[0004] Multiple sclerosis (MS): Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease of the central nervous system (CNS), affecting approximately 900,000 people in the United States and 2.8 million worldwide (Wallin et al., Neurology, 2019;92:e1029-40; Walton et al., Mult Scler, J, 2020;26:1816-21). MS is primarily a disease of young adults, with 70%–80% of patients having an age of onset (i.e., initial clinical presentation to a physician) between 20 and 40 years of age, exhibiting a gender bias influenced by phenotype, with approximately 64%–70% of diagnosed patients being female (Anderson et al. Ann Neurol 1992,31:333-6; Noonan et al. Neurology 2002,58:136-8).

[0005] Traditionally, MS is classified into three clinical phenotypes, one of which is relapsing MS (RMS). While we do not wish to be bound by any theory, the progression of disability across the spectrum in MS may result from two simultaneous inflammatory mechanisms: active inflammation and chronically localized inflammation. These two types of inflammation may contribute to different degrees across different types and stages of MS.

[0006] RMS is associated with an active inflammatory mechanism characterized by focal, bulk T-cell and B-cell infiltration and blood-brain barrier leakage, resulting in classic active demyelinating plaques in the white matter. Chronic compartmentalized inflammation occurs independently of relapse or disease activity and is thought to be responsible for the increased lesions characterized by demyelination and axonal loss (progression biology; Lassmann et al. 2019). While this aspect of inflammation is considered a prominent feature of the progressive form of MS, the RMS phenotype also has signs of progression biology / chronic compartmentalized inflammation, which manifests itself as a chronic, slow accumulation of T-cells and B-cells without blood-brain barrier leakage, and can result in submeningeal demyelinating lesions in the cerebral and cerebellar cortex, as well as slow expansion of pre-existing lesions in the white matter and diffuse chronic inflammation in the white and gray matter that appears normal (Lassmann 2018). Finally, the role of myeloid cells, including macrophages and microglia, can also influence both pathological and clinical outcomes (Absinta et al, 2020).

[0007] In vitro cell-based experiments suggest that BTK antagonism by fenebrutinib leads to inhibition of BCR-dependent B cell proliferation and a reduction in inflammatory cytokine production from myeloid cells (including tumor necrosis factor-α [TNF-α]). Myeloid effector function is triggered in vitro by immune complexes, and there is growing evidence suggesting that B cells and myeloid / microglia may be central to the immunopathology of MS (Hauser et al.; N Engl J Med 2017;376:221-34; Montalban et al. N Engl J Med. 2019;380:2406-17; Howell et al. 2010 Journal of neuropathology and experimental neurology 2010;69:1017-33). BTK inhibition directly affects myeloid cells. Consequently, BTK inhibition may affect microglia, which are associated with pathological features of MS disease progression, independently of relapse.

[0008] BTK inhibitors (BTKi) represent a new class of molecules being studied for the treatment of MS, and to date, no BTKi for the treatment of any form of MS has been approved by the FDA or EMA. While multiple BTKi are being studied in clinical trials for the treatment of various forms of MS, this group of molecules is structurally and pharmacologically diverse, including differences in selectivity, reversibility, covalent vs. non-covalent action, and CNS permeability (Schneider, R., Oh, J. Curr Neurol Neurosci Rep 22, 721-734, 2022). Different drug metabolism and pharmacokinetic (DMPK) properties as well as doping schedules add another layer of complexity. These various factors (individually or in combination) can lead to differences in safety, efficacy, or both in the treatment of MS, making these molecules incompatible.

[0009] Effective treatment for recurrent thyroid syndrome (RMS) remains in need. Methods for treating RMS are provided herein, including methods for reducing the number of new T1 Gd+ lesions and methods for reducing the number of new or expanding T2-weighted lesions using fenebrutinib or a pharmaceutically acceptable salt thereof. [Overview of the project]

[0010] Summary of Disclosure Methods and uses of BTK inhibitors, fenebrutinib, or pharmaceutically acceptable salts of fenebrutinib for the treatment of relapsing-relapsing multiple sclerosis (RMS) are provided herein.

[0011] A method for treating relapsing-relapsing multiple sclerosis (RMS) in patients requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is When evaluated at weeks 4, 8, and 12, the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks after the start of administration should be reduced. To reduce the total number of new gadolinium-enhanced T1 lesions at 4 weeks after the start of administration, To reduce the total number of new gadolinium-enhanced T1 lesions at 8 weeks after the start of administration, To reduce the total number of new gadolinium-enhanced T1 lesions when evaluated at 8 and 12 weeks after the start of administration, To reduce the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after the start of administration, To reduce the incidence of new gadolinium-enhanced T1 lesions, To prevent the occurrence of new gadolinium-enhanced T1 lesions, To reduce the total number of new or enlarging T2-weighted lesions over 12 weeks after the start of administration when evaluated at 4, 8, and 12 weeks, [[ID=!4]]To reduce the total number of new or enlarging T2-weighted lesions at 4 weeks after the start of administration, To reduce the total number of new or enlarging T2-weighted lesions at 8 weeks after the start of administration, To reduce the total number of new or enlarging T2-weighted lesions when evaluated at 8 and 12 weeks after the start of administration, To reduce the total number of new or enlarging T2-weighted lesions by at least 60% at 12 weeks after the start of administration, To reduce the incidence of new or enlarging T2-weighted lesions, To prevent the occurrence of new or enlarging T2-weighted lesions, or To increase the likelihood that the subject has neither (a) any new gadolinium-enhanced T1 lesions, nor (b) any new or enlarging T2-weighted lesions, Also provided herein are methods comprising any one of these combinations.

[0012] In some embodiments of the above method, reduction, prevention, or increase is for subjects with RMS who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In certain embodiments, this subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof is the same subject, but evaluated before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, in the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration. In some embodiments, the subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof is a different subject with RMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and in certain embodiments, the subject does not receive RMS therapy.

[0013] Further herein are provided fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating RMS in subjects requiring treatment of RMS, and treatment comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, and treatment When evaluated at weeks 4, 8, and 12, the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks after the start of administration should be reduced. At 4 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. At 8 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. The goal is to reduce the total number of new gadolinium-enhanced T1 lesions when evaluated at weeks 8 and 12 after the start of administration. To reduce the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after the start of administration. To reduce the incidence of new gadolinium-enhanced T1 lesions, To prevent the development of new gadolinium-enhanced T1 lesions, When evaluated at weeks 4, 8, and 12, the total number of new or expanding T2-weighted lesions should be reduced over the 12 weeks following the start of treatment. To reduce the total number of new or expanding T2-weighted lesions at 4 weeks after the start of administration. To reduce the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration. The goal is to reduce the total number of new or expanding T2-weighted lesions when evaluated at weeks 8 and 12 after the start of administration. At 12 weeks after the start of administration, reduce the total number of new or expanding T2-weighted lesions by at least 60%. To reduce the incidence of new or expanding T2-weighted lesions, To prevent the development of new or expanding T2-weighted lesions, or To increase the likelihood that the subject does not have (a) any new gadolinium-enhanced T1 lesions, and (b) any new or expanding T2-weighted lesions. Or further include any one of these combinations.

[0014] In some embodiments of the compounds for the above use, reduction, prevention, or increase is for subjects having RMS who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In certain embodiments, this subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof is the same subject, but the same subject evaluated before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, in the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration. In some embodiments, the subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof is a different subject having RMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and in certain embodiments, this different subject is not administered RMS therapy.

[0015] Also provided are compounds for use in the manufacture of pharmaceuticals for the treatment of relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment of RMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment comprises any of the methods provided herein. [Brief explanation of the drawing]

[0016] [Figure 1] This is a diagram of the clinical trial design for the clinical trial described in Example 1.

[0017] [Figure 2] This report provides bar graphs summarizing the adjusted rates (combined weeks 4, 8, and 12) and adjusted mean number (at separate time points) of new T1 Gd+ lesions observed in patients treated with fenebrutinib compared to patients treated with placebo. For separate time points, the number of patients refers to those who underwent an evaluable MRI scan at that visit.

[0018] [Figure 3] This report provides bar graphs summarizing the adjusted rates (combined weeks 4, 8, and 12) and adjusted mean number (at separate time points) of new / expanding T2-weighted lesions observed in patients treated with fenebrutinib compared to patients treated with placebo. For separate time points, the number of patients refers to those who underwent an evaluable MRI scan at that visit.

[0019] [Figure 4] This report provides bar graphs summarizing the adjusted rates (combined weeks 4, 8, and 12) and adjusted mean number (at separate time points) of new T1 low-signal lesions observed in patients treated with fenebrutinib compared to patients treated with placebo. For separate time points, the number of patients refers to those who underwent an evaluable MRI scan at that visit.

[0020] [Figure 5]Plot of the concentration of fenebrutinib in cerebrospinal fluid (CSF) samples taken from 11 patients after 12 weeks of continuous fenebrutinib administration. Results are plotted against the IC50 (activity inhibition threshold) and IC90 (maximum inhibition threshold) of fenebrutinib when evaluated in different in vitro assays.

Best Mode for Carrying Out the Invention

[0021] Detailed Description Methods and uses of fenebrutinib, or a pharmaceutically acceptable salt of fenebrutinib, for treating relapsing-remitting multiple sclerosis (RMS) are provided herein.

[0022] Fenebrutinib is a compound of the formula: TIFF2026517012000002.tif51170, and has the following names: GDC-0853, (6 2 S)-2 3 -(hydroxymethyl)-1 7 ,1 7 ,3 1 ,6 2 -tetramethyl-1 3 ,1 4 ,1 7 ,1 8 -tetrahydro-4-aza-1(2)-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-6(1,4)-piperazina-2(2,4),3(3,5),5(2,5)-tripyridina-7(3)-oxetananeheptafane-1 1 (1 6 H),3 6 (3 1 H)-dione, and (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazine-1-yl)pyridine-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridine]-2'-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one It is also known for this.

[0023] The R enantiomer of the compound is as follows: (R)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazine-1-yl)pyridine-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridine]-2'-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazine-1-one.

[0024] Fenebrutinib is a highly selective, orally administered, reversible inhibitor of BTK. U.S. Patent No. 8,716,274, incorporated entirely herein by reference, discloses a class of heteroarylpyridine and aza-pyridone compounds useful for inhibiting Btk, including fenebrutinib. International Publication No. 2017 / 148837, incorporated entirely herein by reference, discloses solid forms and formulations of fenebrutinib and its pharmaceutically acceptable salts.

[0025] I. Definition Please understand that the technical terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit them.

[0026] As used herein, including in the attached claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the content clearly indicates otherwise. Thus, for example, a reference to “a molecule” optionally includes a combination of two or more such molecules.

[0027] As used herein, the term “approximately” refers to the normal range of error for each value, as will be readily understood by those skilled in the art. References to values ​​or parameters with “approximately” in this specification include (and are described) embodiments relating to the value or parameter itself. In some embodiments, the term “approximately” refers to a range of plus or minus 10% for each value. In some embodiments, the term “approximately” refers to a range of plus or minus 5% for each value. In some embodiments, the term “approximately” refers to a range of plus or minus 2% for each value. In some embodiments, the term “approximately” refers to a range of plus or minus 1% for each value.

[0028] It is understood that the aspects and embodiments of the disclosure described herein include "including," "consisting of," and "essentially consisting of."

[0029] The Expanded Disability Status Scale (EDSS) is a scale for quantifying changes in the level of disability over time in individuals with MS. The EDSS is based on a standardized neurological examination and incorporates functional systems (visual, brainstem, pyramidal, cerebellar, sensory, intestinal and bladder, and brain [or mental]) which are assessed and then scored as functional system scores (FSS), and gait, which is scored as a gait score. Each FSS is an ordinal clinical assessment scale ranging from 0 to 5 or 6, and the gait score is assessed from 0 to 16. These assessments are used in combination with observations and information regarding gait and the use of assistive devices to determine the total EDSS score. The EDSS is a disability scale ranging from 0 (normal) to 10.0 (death) in 0.5-point steps (Kurtzke 1983; Kappos 2011). In some embodiments of the methods provided herein, sexual dysfunction and fatigue are not included in the EDSS score.

[0030] As used herein, the term “lesion” refers to a lesion observed on MRI of the central nervous system of the subject. In the examples described herein, the imaging is of the brain. These lesions may include gadolinium-enhanced T1 lesions and new or expanding T2-weighted lesions. These types of lesions are observed using different MRI techniques. Gadolinium-enhanced T1 imaging may be used to image inflammation in acute MS lesions. Inflammation results in increased permeability of the blood-brain barrier, increasing the ability of gadolinium contrast agents to cross the barrier and potentially increasing contrast enhancement in gadolinium-enhanced T1 imaging. Gadolinium-enhanced T1 lesions may be the earliest detectable changes in the onset of most new lesions, indicating active inflammation, which may subside over time as the inflammation subsides. T2-weighted imaging is used to assess the total lesion load or lesion load of a subject, including when the subject does not have acute inflammation. In the acute phase of MS, T2 lesions are often associated with T1 Gd+ lesions, which may decrease in size over time as the edema resolves. T2 lesions can change in signal intensity and size over time depending on the presence of active inflammation, but they can also be persistent indicators of previous inflammatory events. Therefore, the number of new and expanding T2-weighted lesions in a subject can be one way to monitor progression over a period encompassing the entire disease and can be used to assess treatment response. New T2 and Gd+T1 lesions may be observable before obvious clinical signs and symptoms. The terms “T1 Gd+ lesion,” “Gd+T1 lesion,” “gadolinium-enhanced T1 lesion,” and “Gd+-enhanced T1-weighted lesion” may be used interchangeably herein, and other substitutions for these expressions may also be possible. Monitoring of MS may also include evaluation of T1 low-signal lesions. T1 low-signal lesions may appear dark or black on MRI images and are sometimes referred to as “black holes.” T1 low-signal lesions may appear during the acute phase as a result of edema and demyelination, and these lesions may disappear as inflammation resolves. Persistent T1-low signaling lesions observed in the chronic phase represent irreversible axonal loss and correlate with disease progression and clinical impairment.

[0031] The term "pharmaceutical preparation" refers to a preparation in which the biological activity of the active ingredient is effective and which does not contain any further ingredients that are unacceptably toxic to the subject to which the preparation is administered. In some embodiments, such preparations are sterile. A "pharmaceutically acceptable" excipient (vehicle, additive) is one that can be administered to the target mammal in an appropriate amount to provide an effective dose of the active ingredient to be used.

[0032] As used herein, the term “treatment” refers to a clinical intervention designed to alter the natural course of an individual or cell being treated during the course of clinicopathology. Desired effects of treatment may include a reduction in the rate of disease progression, reduction or mitigation of the disease state, and remission or improvement of prognosis. In some embodiments, two or more such effects are achieved. In some embodiments, an individual is “treated” if one or more symptoms associated with the disease or disorder are reduced, the disease or disorder becomes more tolerable to the subject, the rate of regression or decline or the onset or rate of the disease or disorder is delayed or halted, or the final stage of regression is considered less debilitating. For example, an individual is “treated” if one or more symptoms associated with the disease (e.g., MS) are mitigated or eliminated, including, but not limited to, a reduction in symptoms caused by the disease, an improvement in the quality of life of the person with the disease, a reduction in the dose of other drugs required to treat the disease, and / or an extension of the individual’s survival time. Treatment of a particular disease or disorder may, in some embodiments, include, but are not limited to, certain clinical or other endpoints, such as those described in the examples provided herein.

[0033] The phrase "at least" can be rephrased as "greater than." For example, a "decrease of at least 80%" in new gadolinium-enhanced T1 lesions can be rephrased as a "decrease of greater than 80%" in new gadolinium-enhanced T1 lesions.

[0034] Several embodiments described herein demonstrate the provision of doses of fenebrutinib, or an equivalent amount of its pharmaceutically acceptable salt. A method for calculating a corresponding amount of fenebrutinib in its pharmaceutically acceptable salt form, taking into account the difference in molecular weight between the free form of fenebrutinib and the salt form, will be apparent to those skilled in the art. For example, in some embodiments provided herein, a subject is administered approximately 400 mg of fenebrutinib (as in, a 200 mg dose) or its pharmaceutically acceptable salt per day. When the pharmaceutically acceptable salt form is administered in such embodiments, the total weight of the pharmaceutically acceptable salt of fenebrutinib administered daily is greater than 400 mg, but corresponds to approximately 400 mg of the free form of fenebrutinib, because the salt form has a higher molecular weight than the free form of fenebrutinib.

[0035] For therapeutic purposes, “subject” refers to any animal classified as a mammal, including humans, livestock and farm animals, as well as zoo animals, sports animals, and pet animals (dogs, horses, cats, cows, etc.). In some embodiments of the methods provided herein, the subject is human. In some embodiments, the subject is a patient.

[0036] "Before administration" is, for example, the same day that the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof is administered, but may include periods prior to the actual administration, or within one week prior to the first dose, or within two weeks prior to the first dose, or within three weeks prior to the first dose, or within four weeks prior to the first dose, or within five weeks prior to the first dose, or within six weeks prior to the first dose; or more than six weeks prior to the first dose, or 1 to 28 days prior to the first dose, or within 0 to 28 days prior to the first dose. In certain embodiments, this period may also be referred to as the "baseline." Thus, in some embodiments, the baseline may include the same day immediately preceding administration, or within one week prior to the administration of the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof. In other embodiments, the baseline may include within one month, or within 0 to 28 days, or within six weeks prior to the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, baseline is within 12 weeks, 6 months, or 12 months prior to the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0037] II. Treatment Methods This specification provides a method for treating a subject having relapsing multiple sclerosis (RMS), comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, this specification provides fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject. In further embodiments, this specification provides fenebrutinib or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical for the treatment of RMS in a subject requiring treatment of RMS, wherein approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered to the subject. In certain embodiments provided herein, including methods, fenebrutinib for use, or fenebrutinib for use in the manufacture of pharmaceutical products, the effect on a subject (e.g., treatment of RMS) is evaluated by one or more clinical outcomes, for example, by measuring gadolinium-enhanced T1 lesions (T1 Gd+ lesions), new or expanding T2-weighted lesions, or a disability score, e.g., EDSS, or a combination thereof. In some embodiments, the treatment is described through a reduction in the number of lesions, a reduction in the rate of lesions, or an increase in the likelihood of no lesions occurring, where the lesions may be gadolinium-enhanced T1 lesions, new or expanding T2-weighted lesions, or a combination thereof. In some embodiments, such reduction or decrease occurs within 4 weeks of the start of administration, within 8 weeks of the start of administration, or within 12 weeks of the start of administration, or is evaluated at one or more of those time points (e.g., over 12 weeks if evaluated at weeks 4, 8 and 12, or observed in combination at weeks 8 and 12).

[0038] A method for treating relapsing-relapsing multiple sclerosis (RMS) in patients requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is When evaluated at weeks 4, 8, and 12, the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks after the start of administration should be reduced. At 4 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. At 8 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. The goal is to reduce the total number of new gadolinium-enhanced T1 lesions when evaluated at weeks 8 and 12 after the start of administration. To reduce the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after the start of administration. To reduce the incidence of new gadolinium-enhanced T1 lesions, To prevent the development of new gadolinium-enhanced T1 lesions, When evaluated at weeks 4, 8, and 12, the total number of new or expanding T2-weighted lesions should be reduced over the 12 weeks following the start of treatment. To reduce the total number of new or expanding T2-weighted lesions at 4 weeks after the start of administration. To reduce the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration. The goal is to reduce the total number of new or expanding T2-weighted lesions when evaluated at weeks 8 and 12 after the start of administration. At 12 weeks after the start of administration, reduce the total number of new or expanding T2-weighted lesions by at least 60%. To reduce the incidence of new or expanding T2-weighted lesions, To prevent the development of new or expanding T2-weighted lesions, or To increase the likelihood that the subject does not have (a) any new gadolinium-enhanced T1 lesions, and (b) any new or expanding T2-weighted lesions. Or, methods further including any one of these combinations are provided herein.

[0039] Furthermore, a method for treating relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of its pharmaceutically acceptable salt, wherein the treatment is To reduce the total number of new T1 low-signal lesions in subjects at 12 weeks after the start of administration, At 8 weeks after the start of administration, reduce the total number of new T1 low-signal lesions. At 4 weeks after the start of administration, reduce the total number of new T1 low-signal lesions. When evaluated at weeks 4, 8, and 12, the total number of new T1 low-signal lesions at week 12 after the start of administration should be reduced. To reduce the incidence of new T1 low-signal lesions, The rate is evaluated over 4, 8, or 12 weeks after the start of administration to reduce the incidence of new T1 low-signal lesions. To prevent the development of new T1 low-signal lesions, or To prevent the development of new T1 low-signal lesions over 4, 8, or 12 weeks after the start of administration. Or, methods further including any one of these combinations are provided herein.

[0040] In some embodiments of any of the methods described above, or any method disclosed herein, reduction, prevention, or increase is for subjects having RMS who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In certain embodiments, this subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof is the same subject, but the same subject evaluated before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, in the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration. In some embodiments, the subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof is a different subject having RMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and in certain embodiments, this different subject is not administered RMS therapy.

[0041] Further herein are provided fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating RMS in subjects requiring treatment of RMS, and treatment comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, and treatment When evaluated at weeks 4, 8, and 12, the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks after the start of administration should be reduced. At 4 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. At 8 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. The goal is to reduce the total number of new gadolinium-enhanced T1 lesions when evaluated at weeks 8 and 12 after the start of administration. To reduce the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after the start of administration. To reduce the incidence of new gadolinium-enhanced T1 lesions, To prevent the development of new gadolinium-enhanced T1 lesions, When evaluated at weeks 4, 8, and 12, the total number of new or expanding T2-weighted lesions should be reduced over the 12 weeks following the start of treatment. To reduce the total number of new or expanding T2-weighted lesions at 4 weeks after the start of administration. To reduce the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration. The goal is to reduce the total number of new or expanding T2-weighted lesions when evaluated at weeks 8 and 12 after the start of administration. At 12 weeks after the start of administration, reduce the total number of new or expanding T2-weighted lesions by at least 60%. To reduce the incidence of new or expanding T2-weighted lesions, To prevent the development of new or expanding T2-weighted lesions, or To increase the likelihood that the subject does not have (a) any new gadolinium-enhanced T1 lesions, and (b) any new or expanding T2-weighted lesions. Or, methods further including any one of these combinations are provided herein.

[0042] Further herein are provided fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating RMS in subjects requiring treatment of RMS, and treatment comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, and treatment To reduce the total number of new T1 low-signal lesions in subjects at 12 weeks after the start of administration, At 8 weeks after the start of administration, reduce the total number of new T1 low-signal lesions. At 4 weeks after the start of administration, reduce the total number of new T1 low-signal lesions. When evaluated at weeks 4, 8, and 12, the total number of new T1 low-signal lesions at week 12 after the start of administration should be reduced. To reduce the incidence of new T1 low-signal lesions, The rate is evaluated over 4, 8, or 12 weeks after the start of administration to reduce the incidence of new T1 low-signal lesions. To prevent the development of new T1 low-signal lesions, or To prevent the development of new T1 low-signal lesions over 4, 8, or 12 weeks after the start of administration. Or, methods further including any one of these combinations are provided herein.

[0043] In some embodiments of any of the above compounds for use or any compound for use disclosed herein, reduction, prevention, or increase is for subjects having RMS that have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In certain embodiments, this subject not administered fenebrutinib or a pharmaceutically acceptable salt thereof is the same subject, but the same subject evaluated before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration. In some embodiments, the subject not administered fenebrutinib or a pharmaceutically acceptable salt thereof is a different subject having RMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and in certain embodiments, this different subject is not administered RMS therapy.

[0044] Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical product for the treatment of relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment of RMS, wherein the pharmaceutical product comprises approximately 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof, and the pharmaceutical product is administered to the subject twice daily, and the treatment is, When evaluated at weeks 4, 8, and 12, the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks after the start of administration should be reduced. At 4 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. At 8 weeks after the start of administration, reduce the total number of new gadolinium-enhanced T1 lesions. The goal is to reduce the total number of new gadolinium-enhanced T1 lesions when evaluated at weeks 8 and 12 after the start of administration. To reduce the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after the start of administration. To reduce the incidence of new gadolinium-enhanced T1 lesions, To prevent the development of new gadolinium-enhanced T1 lesions, When evaluated at weeks 4, 8, and 12, the total number of new or expanding T2-weighted lesions should be reduced over the 12 weeks following the start of treatment. To reduce the total number of new or expanding T2-weighted lesions at 4 weeks after the start of administration. To reduce the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration. The goal is to reduce the total number of new or expanding T2-weighted lesions when evaluated at weeks 8 and 12 after the start of administration. At 12 weeks after the start of administration, reduce the total number of new or expanding T2-weighted lesions by at least 60%. To reduce the incidence of new or expanding T2-weighted lesions, To prevent the development of new or expanding T2-weighted lesions, or To increase the likelihood that the subject does not have (a) any new gadolinium-enhanced T1 lesions, and (b) any new or expanding T2-weighted lesions. Or any one of these combinations.

[0045] Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical product for the treatment of relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment of RMS, wherein the pharmaceutical product comprises approximately 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof, and the pharmaceutical product is administered to the subject twice daily, and the treatment is, To reduce the total number of new T1 low-signal lesions in subjects at 12 weeks after the start of administration, At 8 weeks after the start of administration, reduce the total number of new T1 low-signal lesions. At 4 weeks after the start of administration, reduce the total number of new T1 low-signal lesions. When evaluated at weeks 4, 8, and 12, the total number of new T1 low-signal lesions at week 12 after the start of administration should be reduced. To reduce the incidence of new T1 low-signal lesions, The rate is evaluated over 4, 8, or 12 weeks after the start of administration to reduce the incidence of new T1 low-signal lesions. To prevent the development of new T1 low-signal lesions, or To prevent the development of new T1 low-signal lesions over 4, 8, or 12 weeks after the start of administration. Or any one of these combinations.

[0046] In some embodiments of any of the above compounds for use in the manufacture of pharmaceuticals or any compound for use disclosed herein, reduction, prevention, or increase is in subjects having RMS that have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In certain embodiments, this subject not administered fenebrutinib or a pharmaceutically acceptable salt thereof is the same subject, but the same subject evaluated before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, in the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration. In some embodiments, the subject not administered fenebrutinib or a pharmaceutically acceptable salt thereof is a different subject having RMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and in certain embodiments, this different subject is not administered RMS therapy.

[0047] Further provided herein are methods for treating multiple sclerosis (MS) in subjects requiring treatment for MS, comprising orally administering a BTK inhibitor in an amount sufficient to reach a cerebrospinal fluid (CSF) concentration above an activity inhibition threshold for inhibition of B cell activation, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof. Further provided herein are fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating MS in subjects requiring treatment for MS, wherein the treatment comprises orally administering a BTK inhibitor in an amount sufficient to reach a cerebrospinal fluid (CSF) concentration above an activity inhibition threshold for inhibition of B cell activation, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof. Small molecule BTK inhibitors for use in the manufacture of pharmaceuticals for treating MS in subjects requiring treatment of MS, wherein the pharmaceuticals contain a BTK inhibitor sufficient to cause daily oral administration to a subject to reach a cerebrospinal fluid (CSF) concentration higher than the activity inhibition threshold for the BTK inhibitor, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof.

[0048] Each of the methods, uses, and treatments provided is described in more detail herein.

[0049] A. Gadolinium-enhanced T1 lesions In some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions over 12 weeks from the start of administration, as evaluated at weeks 4, 8, and 12. In some embodiments, a method for reducing the total number of new gadolinium-enhanced T1 lesions in a subject having RMS requiring a reduction in the total number of new gadolinium-enhanced T1 lesions is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number reduces over 12 weeks from the start of administration, as evaluated at weeks 4, 8, and 12. Further provided is a fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof to the subject twice daily, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions over 12 weeks from the start of administration, as evaluated at weeks 4, 8, and 12. Further provided is a fenebrutinib or a pharmaceutically acceptable salt thereof for use in reducing the total number of new gadolinium-enhanced T1 lesions in subjects with RMS requiring a reduction in the total number of new gadolinium-enhanced T1 lesions, comprising administering approximately 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof to the subject twice daily, wherein the total number is reduced over 12 weeks from the start of administration, as evaluated at weeks 4, 8, and 12. In some such embodiments of the methods and uses provided herein, the total number of new gadolinium-enhanced T1 lesions is reduced by at least 30%, or at least 40%, or at least 50%, over 12 weeks after the start of administration, as assessed at weeks 4, 8, and 12. In some embodiments, the reduction is at least 60%. In certain embodiments, the reduction is at least 65%.In some embodiments, the reduction is 69%. In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, for a subject, fenebrutinib is administered orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib. Further, the use of fenebrutinib or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical for use in any of the methods or uses provided herein is provided.

[0050] In other embodiments, treatment comprises reducing the total number of new gadolinium-enhanced T1 lesions within four weeks of initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment comprises reducing the total number of new gadolinium-enhanced T1 lesions at four weeks after initiation of administration. In some such embodiments, a method for reducing the total number of new gadolinium-enhanced T1 lesions is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the reduction occurs at four weeks after initiation of administration. Further provided herein is a method for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions at four weeks after the start of administration. Further provided is a method for use in reducing the total number of new gadolinium-enhanced T1 lesions in subjects having RMS requiring treatment, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at four weeks after the start of administration. In some such embodiments of the method and use provided herein, the total number of new gadolinium-enhanced T1 lesions is reduced by at least 15% at four weeks. In some embodiments, the reduction is at least 20% at four weeks. In some embodiments, the reduction is 22% at week 4. In certain embodiments, the reduction is a relative reduction compared to a case where fenebrutinib or a pharmaceutically acceptable salt thereof was not administered.In some embodiments, fenebrutinib is administered orally. In some embodiments, a subject receives fenebrutinib orally in the form of two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.

[0051] In further embodiments, the treatment includes reducing the total number of new gadolinium-enhanced T1 lesions within eight weeks of the start of administration. Accordingly, in some embodiments, a method is provided herein for treating RMS in a subject requiring treatment of RMS, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment includes reducing the total number of new gadolinium-enhanced T1 lesions at eight weeks after the start of administration. In some embodiments, a method is provided herein for reducing the total number of new gadolinium-enhanced T1 lesions in a subject having RMS requiring a reduction in the total number of new gadolinium-enhanced T1 lesions, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at eight weeks after the start of administration. Further provided herein is a method for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions at 8 weeks after the start of administration. Further provided is a method for use in reducing the total number of new gadolinium-enhanced T1 lesions in subjects having RMS requiring treatment, comprising administering to a subject about 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at 8 weeks after the start of administration. In some such embodiments of the method and use provided herein, the total number of new gadolinium-enhanced T1 lesions is reduced by at least 60% at 8 weeks. In some such embodiments, the reduction is at least 70% at week 8. In some embodiments, the reduction is at least 80% at week 8. In some embodiments, the reduction is at least 90% at week 8.In some embodiments, the reduction is 92% at 8 weeks. In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, fenebrutinib is administered orally. In some embodiments, subjects receive fenebrutinib orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.

[0052] In further embodiments, the treatment includes reducing the total number of new gadolinium-enhanced T1 lesions as evaluated at weeks 8 and 12 after the start of administration. Accordingly, in some embodiments, a method is provided herein for treating RMS in a subject requiring treatment of RMS, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment includes reducing the total number of new gadolinium-enhanced T1 lesions at weeks 8 and 12 after the start of administration. In some embodiments, a method is provided herein for reducing the total number of new gadolinium-enhanced T1 lesions in a subject having RMS requiring a reduction in the total number of new gadolinium-enhanced T1 lesions, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at weeks 8 and 12 after the start of administration. Further provided herein is a method for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions at weeks 8 and 12 after the start of administration. Furthermore, provided is a method for use in reducing the total number of new gadolinium-enhanced T1 lesions in subjects having RMS requiring a reduction in the total number of new gadolinium-enhanced T1 lesions, comprising administering to a subject about 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at weeks 8 and 12 after the start of administration. In some such embodiments of the method and use provided herein, the total number of new gadolinium-enhanced T1 lesions at weeks 8 and 12 is reduced by at least 60%. In some embodiments, the reduction is at least 70%. In some embodiments, the reduction is at least 80%. In some embodiments, the reduction is at least 90%.In some embodiments, the total number of new gadolinium-enhanced T1 lesions is reduced by 92% at weeks 8 and 12. In certain embodiments, the reduction is relative to the case where fenebrutinib or a pharmaceutically acceptable salt thereof was not administered. In some embodiments, fenebrutinib is administered orally. In some embodiments, subjects receive fenebrutinib orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.

[0053] In other embodiments, treatment includes reducing the total number of new gadolinium-enhanced T1 lesions by at least 60% within 12 weeks of initiation of administration. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment includes reducing the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In some such embodiments, a method for reducing the total number of new gadolinium-enhanced T1 lesions in a subject requiring a reduction in the total number of new gadolinium-enhanced T1 lesions is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the reduction is at least 60% at 12 weeks after initiation of administration. Further provided herein is a method for using fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions by at least 60% at 12 weeks after the start of administration. Further provided herein is a method for using fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof for use in subjects having RMS requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof twice daily, wherein the total number of new gadolinium-enhanced T1 lesions is reduced by at least 60% at 12 weeks after the start of administration. In some such embodiments of the method and use provided herein, the total number of new gadolinium-enhanced T1 lesions is reduced by at least 70% at 12 weeks. In some embodiments, the reduction is at least 80% at week 12. In some embodiments, the reduction is 90% at week 12.In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, fenebrutinib is administered orally. In some embodiments, for a subject with a total daily dose of 400 mg of fenebrutinib, fenebrutinib is administered orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib.

[0054] In further embodiments, the treatment includes reducing the incidence of new gadolinium-enhanced T1 lesions. Accordingly, in some embodiments, a method is provided herein for reducing the incidence of new gadolinium-enhanced T1 lesions in subjects having RMS requiring a reduction in the incidence of new gadolinium-enhanced T1 lesions, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. Furthermore, fenebrutinib or a pharmaceutically acceptable salt thereof is provided for use in reducing the incidence of new gadolinium-enhanced T1 lesions in subjects having RMS requiring a reduction in the incidence of new gadolinium-enhanced T1 lesions, comprising administering to the subject about 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof twice daily. In certain embodiments of the method and compound for use, the incidence of new gadolinium-enhanced T1 lesions is reduced when measured at weeks 4, 8 and 12 after the start of administration. In some embodiments, the rate decreases by at least 40%, e.g., at least 50%, or at least 60%, or by 69%. In some embodiments, the rate over 12 weeks after the start of administration decreases by at least 40%, e.g., at least 50%, or at least 60%, or by 69%. In some embodiments, the decrease is compared to the same subject evaluated immediately before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., the preceding 12 weeks, 6 months, or 12 months). In some embodiments, fenebrutinib is administered orally. In some embodiments, the subject is orally administered fenebrutinib as two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib. In some embodiments, the rate is an adjusted rate.

[0055] A method for preventing the development of new gadolinium-enhanced T1 lesions in subjects with RMS requiring prevention of such development, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. Further provided herein is a method for preventing the development of new gadolinium-enhanced T1 lesions in subjects with RMS requiring prevention of such development, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. In some embodiments of the method for preventing such development or of the compound for use in preventing such development, the development is prevented within 4 weeks after the start of administration. In some embodiments, the development is prevented within 8 weeks after the start of administration. In some embodiments, the development is prevented within 12 weeks after the start of administration. In some embodiments, prevention of the development of new gadolinium-enhanced T1 lesions includes a reduction in the number of new gadolinium-enhanced T1 lesions, which is a reduction when assessed individually at weeks 4, 8, or 12, or when assessed over 12 weeks at weeks 4, 8, or 12, or when assessed at weeks 8 and 12, and the reduction is as described elsewhere in this specification (e.g., with a reduction of at least a specified percentage over a certain period, as described elsewhere). In some embodiments, fenebrutinib is administered orally. In some embodiments, for a total daily dose of 400 mg of fenebrutinib, fenebrutinib is administered orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib.

[0056] In some embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, including the reduction or prevention of novel gadolinium-enhanced T1 (when individually assessed at weeks 4, 8, or 12, or when assessed at weeks 4, 8, or 12 over 12 weeks, or when assessed at weeks 8 and 12, or any other combination, or a reduction in the rate), the comparison is against a subject not administered with fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, this comparison subject is the same subject before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, but is evaluated, for example, four weeks, eight weeks, twelve weeks, six months, or twelve months prior to initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, this comparison subject is another subject having RMS that has not been administered with fenebrutinib or a pharmaceutically acceptable salt thereof, for example, another subject having RMS that has not received any RMS treatment.

[0057] In certain embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, the reduction or prevention of the occurrence of new gadolinium-enhanced T1 lesions discussed (including, when individually assessed at week 4, week 8, or week 12, or when assessed at week 4, week 8, or week 12 over a 12-week period, or when assessed at week 8 and week 12, or any other combination, or as a reduction in rate) is clinically illustrated by comparing subjects (or groups of subjects) administered with fenebrutinib or a pharmaceutically acceptable salt thereof with subjects (or groups of subjects) not administered with RMS therapy (e.g., an inactive comparator, or placebo). In some embodiments, the comparison is against the same subjects before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, evaluated in the same subjects during the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the comparison is against a different subject not administered with RMS therapy. Based on this data, it would generally be expected that a single individual taking fenebrutinib or a pharmaceutically acceptable salt thereof would experience a relative reduction or prevention of the development of such new gadolinium-enhanced T1 lesions compared to the same individual not receiving RMS therapy. In some embodiments, reduction refers to a reduction in the incidence of new lesions. In some embodiments, rate refers to an adjusted rate.

[0058] B. New or expanding T2-weighted lesions Provided herein are methods for treating RMS in subjects requiring treatment of RMS, wherein the treatment comprises reducing the number of new or expanding T2-weighted lesions over time, or reducing the incidence of new or expanding T2-weighted lesions. Similarly, provided herein are fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, wherein the treatment comprises reducing the number of new or expanding T2-weighted lesions over time, or reducing the incidence of new or expanding T2-weighted lesions. In some embodiments, the subjects are administered fenebrutinib. In some embodiments, the subjects are orally administered 200 mg of fenebrutinib twice daily, with a total daily dose of 400 mg.

[0059] In some embodiments of the methods and compounds for use provided herein, treatment comprises reducing the total number of new or expanding T2-weighted lesions over 12 weeks following the initiation of administration of an equivalent amount of fenebrutinib or a pharmaceutically acceptable salt thereof, as assessed at weeks 4, 8, and 12. Accordingly, in some embodiments, methods for treating RMS in a subject requiring treatment of RMS are provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein treatment comprises reducing the total number of new or expanding T2-weighted lesions over 12 weeks following the initiation of administration, as assessed at weeks 4, 8, and 12. Furthermore, this specification also provides a method for reducing the total number of new or expanding T2-weighted lesions in a subject having RMS requiring a reduction in the total number of new or expanding T2-weighted lesions, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced over 12 weeks from the start of administration, as assessed at weeks 4, 8, and 12. Further provided is a fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in a subject requiring treatment of RMS, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new or expanding T2-weighted lesions over 12 weeks from the start of administration, as assessed at weeks 4, 8, and 12. Furthermore, there is provided a fenebrutinib or a pharmaceutically acceptable salt thereof for use in reducing the total number of new or expanding T2-weighted lesions in subjects with RMS requiring a reduction in the total number of new or expanding T2-weighted lesions, comprising administering approximately 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof to the subject twice daily, wherein the total number is reduced over 12 weeks from the start of administration, as assessed at weeks 4, 8, and 12.In some such embodiments of the methods and uses provided herein, the total number of new or expanding T2-weighted lesions over 12 weeks after the start of administration is reduced by at least 50%, as assessed at weeks 4, 8, and 12. In some embodiments, the reduction is at least 60%. In certain embodiments, the reduction is at least 70%. In some embodiments, the reduction is 73.5%. In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, fenebrutinib is administered orally. In some embodiments, for a total daily dose of 400 mg of fenebrutinib, fenebrutinib is administered orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib.

[0060] In other embodiments, treatment includes reducing the total number of new or expanding T2-weighted lesions at four weeks after the initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein treatment includes reducing the total number of new or expanding T2-weighted lesions at four weeks after the initiation of administration. In some such embodiments, a method is provided for reducing the total number of new or expanding T2-weighted lesions in a subject having RMS requiring treatment of RMS, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at four weeks after the initiation of administration. Further provided herein is a method for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof twice daily, wherein the treatment comprises reducing the total number of new or expanding T2-weighted lesions at four weeks after the start of administration. Also provided is a method for use in reducing the total number of new or expanding T2-weighted lesions in subjects having RMS requiring a reduction in the total number of new or expanding T2-weighted lesions, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of the pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at four weeks after the start of administration. In some such embodiments of the method and use provided herein, the total number of new or expanding T2-weighted lesions is reduced by at least 30% at four weeks. In some embodiments, the reduction is at least 40% at week 4. In some embodiments, the reduction is 49% at week 4.In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, fenebrutinib is administered orally. In some embodiments, for a subject with a total daily dose of 400 mg of fenebrutinib, fenebrutinib is administered orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib.

[0061] In further embodiments, the treatment includes reducing the total number of new or expanding T2-weighted lesions at 8 weeks after the initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment includes reducing the total number of new or expanding T2-weighted lesions at 8 weeks after the initiation of administration. In some such embodiments, a method is provided for reducing the total number of new or expanding T2-weighted lesions in a subject having RMS requiring treatment of RMS, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at 8 weeks after the initiation of administration. Further provided herein is a method for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment comprises reducing the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration. Also provided is a method for use in reducing the total number of new or expanding T2-weighted lesions in subjects having RMS requiring a reduction in the total number of new or expanding T2-weighted lesions, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the total number is reduced at 8 weeks after the start of administration. In some such embodiments of the method and use provided herein, the total number of new or expanding T2-weighted lesions is reduced by at least 60% at 8 weeks. In some embodiments, the reduction is at least 70% at week 8. In some embodiments, the reduction is at least 80% at week 8.In some embodiments, the reduction is at least 90% at 8 weeks. In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, subjects are orally administered fenebrutinib in the form of two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.

[0062] In further embodiments, treatment includes reducing the total number of new or expanding T2-weighted lesions as evaluated at weeks 8 and 12 after the initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein treatment includes reducing the total number of new or expanding T2-weighted lesions at weeks 8 and 12 after the initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In some such embodiments, a method for reducing the total number of new or expanding T2-weighted lesions at weeks 8 and 12 after the initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof is provided herein. In some such embodiments, the number of new or expanding T2-weighted lesions is reduced by at least 60% at weeks 8 and 12. In some embodiments, the reduction is at least 70%. In some embodiments, the reduction is at least 80%. In some embodiments, the reduction is at least 90%. In some embodiments, the reduction is 93%. In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, fenebrutinib is administered orally. In some embodiments, for a total daily dose of 400 mg of fenebrutinib, the subject is administered fenebrutinib orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib.

[0063] In other embodiments, treatment comprises reducing the total number of new or expanding T2-weighted lesions by at least 60% at 12 weeks after initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment comprises reducing the total number of new or expanding T2-weighted lesions by at least 60% at 12 weeks after initiation of administration. In some such embodiments, a method is provided for reducing the total number of new or expanding T2-weighted lesions in a subject having RMS requiring treatment of RMS, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the reduction is at least 60% at 12 weeks after initiation of administration. Further provided herein is a method for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering to a subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein the treatment reduces the total number of new or expanding T2-weighted lesions by at least 60% at 12 weeks after the start of administration. In some such embodiments of the methods and uses provided herein, the total number of new or expanding T2-weighted lesions is reduced by at least 70% at week 12. In some embodiments, the reduction is at least 80% at week 12.In some embodiments, the reduction is at least 90% at week 12. In further embodiments, the reduction is 95% at week 12. In certain embodiments, the reduction is a relative reduction compared to no administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, fenebrutinib is administered orally. In some embodiments, for a total daily dose of 400 mg of fenebrutinib, the subject receives fenebrutinib orally as two tablets per day, each containing 200 mg of fenebrutinib, or as four tablets per day, each containing 100 mg of fenebrutinib.

[0064] In further embodiments, the treatment includes reducing the incidence of new or expanding T2-weighted lesions. Accordingly, in some embodiments, a method for reducing the incidence of new or expanding T2-weighted lesions in subjects having RMS requiring a reduction in the incidence of new or expanding T2-weighted lesions is provided herein, comprising administering about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject. Furthermore, fenebrutinib or a pharmaceutically acceptable salt thereof is provided for use in reducing the incidence of new or expanding T2-weighted lesions in subjects having RMS requiring a reduction in the incidence of new or expanding T2-weighted lesions, comprising administering about 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof to the subject twice daily. In certain embodiments of the method and the compound for use, the incidence of new or expanding T2-weighted lesions is reduced when measured at weeks 4, 8, and 12 after the start of administration. In some embodiments, the rate decreases by at least 40%, e.g., at least 50%, or at least 60%, or at least 70%, or 74%. In some embodiments, the rate over 12 weeks after the start of administration decreases by at least 40%, e.g., at least 50%, or at least 60%, or at least 70%, or 74%. In some embodiments, the decrease is compared to the same subject evaluated immediately before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., the preceding 12 weeks, 6 months, or 12 months). In some embodiments, the decrease is compared to another subject with RMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., a subject who has not been administered any RMS therapy). In some embodiments, fenebrutinib is administered orally.In some embodiments, subjects are orally administered fenebrutinib in the form of two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib. In some embodiments, the rate is an adjusted rate.

[0065] A method for preventing the development of new or expanding T2-weighted lesions in subjects with RMS requiring prevention of such development, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. Further provided herein is a method for preventing the development of new or expanding T2-weighted lesions in subjects with RMS requiring prevention of such development, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. In some embodiments of the method for preventing such development or of the compound for use in preventing such development, the development is prevented within 4 weeks after the start of administration. In some embodiments, the development is prevented within 8 weeks after the start of administration. In some embodiments, the development is prevented within 12 weeks after the start of administration. In some embodiments, prevention of the development of new or expanding T2-weighted lesions includes a reduction in the number of new or expanding T2-weighted lesions, which is a reduction when assessed individually at weeks 4, 8, or 12, or when assessed over 12 weeks at weeks 4, 8, or 12, or when assessed at weeks 8 and 12, and the reduction is as described elsewhere in this specification (e.g., with a reduction of at least a specified percentage over a period of time, as described elsewhere). In some embodiments, fenebrutinib is administered orally. In some embodiments, subjects are orally administered fenebrutinib as two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.

[0066] In some embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, including the reduction or prevention of the occurrence of new or expanding T2-weighted lesions (when individually assessed at weeks 4, 8, or 12, or when assessed at weeks 4, 8, or 12 over 12 weeks, or when assessed at weeks 8 and 12, or any other combination, or a reduction in the rate of) discussed herein, the comparison is against subjects who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, this comparison subject is the same subject before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, but is, for example, the same subject evaluated 4 weeks, 8 weeks, 12 weeks, 6 months, or 12 months prior to initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the comparison subject is another subject having RMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, for example, another subject having RMS that has not been administered any RMS treatment.

[0067] In certain embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, the reduction or prevention of the occurrence of new or expanding T2-weighted lesions (including, when individually assessed at time 4, 8, or 12 weeks, or when assessed at 4, 8, or 12 weeks over 12 weeks, or when assessed at 8 and 12 weeks, or any other combination, or as a reduction in rate) discussed herein is clinically exemplified by comparing subjects (or groups of subjects) administered with fenebrutinib or a pharmaceutically acceptable salt thereof with subjects (or groups of subjects) not administered with RMS therapy (e.g., an inactive comparator, or placebo). Based on this data, it would generally be expected that a single individual taking fenebrutinib or a pharmaceutically acceptable salt thereof would experience a relative reduction or prevention of the occurrence of such new or expanding T2-weighted lesions compared to the same individual not receiving RMS therapy. In some embodiments, reduction is a reduction in incidence. In some embodiments, rate is an adjusted rate.

[0068] C. Possibility of both new gadolinium-enhanced T1 lesions and new or expanding T2-weighted lesions. Provided herein is a method for treating RMS in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is characterized by an increased likelihood of (a) the subject not having any new gadolinium-enhanced T1 lesions and (b) any new or enlarged T2-weighted lesions. Similarly, provided herein is a pharmaceutically acceptable salt of fenebrutinib or the same for use in the treatment of RMS in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily to the subject, wherein the treatment is characterized by an increased likelihood of the subject not having any new gadolinium-enhanced T1 lesions and (b) any new or enlarged T2-weighted lesions. In further embodiments, a method is provided herein for increasing the likelihood that a subject having RMS will not have (a) any new gadolinium-enhanced T1 lesions and (b) any new or expanding T2-weighted lesions, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. Fenebrutinib or a pharmaceutically acceptable salt thereof is provided herein for increasing the likelihood that a subject having RMS will not have (a) any new gadolinium-enhanced T1 lesions and (b) any new or expanding T2-weighted lesions, comprising administering the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. In some embodiments of the method and use provided herein for increasing the likelihood of not having new lesions, the subject is at least twice as likely to not have (a) any new gadolinium-enhanced T1 lesions and (b) any new or expanding T2-weighted lesions. In some embodiments, subjects are at least three times more likely to have neither (a) any new gadolinium-enhanced T1 lesions nor (b) any new or expanding T2-weighted lesions.In some embodiments, a subject is four times more likely to have neither (a) any new gadolinium-enhanced T1 lesions nor (b) any new or expanding T2-weighted lesions. Increasing the likelihood of “not having” can also be expressed as increasing the likelihood of “not developing.” In some embodiments, this increase in the likelihood of not having or developing both types of lesions is over a specific period. For example, in some embodiments, the likelihood of not developing the new lesions described is over the first 12 weeks after the start of administration, as measured at weeks 4, 8, and 12. Thus, fenebrutinib or a pharmaceutically acceptable salt thereof, or a method thereof, is provided herein for use in increasing the likelihood that a subject will not have neither (a) any new gadolinium-enhanced T1 lesions nor (b) any new or expanding T2-weighted lesions, over the first 12 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, and the increase in likelihood is at least twofold. In some embodiments, the increase is at least threefold over the first 12 weeks after the start of administration. In some embodiments, the increase is at least fourfold over the first 12 weeks after the start of administration. In some embodiments, fenebrutinib is administered orally. In some embodiments, subjects are orally administered fenebrutinib as two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib. In some embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, the method involves increasing the likelihood that a subject will (a) have no new gadolinium-enhanced T1 lesions and (b) have no new or enlarged T2-weighted lesions (when assessed individually at weeks 4, 8, or 12, or when assessed at weeks 4, 8, or 12 over 12 weeks, or when assessed at weeks 8 and 12, or any other combination), and the comparison is against a subject not administered with fenebrutinib or any pharmaceutically acceptable salt thereof.In some embodiments, this comparison subject is the same subject before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, but is evaluated four weeks, eight weeks, twelve weeks, six months, or twelve months prior to initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, this comparison subject is another subject having RMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, for example, another subject having RMS that has not received any RMS treatment.

[0069] D.T1 low signal intensity lesion Provided herein are methods for treating RMS in subjects requiring treatment of RMS, wherein the treatment comprises reducing the number of new T1 low-signal lesions over time or reducing the incidence of new T1 low-signal lesions. Similarly, provided herein are fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, wherein the treatment comprises reducing the number of new T1 low-signal lesions over time or reducing the incidence of new T1 low-signal lesions. In some embodiments, the subjects are administered fenebrutinib. In some embodiments, the subjects are orally administered 200 mg of fenebrutinib twice daily, with a total daily dose of 400 mg. In some embodiments, the subjects are human.

[0070] In some embodiments of the methods and compounds for use provided herein, treatment comprises reducing the total number of new T1 low-signal lesions after initiation of administration of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, a method for treating RMS in a subject requiring treatment of RMS is provided herein, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein treatment comprises reducing the total number of new T1 low-signal lesions after initiation of administration. Further provided are fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating RMS in a subject requiring treatment of RMS, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily, wherein treatment comprises reducing the total number of new T1 low-signal lesions. In some embodiments of the methods and compounds for use provided herein, the reduction extends over 12 weeks after initiation of administration. In some embodiments, the reduction extends over 4 weeks. In some embodiments, the decline lasts for 8 weeks. In some embodiments, the decline lasts for 12 weeks when evaluated at weeks 4, 8, and 12.

[0071] In some such embodiments of the methods and uses provided herein, the total number of new T1 low-signal lesions is reduced by at least 40%. In some embodiments, the reduction is at least 50%. In certain embodiments, the reduction is at least 60%. In some embodiments, the reduction is 64%. In some embodiments, the reduction over 12 weeks is at least 40%, e.g., at least 50%, e.g., at least 55%, or 58%. In some embodiments, the reduction over 8 weeks is at least 40%, e.g., at least 50%, or at least 60%, or 64%. In some embodiments, the reduction over 4 weeks is at least 30%, e.g., at least 40%, or at least 45%, or 48%. In some embodiments, the combined reduction at weeks 4, 8, and 12 is at least 40%, e.g., at least 50%, or at least 60%, or 64%. In certain embodiments, the reduction is a relative reduction compared to a case where fenebrutinib or a pharmaceutically acceptable salt thereof was not administered. In some embodiments, the reduction is compared to the same subject evaluated immediately before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., the preceding 12 weeks, 6 months, or 12 months). In some embodiments, fenebrutinib is administered orally. In some embodiments, the subject is orally administered fenebrutinib in the form of two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib. In some embodiments, the subject is human.

[0072] In further embodiments, the treatment includes reducing the incidence of new T1 low-signal lesions. Accordingly, methods for reducing the incidence of new T1 low-signal lesions in subjects having RMS requiring a reduction in the incidence of new T1 low-signal lesions are provided herein, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject. Furthermore, fenebrutinib or a pharmaceutically acceptable salt thereof is provided for use in reducing the incidence of new T1 low-signal lesions in subjects having RMS requiring a reduction in the incidence of new T1 low-signal lesions, comprising administering approximately 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof to the subject twice daily. In certain embodiments of the method and the compound for use, the incidence of new T1 low-signal lesions is reduced when measured at weeks 4, 8, and 12 after the start of administration. In some embodiments, the rate is measured at week 12 after the start of administration. In some embodiments, the rate is measured at 8 weeks after the start of administration. In some embodiments, the rate is measured at 4 weeks after the start of administration. In some embodiments, the rate is measured over 12 weeks after the start of administration, when measured at 4, 8, and 12 weeks. In some embodiments, the rate decreases by at least 40%, e.g., at least 50%, or at least 60%, or by 64%. In some embodiments, the rate over 12 weeks after the start of administration decreases by at least 40%, e.g., at least 50%, or at least 60%, or by 64%. In some embodiments, the decrease is compared to the same subject evaluated immediately before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., the preceding 12 weeks, 6 months, or 12 months, etc.). In some embodiments, fenebrutinib is administered orally. In some embodiments, subjects are orally administered fenebrutinib in the form of two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.In some embodiments, the subject is human. In some embodiments, the rate is an adjusted rate.

[0073] A method for preventing the development of new T1 low-signal lesions in subjects with RMS requiring prevention of the development of new T1 low-signal lesions, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. Furthermore, a pharmaceutically acceptable salt of fenebrutinib or the same is provided for use in preventing the development of new T1 low-signal lesions in subjects with RMS requiring prevention of the development of new T1 low-signal lesions, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily. In some embodiments of the method for preventing such development or of the compound for use in preventing such development, the development is prevented within 4 weeks after the start of administration. In some embodiments, the development is prevented within 8 weeks after the start of administration. In some embodiments, the development is prevented within 12 weeks after the start of administration. In some embodiments, prevention of the development of new T1 low-signal lesions includes a reduction in the number of new T1 low-signal lesions, which is a reduction when evaluated individually at weeks 4, 8, or 12, or when evaluated over 12 weeks at weeks 4, 8, or 12, or when evaluated at weeks 8 and 12, and the reduction is as described elsewhere herein (e.g., with a reduction of at least a specified percentage over a certain period, as described elsewhere). In some embodiments, prevention is compared to the same subject evaluated immediately before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., the preceding 12 weeks, 6 months, or 12 months, etc.). In some embodiments, the subject is human. In some embodiments, fenebrutinib is administered orally. In some embodiments, subjects are orally administered fenebrutinib in the form of two tablets per day, each containing 200 mg of fenebrutinib, or four tablets per day, each containing 100 mg of fenebrutinib, for a total daily dose of 400 mg of fenebrutinib.

[0074] In some embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, including methods for reducing or preventing the occurrence of new gadolinium-enhanced T1 lesions (when individually assessed at weeks 4, 8, or 12, or when assessed over weeks 4, 8, or 12, or when assessed at weeks 8 and 12, or by rate, or any other combination), the comparison is against subjects not administered with fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, this comparison subject is the same subject prior to initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, but is, for example, the same subject evaluated 4 weeks, 8 weeks, 12 weeks, 6 months, or 12 months prior to initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the comparison subject is another subject having RMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, for example, another subject having RMS that has not been administered any RMS treatment.

[0075] In certain embodiments of the methods, compounds for use, and compounds for use in the manufacture of pharmaceuticals provided herein, the reduction or prevention of the occurrence of new T1 low-signal lesions (including, when individually assessed at 4, 8, or 12 weeks, or when assessed at 4, 8, or 12 weeks over 12 weeks, or when assessed at 8 and 12 weeks, or any other combination, or as a reduction in rate) discussed herein is clinically illustrated by comparing subjects (or groups of subjects) administered with fenebrutinib or a pharmaceutically acceptable salt thereof with subjects (or groups of subjects) not administered with RMS therapy (e.g., an inactive comparator, or placebo). In some embodiments, the comparison is against the same subjects before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, evaluated in the same subjects during the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the comparison is against a different subject not administered with RMS therapy. Based on this data, it would generally be expected that a single individual taking fenebrutinib or a pharmaceutically acceptable salt thereof would experience a relative reduction or prevention of the development of such new T1 low-signal lesions compared to the same individual not receiving RMS therapy. In some embodiments, reduction refers to a reduction in incidence. In some embodiments, rate refers to an adjusted rate.

[0076] E. Cerebrospinal fluid concentration Provided herein are methods for treating MS in subjects requiring treatment, comprising orally administering to the subject a BTK inhibitor in an amount sufficient to reach a cerebrospinal fluid (CSF) concentration above an activity inhibition threshold for inhibition of B cell activation, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof. Similarly, provided herein are BTK inhibitors for use in the treatment of MS in subjects requiring treatment, wherein the treatment comprises orally administering to the subject a BTK inhibitor in an amount sufficient to reach a CSF concentration above an activity inhibition threshold for inhibition of B cell activation, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof. In some embodiments, MS is RMS. In some embodiments, MS is PPMS. In some embodiments, the BTK inhibitor is fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is orally administered 200 mg of fenebrutinib twice daily, which comprises a total daily dose of 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is orally administered fenebrutinib. In some embodiments, the subject is human.

[0077] In certain embodiments of the methods and uses provided herein, the CSF concentration of the BTK inhibitor is higher than the activity inhibition threshold for inhibiting B cell activation. In some embodiments, the CSF concentration of the BTK inhibitor is higher than the maximum inhibition threshold for inhibiting B cell activation. In some embodiments, the activity inhibition threshold, or the maximum inhibition threshold, or both, for inhibiting B cell activation is determined by an in vitro cell assay. In some such embodiments, an in vitro CD69 expression assay, e.g., anti-IgM-induced expression of CD69 on B cells, is used. CD69 is a B cell activation marker that can be used to assess the inhibition of B cell activation. In some embodiments, the activity inhibition threshold is the IC in such assays. 50 Therefore, the maximum inhibition threshold is IC in such assays.90 In certain embodiments, the anti-IgM-inducible expression of CD69 on B cells is measured by a human whole blood assay. Methods for performing such assays are known to those skilled in the art and can be found, for example, in Crawford JJ, et al. JMed Chem 2018;6:2227-2245. In some embodiments, the anti-IgM-inducible expression of CD69 on B cells is evaluated in a human whole blood assay. インビトロ The activity inhibition threshold for inhibiting B cell activation, as determined by cell assays, is IC 50 The maximum inhibition threshold is either IC90 or both, and the assay is performed using at least three separate blood donors, e.g., 3 to 10 blood donors, e.g., 4, 5, 6, 7, 8, 9, or 10 blood donors, and where applicable, IC 50 , or IC 90or both are averages of multiple trials. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration that is 20% below the maximum inhibition threshold for inhibiting B cell activation. For example, if the maximum inhibition threshold is 100 ng / mL, 20% below that threshold is 80 ng / mL, and the CSF concentration is above 80 ng / mL. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration of 20% to 250% of the maximum inhibition threshold for inhibiting B cell activation. For example, if the maximum inhibition threshold is 100 ng / mL, 20% to 250% of that threshold is 20 ng / mL to 250 ng / mL. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration of 20% to 225%, 25% to 200%, 30% to 190%, or 40% to 170% of the maximum inhibition threshold for inhibiting B cell activation. In some embodiments, the BTK inhibitor is fenebrutinib or a pharmaceutically acceptable salt thereof, and the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of at least 11 ng / mL. In some embodiments, the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of at least 15 ng / mL, or at least 20 ng / mL, or at least 30 ng / mL, or at least 33 ng / mL, or at least 43.5 ng / mL. In some embodiments, the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of 11 ng / mL to 80 ng / mL, or 15 ng / mL to 80 ng / mL, or 30 ng / mL to 80 ng / mL, or 33 ng / mL to 75 ng / mL. In some embodiments, the CSF concentration is achieved at least 12 weeks after the start of oral administration of the BTK inhibitor. In some embodiments, the CSF concentration is achieved at least 8 weeks after the start of oral administration of the BTK inhibitor. In some embodiments, CSF concentration is achieved at least 4 weeks after initiation of oral administration of the BTK inhibitor.

[0078] In certain embodiments of the methods and uses provided herein, the CSF concentration of the BTK inhibitor is higher than the activity inhibition threshold for inhibiting myeloid cell activation. In some embodiments, the CSF concentration of the BTK inhibitor is higher than the maximum inhibition threshold for inhibiting myeloid cell activation. In some embodiments, myeloid cells are basophils. In some embodiments, the activity inhibition threshold, or the maximum inhibition threshold, or both, for inhibiting myeloid cell activation is determined by an in vitro cell assay. In some such embodiments, an in vitro assay is used that measures the expression of cell surface markers of myeloid cells, e.g., the expression of cell surface markers of basophils, the expression of CD63 by FcεR-mediated basophil activation, which is assessed by the surface expression of CD63. CD63 is a marker whose cell surface expression may be used to assess the inhibition of myeloid activation, e.g., basophil activation. In some embodiments, the activity inhibition threshold is the IC in such assays. 50 Therefore, the maximum inhibition threshold is IC in such assays. 90 In certain embodiments, FcεR-induced CD63 expression on myeloid cells (basophils) is measured by a human whole blood assay. Methods for performing such assays are known to those skilled in the art and can be found, for example, in Crawford JJ, et al. JMed Chem 2018;6:2227-2245. In some embodiments, the activity inhibition threshold for inhibiting myeloid cells, determined by an in vitro cell assay evaluating FcεR-induced CD63 expression on myeloid cells (basophils) in a human whole blood assay, is IC 50 Either the maximum inhibition threshold is IC 90 The assay is performed using at least three separate blood donors, for example, 3 to 10 blood donors, for example, 4, 5, 6, 7, 8, 9, or 10 blood donors, and IC 50 , or IC 90or both are averages of multiple trials, where applicable. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration above 20% below the maximum inhibition threshold for inhibition of myeloid cell activation. For example, if the maximum inhibition threshold is 100 ng / mL, 20% below that threshold is 80 ng / mL, and the CSF concentration is above 80 ng / mL. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration of 20% to 250% of the maximum inhibition threshold for inhibition of myeloid cell activation. For example, if the maximum inhibition threshold is 100 ng / mL, 20% to 250% of that threshold is 20 ng / mL to 250 ng / mL. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration of 20% to 225%, 25% to 200%, 30% to 190%, or 40% to 170% of the maximum inhibition threshold for inhibition of myeloid cell activation. In some embodiments, the BTK inhibitor is fenebrutinib or a pharmaceutically acceptable salt thereof, and the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of at least 11 ng / mL. In some embodiments, the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of at least 15 ng / mL, or at least 20 ng / mL, or at least 30 ng / mL, or at least 33 ng / mL, or at least 43.5 ng / mL. In some embodiments, the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of 11 ng / mL to 80 ng / mL, or 15 ng / mL to 80 ng / mL, or 30 ng / mL to 80 ng / mL, or 33 ng / mL to 75 ng / mL. In some embodiments, the CSF concentration is achieved at least 12 weeks after the start of oral administration of the BTK inhibitor. In some embodiments, the CSF concentration is achieved at least 8 weeks after the start of oral administration of the BTK inhibitor. In some embodiments, CSF concentration is achieved at least 4 weeks after initiation of oral administration of the BTK inhibitor.

[0079] In certain embodiments of the methods and uses provided herein, the CSF concentration of the BTK inhibitor is higher than the activity inhibition threshold for BTK inhibition. In some embodiments, the CSF concentration of the BTK inhibitor is higher than the maximum inhibition threshold for BTK inhibition. In some embodiments, the activity inhibition threshold, or the maximum inhibition threshold, or both, for inhibiting BTK is determined by an in vitro cell assay. In some such embodiments, the in vitro assay evaluates Btk Y223 autophosphorylation in the blood. In some embodiments, the activity inhibition threshold is the IC in such assays. 50 Therefore, the maximum inhibition threshold is IC in such assays. 90 In certain embodiments, Btk Y223 autophosphorylation is measured by a human whole blood assay. Methods for performing such assays are known to those skilled in the art and can be found, for example, in Crawford JJ, et al. JMed Chem 2018;6:2227-2245. In some embodiments, the activity inhibition threshold for inhibiting Btk Y223 autophosphorylation in blood in a human whole blood assay is IC 50 Either the maximum inhibition threshold is IC 90 The assay is performed using at least three separate blood donors, for example, 3 to 10 blood donors, for example, 4, 5, 6, 7, 8, 9, or 10 blood donors, and IC 50 , or IC 90or both are averages of multiple trials, where applicable. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration exceeding 20% ​​below the maximum inhibition threshold for BTK inhibition. For example, if the maximum inhibition threshold is 100 ng / mL, 20% below that threshold is 80 ng / mL, and the CSF concentration is greater than 80 ng / mL. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration of 20% to 250% of the maximum inhibition threshold for BTK inhibition. For example, if the maximum inhibition threshold is 100 ng / mL, 20% to 250% of that threshold is 20 ng / mL to 250 ng / mL. In some embodiments, subjects are orally administered a sufficient amount of BTK inhibitor to reach a CSF concentration of 20% to 225%, 25% to 200%, 30% to 190%, or 40% to 170% of the maximum inhibition threshold for BTK inhibition. In some embodiments, the BTK inhibitor is fenebrutinib or a pharmaceutically acceptable salt thereof, and the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of at least 11 ng / mL. In some embodiments, the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of at least 15 ng / mL, or at least 20 ng / mL, or at least 30 ng / mL, or at least 33 ng / mL, or at least 43.5 ng / mL. In some embodiments, the subject is orally administered an amount of the BTK inhibitor sufficient to reach a CSF concentration of 11 ng / mL to 80 ng / mL, or 15 ng / mL to 80 ng / mL, or 30 ng / mL to 80 ng / mL, or 33 ng / mL to 75 ng / mL. In some embodiments, the CSF concentration is achieved at least 12 weeks after the start of oral administration of the BTK inhibitor. In some embodiments, the CSF concentration is achieved at least 8 weeks after the start of oral administration of the BTK inhibitor. In some embodiments, CSF concentration is achieved at least 4 weeks after initiation of oral administration of the BTK inhibitor.

[0080] A method for treating MS in a subject requiring treatment of MS is further provided herein, comprising the step of orally administering a BTK inhibitor in an amount sufficient to achieve a CSF-to-plasma concentration ratio of at least 2%. Similarly, a BTK inhibitor for use in the treatment of MS in a subject requiring treatment of MS is provided herein, wherein the treatment comprises orally administering a BTK inhibitor in an amount sufficient to achieve a CSF-to-plasma concentration ratio of at least 2%. In some embodiments of the methods and uses herein, the CSF-to-plasma concentration ratio is at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, or at least 5%, or 2%-14%, 2%-12%, 3%-12%, 3%-10%, or 4%-8%. Percentage-based ratios may be expressed as relative numbers, for example, 5% may be expressed as 1:20. In some embodiments, the concentrations of the BTK inhibitor in CSF and plasma are evaluated in CSF and plasma samples taken from the same patient on the same day. In some embodiments, the ratio is achieved within 4 weeks of initiation of BTK inhibitor administration, or within 8 weeks of initiation of BTK inhibitor administration, or within 12 weeks of initiation of BTK inhibitor administration. In some embodiments, MS is RMS. In some embodiments, MS is PPMS. In some embodiments, the BTK inhibitor is fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is orally administered 200 mg of fenebrutinib twice daily, which constitutes a total daily dose of 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is orally administered fenebrutinib. In some embodiments, the subject is human.

[0081] In some embodiments, the CSF concentration is greater than at least two of the following: the inhibitory threshold for inhibiting B cell activation, the inhibitory threshold for inhibiting myeloid cell activation, and the inhibitory threshold for inhibiting BTK. In some embodiments, all three are satisfied. Accordingly, embodiments are contemplated herein that combine any two, all three, or any multiple of the embodiments relating to B cell activation inhibition, myeloid cell activation inhibition, and BTK inhibition described herein. In some embodiments, the embodiments relating to the CSF-to-plasma concentration ratio are combined alone or in multiples with any of the other CSF concentration embodiments, including the inhibitory threshold embodiments described herein.

[0082] F. Statistical significance In some embodiments of the methods and compounds for use provided herein, the comparisons discussed (e.g., a decrease in number, or an increase in probability, or a change in rate, etc.) are significant and measured in comparison to another subject (or more subjects) having RMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., including administration of an inactive placebo). In some such embodiments, for example, administration of fenebrutinib or a pharmaceutically acceptable salt thereof significantly reduces one or more MRI markers of RMS disease activity in the brain compared to placebo. These MRI markers may independently include the number of new gadolinium-enhanced T1 lesions and the number of new or expanding T2-weighted lesions. MRI markers may also include T1 low-signal lesions. In some such embodiments, a statistically significant comparison is one in which the p-value for such comparison is <0.05. Therefore, in some embodiments, administration of 200 mg of fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt to subjects with RMS requiring it resulted in a significant reduction in the number of new gadolinium-enhanced T1 lesions, as measured at 12 weeks, 8 weeks, or 4 weeks after the start of administration. In some embodiments, administration of 200 mg of fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt to subjects with RMS requiring it resulted in a significant reduction in the number of new or expanding T2-weighted lesions, as measured at 12 weeks, 8 weeks, or 4 weeks after the start of administration. In some embodiments, administration of 200 mg of fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt to subjects with RMS requiring it significantly reduced the incidence of new gadolinium-enhanced T1 lesions, or significantly reduced the incidence of new or expanding T2-weighted lesions, or significantly increased the likelihood of having neither new gadolinium-enhanced T1 lesions nor new or expanding T2-weighted lesions.In some embodiments, administration of 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof to subjects with RMS requiring it resulted in a significant reduction in the number of new T1 low-signal lesions, measured at 12 weeks, 8 weeks, or 4 weeks after the start of administration. In some embodiments, administration of 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof to subjects with RMS requiring it resulted in a significant reduction in the incidence of new T1 low-signal lesions, measured at 12 weeks, 8 weeks, or 4 weeks after the start of administration. In some embodiments, the comparison is with the same subjects before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, for example, evaluated in the same subjects during the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the comparison is with a different subject that has not received RMS therapy.

[0083] Each of the embodiments of the methods, uses, and treatments described herein may be combined in any number of permutations without limitation, provided that it is logically feasible.

[0084] Enumerated embodiments Embodiment 1. A method for treating relapsing multiple sclerosis (RMS) in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions in the subject over 12 weeks from the start of administration, as evaluated at weeks 4, 8, and 12.

[0085] Embodiment 2. A method for treating RMS in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions at 8 weeks after the start of administration.

[0086] Embodiment 3. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions as evaluated at 8 and 12 weeks after the start of administration.

[0087] Embodiment 4. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the total number of new or expanding T2-weighted lesions over 12 weeks following the start of administration, as evaluated at weeks 4, 8, and 12.

[0088] Embodiment 5. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration.

[0089] Embodiment 6. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the total number of new or expanding T2-weighted lesions as evaluated at 8 and 12 weeks after the start of administration.

[0090] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the reduction is at least 60%.

[0091] Embodiment 8. A method for treating RMS in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the incidence of new gadolinium-enhanced T1 lesions.

[0092] Embodiment 9. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment comprises preventing the development of new gadolinium-enhanced T1 lesions.

[0093] Embodiment 10. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment reduces the incidence of new or expanding T2-weighted lesions.

[0094] Embodiment 11. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment comprises preventing the development of new or expanding T2-weighted lesions.

[0095] Embodiment 12. A method for treating RMS in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is likely to be free from (a) any new gadolinium-enhanced T1 lesions and (b) any new or enlarged T2-weighted lesions.

[0096] Embodiment 13. The method of Embodiment 12, wherein the subject is at least twice as likely to have (a) no new gadolinium-enhanced T1 lesions and (b) no new or expanding T2-weighted lesions during the first 12 weeks after the start of administration.

[0097] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein 200 mg of fenebrutinib is administered orally twice daily.

[0098] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein 200 mg of fenebrutinib is administered orally twice daily as two tablets, each containing 200 mg of fenebrutinib.

[0099] Embodiment 16. The method according to any one of Embodiments 1 to 14, wherein 200 mg of fenebrutinib is administered orally twice daily as four tablets, each containing 100 mg of fenebrutinib.

[0100] Embodiment 17. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of relapsing multiple sclerosis (RMS), comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a subject, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions in the subject over 12 weeks after the start of administration, as evaluated at weeks 4, 8, and 12.

[0101] Embodiment 18. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, wherein the treatment comprises reducing the total number of new gadolinium-enhanced T1 lesions at 8 weeks after the start of administration.

[0102] Embodiment 19. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a target, wherein the treatment reduces the total number of new gadolinium-enhanced T1 lesions as evaluated at weeks 8 and 12 after the start of administration.

[0103] Embodiment 20. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, wherein the treatment reduces the total number of new or expanding T2-weighted lesions over 12 weeks after the start of administration, as evaluated at weeks 4, 8, and 12.

[0104] Embodiment 21. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the target, wherein the treatment comprises reducing the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration.

[0105] Embodiment 22. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, wherein the treatment reduces the total number of new or expanding T2-weighted lesions as evaluated at weeks 8 and 12 after the start of administration.

[0106] Embodiment 23. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to any one of Embodiments 17-22, wherein the reduction is at least 60%.

[0107] Embodiment 24. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment comprises reducing the incidence of new gadolinium-enhanced T1 lesions.

[0108] Embodiment 25. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment comprises preventing the development of new gadolinium-enhanced T1 lesions.

[0109] Embodiment 26. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment comprises reducing the incidence of new or expanding T2-weighted lesions.

[0110] Embodiment 27. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment comprises preventing the development of new or expanding T2-weighted lesions.

[0111] Embodiment 28. Fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering about 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment increases the likelihood that (a) the subject will not have any new gadolinium-enhanced T1 lesions, and (b) the subject will not have any new or expanding T2-weighted lesions.

[0112] Embodiment 29. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use as described in Embodiment 28, wherein the subject is at least twice as likely to have (a) no new gadolinium-enhanced T1 lesions and (b) no new or enlarging T2-weighted lesions during the first 12 weeks following the initiation of administration.

[0113] Embodiment 30. Fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 17 to 29, administered orally twice daily at a dose of 200 mg.

[0114] Embodiment 31. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to any one of Embodiments 17 to 30, administered orally twice daily as two tablets, each containing 200 mg of fenebrutinib.

[0115] Embodiment 32. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to any one of Embodiments 17 to 30, administered orally twice daily as four tablets, each containing 100 mg of fenebrutinib.

[0116] Embodiment 33. A compound for use in the manufacture of a pharmaceutical for the treatment of relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment of RMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment comprises the method according to any one of Embodiments 1 to 16.

[0117] Embodiment 34. A method for treating multiple sclerosis (MS) in a subject requiring treatment for MS, A method comprising orally administering a BTK inhibitor in an amount sufficient to reach a cerebrospinal fluid (CSF) concentration higher than the threshold for inhibition of activity for inhibition of B cell activation, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof.

[0118] Embodiment 35. The method according to Embodiment 34, wherein the CSF concentration is higher than the activity inhibition threshold for inhibiting B cell activation.

[0119] Embodiment 36. The method according to Embodiment 34, wherein the CSF concentration is higher than the activity inhibition threshold for inhibiting myeloid cell activation.

[0120] Embodiment 37. The method according to Embodiment 34, wherein the CSF concentration is higher than the activity inhibition threshold for BTK inhibition.

[0121] Embodiment 38. The method according to Embodiment 34, wherein the CSF concentration is greater than at least two of the following: the inhibitory threshold for inhibiting B cell activation, the inhibitory threshold for inhibiting myeloid cell activation, or the inhibitory threshold for inhibiting BTK.

[0122] Embodiment 39. The method according to Embodiment 34, wherein the CSF concentration is greater than all three of the inhibitory thresholds for inhibiting B cell activation, for inhibiting myeloid cell activation, and for inhibiting BTK.

[0123] Embodiment 40. The IC of B cell activation inhibition is assessed using an in vitro cell assay that measures B cell activation markers. 50 Therefore, the activity inhibition threshold for inhibiting myeloid cell activation is assessed using an in vitro cell assay that measures myeloid cell activation markers. 50 The activity inhibition threshold for BTK inhibition is evaluated using an in vitro cell assay that measures BTK activity. 50 The method according to any one of embodiments 34 to 39.

[0124] Embodiment 41. The method according to any one of Embodiments 34 to 40, wherein the subject is orally administered a BTK inhibitor in an amount sufficient to reach a CSF concentration that is 20% below (a) the maximum inhibition threshold for inhibition of B cell activation, (b) the maximum inhibition threshold for inhibition of myeloid cell activation, or (c) the maximum inhibition threshold for inhibition of BTK, or any combination thereof.

[0125] Embodiment 42. The method according to any one of Embodiments 34 to 41, wherein the subject is orally administered a BTK inhibitor in an amount sufficient to reach a CSF concentration higher than (a) the maximum inhibition threshold for inhibition of B cell activation, (b) the maximum inhibition threshold for inhibition of myeloid cell activation, or (c) the maximum inhibition threshold for inhibition of BTK, or any combination thereof.

[0126] Embodiment 43. The method according to Embodiment 41 or 42, wherein the CSF concentration is greater than 20% below the maximum inhibition threshold for inhibition of B cell activation.

[0127] Embodiment 44. The method according to any one of Embodiments 41 to 43, wherein the CSF concentration is higher than the maximum inhibition threshold for inhibition of B cell activation.

[0128] Embodiment 45. The method according to Embodiment 41 or 42, wherein the CSF concentration is greater than 20% below the maximum inhibition threshold for inhibition of myeloid cell activation.

[0129] Embodiment 46. The method according to any one of Embodiments 41, 42, or 45, wherein the CSF concentration is higher than the maximum inhibition threshold for inhibition of myeloid cell activation.

[0130] Embodiment 47. The method according to Embodiment 41 or 42, wherein the CSF concentration is greater than 20% below the maximum inhibition threshold for BTK inhibition.

[0131] Embodiment 48. The method according to any one of Embodiments 41, 42, or 47, wherein the CSF concentration is higher than the maximum inhibition threshold for BTK inhibition.

[0132] Embodiment 49. The method according to any one of Embodiments 41 to 56, wherein the CSF concentration is higher than the maximum inhibition threshold for all three: inhibition of B cell activation, inhibition of myeloid cell activation, or inhibition of BTK.

[0133] Embodiment 50. The maximum inhibition threshold for inhibiting B cell activation is evaluated using an in vitro cell assay that measures B cell activation markers, and the IC for inhibiting B cell activation is... 90 Therefore, the maximum inhibition threshold for myeloid cell activation inhibition was assessed using an in vitro cell assay that measures myeloid cell activation markers, and the IC for myeloid cell activation inhibition was 90 Therefore, the maximum inhibition threshold for BTK inhibition, when evaluated using an in vitro cell assay that measures BTK autophosphorylation activity, is the IC for BTK inhibition. 90 The method according to any one of embodiments 41 to 49.

[0134] Embodiment 51. The method according to any one of Embodiments 34 to 50, wherein the BTK inhibitor is fenebrutinib or a pharmaceutically acceptable salt thereof.

[0135] Embodiment 52. The method according to Embodiment 51, wherein the CSF concentration is at least 11 ng / mL.

[0136] Embodiment 53. The method according to Embodiment 51, wherein the CSF concentration is at least 33 ng / mL.

[0137] Embodiment 54. The method according to Embodiment 53, wherein the CSF concentration is at least 43.5 ng / mL.

[0138] Embodiment 55. The method according to any one of Embodiments 34 to 54, wherein the CSF concentration is achieved at least 12 weeks after the start of oral administration of the BTK inhibitor.

[0139] Embodiment 56. The method according to any one of Embodiments 34 to 55, wherein the MS is primary progressive mass sterilization (PPMS).

[0140] Embodiment 57. The method according to any one of Embodiments 34 to 56, wherein MS is recurrent MS (RMS).

[0141] Embodiment 58. The method according to any one of Embodiments 34 to 57, wherein the CSF-to-plasma ratio of the BTK inhibitor in the subject is at least 4%.

[0142] Embodiment 59. The method according to any one of Embodiments 34 to 58, wherein the subject is orally administered 200 mg of the BTK inhibitor fenebrutinib twice daily in a total daily dose of 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt of fenebrutinib.

[0143] Embodiment 60. A method for treating RMS in a subject requiring treatment of RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment comprises reducing the total number of new T1 low-signal lesions in the subject.

[0144] Embodiment 61. The method according to Embodiment 60, wherein the total number of new T1 low-signal lesions decreases at 12 weeks after the start of administration.

[0145] Embodiment 62. The method according to Embodiment 60, wherein the total number of new T1 low-signal lesions decreases at 8 weeks after the start of administration.

[0146] Embodiment 63. The method according to Embodiment 60, wherein the total number of new T1 low-signal lesions decreases at 4 weeks after the start of administration.

[0147] Embodiment 64. The method according to Embodiment 60, wherein the total number of new T1 low-signal lesions decreases at 12 weeks after the start of administration, as evaluated at 4, 8, and 12 weeks.

[0148] Embodiment 65. The method according to any one of Embodiments 60 to 64, wherein the reduction is at least 40%.

[0149] Embodiment 66. The method according to any one of Embodiments 60-62 or 64, wherein the reduction is at least 50%.

[0150] Embodiment 67. The method according to any one of Embodiments 60, 62, or 64, wherein the reduction is at least 60%.

[0151] Embodiment 68. A method for treating RMS in a subject requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment reduces the incidence of new T1 low-signal lesions.

[0152] Embodiment 69. The method according to Embodiment 68, wherein the rate is evaluated over 4, 8, or 12 weeks after the start of administration.

[0153] Embodiment 70. A method for treating RMS in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment includes preventing the development of new T1 low-signal lesions.

[0154] Embodiment 71. The method according to Embodiment 70, wherein the occurrence is prevented for 4 weeks, 8 weeks, or 12 weeks after the start of administration.

[0155] Embodiment 7: The method according to any one of Embodiments 34 to 71, wherein 2,200 mg of fenebrutinib is administered orally twice daily.

[0156] Embodiment 73. The method according to any one of Embodiments 34 to 71, wherein 200 mg of fenebrutinib is administered orally twice daily as two tablets, each containing 200 mg of fenebrutinib.

[0157] Embodiment 74. The method according to any one of Embodiments 34 to 71, wherein 200 mg of fenebrutinib is administered orally twice daily as four tablets, each containing 100 mg of fenebrutinib.

[0158] Embodiment 75. The method according to any one of Embodiments 2, 3, 5, or 6, wherein the reduction is at least 80%.

[0159] Embodiment 76. The method according to any one of Embodiments 2, 3, 5, or 6, wherein the reduction is at least 90%.

[0160] Embodiment 77. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to any one of Embodiments 18, 19, 21, or 22, wherein the reduction is at least 80%.

[0161] Embodiment 78. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to any one of Embodiments 18, 19, 21, or 22, wherein the reduction is at least 90%.

[0162] Embodiment 79. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use in the manner of Embodiment 12 or Embodiment 28, the possibility of which is increased by at least three times.

[0163] Embodiment 80. Fenebrutinib or a pharmaceutically acceptable equivalent amount of its salt for use in any of the methods of Embodiments 34 to 74.

[0164] Embodiment 81. The method according to any one of Embodiments 1-16, 34-74, or 79, wherein the comparison is with the same subject evaluated before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0165] Embodiment 82. The method according to Embodiment 81, wherein the same subject is evaluated during the 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 83. The method according to any one of Embodiments 1-16, 34-74, or 79, wherein the comparison is with a different subject who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 84. The method according to any one of Embodiments 1-16, 34-74, or 79, wherein the comparison is with the same subject evaluated before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0168] Embodiment 85. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use in any one of Embodiments 17-33 or 75-79, wherein the comparison is with the same subject evaluated before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0169] Embodiment 86. The same subject is evaluated for 12 weeks, 6 months, or 12 months immediately preceding the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, as used in Embodiment 89.

[0170] Embodiment 87. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use in any one of Embodiments 17-33 or 75-79, wherein the comparison is with the same subject evaluated before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0171] Embodiment 88. A compound for use in the manufacture of a pharmaceutical for the treatment of a subject requiring treatment, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment comprises the method according to any one of Embodiments 34-74, 79 or 81-84. [Examples]

[0172] This disclosure will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the invention.

[0173] Example 1: A randomized, double-blind, placebo-controlled study to investigate the efficacy of fenebrutinib in relapsing-remitting multiple sclerosis (Phase II). This Phase II study was conducted to evaluate the effect of fenebrutinib on magnetic resonance imaging (MRI) in participants with progressive muscle stenosis (RMS). Participants were randomized to receive either fenebrutinib or placebo. In addition to MRI assessments, participants were also monitored for other clinical outcomes of the disease, including disability progression and MS relapse, as described more fully below.

[0174] Study Design: This clinical trial included a double-blind treatment (DBT) phase in which participants were randomized in a 2:1 ratio to receive either 200 mg of BID oral fenebrutinib or an inactive placebo for 12 weeks. Participants were instructed to self-administer a total daily dose of 400 mg of fenebrutinib (or placebo) orally, two 100 mg tablets in the morning and two 100 mg tablets in the evening. A diagram of the study design is shown in Figure 1.

[0175] A total of 109 adults aged 18–55 years with RMS were enrolled in the study: 73 in the fenebrutinib group and 36 in the placebo group. Three patients in the fenebrutinib group did not complete the treatment phase, while all patients in the placebo group completed the treatment phase. Therefore, the analysis of outcomes in the double-blind phase of this study included 70 patients in the fenebrutinib group and 36 patients in the placebo group.

[0176] MRI Measurements: The primary efficacy endpoint in this study was the total number of new gadolinium-enhanced T1 (T1Gd+) lesions on brain MRI measured at weeks 4, 8, and 12 of administration. Secondary efficacy outcomes were (1) the total number of new or expanding T2-weighted lesions on brain MRI measured at weeks 4, 8, and 12, and (2) the proportion of participants without new Gd-enhanced T1 lesions or new or expanding T2-weighted lesions observed on brain MRI at weeks 4, 8, and 12. Radiographic assessment of the primary efficacy parameters was performed for each participant at screening and at weeks 4, 8, and 12 using a standardized MRI protocol.

[0177] Exploratory endpoints included the total number of new T1 low-signal lesions on MRI at weeks 4, 8, and 12, fenebrutinib concentrations in CSF collected at baseline and from week 12 onward, and plasma pharmacokinetics.

[0178] Clinical Outcome Assessment: Disability was measured using the Expanded Disability Status Scale (EDSS). The EDSS is based on standardized neurological examinations and incorporates functional systems (visual, brainstem, pyramidal, cerebellar, sensory, intestinal and bladder, and brain [or mental]) which are assessed and then scored as functional system scores (FSS), and gait, which is scored as a gait score. Each FSS is an ordinal clinical assessment scale ranging from 0 to 5 or 6, and the gait score is assessed from 0 to 16. These assessments are used in combination with observations and information regarding gait and assistive device use to determine the total EDSS score. The EDSS is a disability scale ranging from 0 (normal) to 10.0 (death) in 0.5-point steps (Kurtzke 1983; Kappos 2011). All FSS, gait scores, and total EDSS scores were obtained electronically.

[0179] MS Relapse Assessment: In this study, a relapse, as defined in the protocol, was defined as the occurrence of a new or worsening neurological symptom attributed to MS, preceded by a relatively stable or improving neurological condition for at least 30 days. The symptom must last longer than 24 hours and must not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reaction to concomitant medication). A new or worsening neurological symptom must be accompanied by objective neurological deterioration consistent with an increase in at least one of the following: • Half a step (0.5 points) on the EDSS scale • 2 points for one of the selected FSS listed below • 1 point for two or more of the selected FSS listed below.

[0180] This change must affect one of the following selected FSSs: pyramidal tract, gait, cerebellum, brainstem, sensation, or vision. Transient seizures, sexual dysfunction, fatigue, mood changes, or bladder or bowel emergency or incontinence were not sufficient to establish a relapse.

[0181] Patients were eligible for this study if they met certain eligibility criteria, including: • Age at the time of signing the consent form: 18 to 55 years old • Diagnosis of RMS according to the revised 2017 McDonald's criteria (Thompson et al. 2018) and one of the following: - Clinical relapses recorded at least twice within the past two years or clinical relapses recorded once within 12 months of screening (but not within 30 days prior to screening) - Documented evidence of the presence of at least one T1 Gd+ lesion on MRI during the 6 months prior to randomization (may include screening MRI). Note: RMS may include active secondary progressive MS as defined by Lublin 2014. • Expansion of the Expanded Disability Status Scale (EDSS) score from 0 to 5.5 during screening.

[0182] Participants were excluded from the study if they met certain exclusion criteria, including: • Disease duration exceeding 10 years from symptom onset and EDSS score <2.0 at screening. • Diagnosis of primary progressive MS or inactive secondary progressive MS • The presence of other neurological disorders that may interfere with the diagnosis of MS or the evaluation of efficacy or safety in the study. • Prior treatment with fenebrutinib or another BTK inhibitor for any indication Treatment with a strong CYP3A4 inhibitor, or a strong or moderate CYP3A4 inducer, within 7 days prior to randomization or 5 drug elimination half-lives (whichever is longer). • Treatment with a CYP3A4 substrate having a narrow therapeutic range within 7 days prior to randomization or within the longer of five drug elimination half-lives.

[0183] Statistical discussion: Assuming 0.7 new T1 Gd+ lesions per scan and a 3% dropout rate in the placebo group, the study had 90% power to detect a 60% reduction in the primary endpoint.

[0184] Baseline disease characteristics: A summary of baseline disease characteristics is provided in Table 1. [Table 1]

[0185] Results: Primary endpoint (total number of new T1 Gd+ lesions at combined weeks 4, 8, and 12): The primary endpoint of this study was met. In the treatment group (n=70), a relative reduction of 69% in new T1 Gd+ lesions was observed compared to placebo, with a p-value of 0.0022. A summary of the primary endpoint analysis is shown in Table 2. Supplementary analyses of the primary endpoint (categorized by visit) are shown in Tables 3 and 4. Figure 2 shows some of the data from these tables and provides a bar graph to provide additional analysis. In this figure, the large arrows indicate the relative reduction in lesions (95% confidence interval). The proportion of patients with new T1 Gd+ lesions is calculated by dividing the number of participants with new lesions at that particular visit alone by the number of participants who underwent scans at that particular visit alone at the specified week. Very few patients had new lesions after week 4 of treatment with fenebrutinib. There was a 90% reduction at week 12, with only 3.2% of patients having new T1 Gd+ lesions. Overall, 38% (n=73) of FEN patients and 33% (n=36) of PBO patients experienced adverse events (AEs). No serious AEs or deaths were reported. [Table 2] a The unadjusted lesion rate is calculated by dividing the total number of lesions in all patients in the studied group by the total number of scans. Adjusted rates and rate ratios are estimated from a negative binomial regression model of the total number of events adjusted for the following covariate: the presence of any T1Gd+ lesion at baseline. A log of MRI scan counts is included as an offset. [Table 3] [Table 4]

[0186] Results: Secondary endpoint - Total number of new or expanding T2-weighted lesions combined at weeks 4, 8, and 12: This secondary endpoint was met, and a summary of the analysis of this secondary endpoint is provided in Table 5. Supplementary analyses of the secondary endpoint (categorized by visit) are shown in Tables 6 and 7. Figure 3 shows some of the data from these tables and provides a bar graph to provide additional analysis. In this figure, the large arrows indicate the relative decrease in lesions (95% confidence interval). The percentage of patients with new / expanding T2-weighted lesions is calculated by dividing the number of participants with new lesions at that particular visit alone by the number of participants who underwent scans at that particular visit alone at the specified week. At week 12, there was a 95% decrease, with only 3.2% of patients having new / expanding lesions. [Table 5] [Table 6] [Table 7]

[0187] Results: Secondary endpoint – proportion of participants without new Gd+-enhanced T1 lesions and new or expanding T2-weighted lesions at weeks 4, 8, and 12: This secondary endpoint was also met, and a summary of the analysis is provided in Table 8. A supplementary analysis of this secondary endpoint at each visit at weeks 4, 8, and 12 is shown in Table 9. Patients in the fenebrutinib group were four times more likely to be free of new T1 Gd+ lesions and new or expanding T2-weighted lesions at weeks 4, 8, and 12 compared to patients in the placebo group. [Table 8] [Table 9]

[0188] Results: Exploratory Endpoint - Low-Intensity T1 Lesions: The number of T1 low-intensity lesions was assessed as an exploratory endpoint at weeks 4, 8, and 12. Treatment with fenebrutinib reduced T1 low-intensity lesions at all three time points, and compared to placebo, very few patients had new lesions at week 4 post-treatment. The results of the analysis are shown in Table 10. Figure 4 shows some of the data from this table and provides a bar graph to provide additional analysis. In this figure, the large arrows indicate the relative reduction in lesions (95% confidence interval). The proportion of patients with new T1 low-intensity lesions is calculated by dividing the number of participants with new lesions at that particular visit alone by the number of participants who underwent scans at that particular visit alone at the specified week. There was a 58% reduction at week 12, with only 3.2% of patients having new low-intensity T1 lesions. [Table 10]

[0189] Results: Exploratory endpoint - CSF evaluation: Cerebral spinal cord (CSF) samples were collected from 11 patients after 12 weeks of continuous fenebrutinib administration. Plasma samples were collected simultaneously from 4 of the 11 patients. The concentration of fenebrutinib in CSF at week 12 was evaluated and compared with the IC50 (activity inhibition threshold) and IC90 (maximum inhibition threshold) of fenebrutinib evaluated by different in vitro assays, as shown in Figure 5. From the figure, (a) the mean fenebrutinib CSF concentration is after 12 weeks of continuous fenebrutinib administration. (1) Data from the CD63 and CD69 assays were previously presented by Weber MS, et al. at the AAN 2021 Virtual Annual Meeting, April 17-22. (P15.091). (2) Data on the phospho-BTK assay have been previously presented in Keaney J, et al. J Neuroimmune Pharmacol 2019;14:448-461. An analysis of CSF, plasma fenebrutinib concentrations, and proportions for the four patients from whom plasma samples were collected is shown in Table 11. [Table 11]

[0190] As shown in Figure 5, CSF fenebrutinib concentrations in all 11 patients were within the effective range (IC50 of fenebrutinib as assessed by the CD63, CD69, and phospho-BTK inhibition assays described above), and the mean fenebrutinib CSF concentration (43.1 ng / mL) was comparable to the IC90 of fenebrutinib as assessed in different in vitro human whole blood assays (CD69: 43.2 ng / mL; CD63: 41.2 ng / mL; phospho-BTK: 40.4 ng / mL). CD63 is a myeloid cell activation marker, CD69 is a B cell activation marker, and the phospho-BTK assay assesses target engagement by inhibition of anti-IgM-induced BTK Y223 autophosphorylation in human whole blood. Procedures for performing these three assays can be found in Crawford JJ, et al. JMed Chem 2018;6:2227-2245. Fenebrutinib has a dual mechanism of action, inhibiting the activation of both B cells and myeloid cells. Therefore, the data in Figure 5 show that the fenebrutinib concentrations observed in CSF after 12 weeks of continuous administration were within the activity range for both mechanisms of action assessed by in vitro cell assays for CD63 and CD69, as well as for BTK target engagement assessed by phospho-BTK in vitro assay, and were comparable to the maximum inhibition threshold. The fenebrutinib concentrations observed in CSF after 12 weeks of continuous administration also indicated that fenebrutinib was present in CSF at levels sufficient to reduce the activation of B cells and microglial progenitor cells in vitro. The CSF-to-plasma ratio demonstrates the CNS access of fenebrutinib in patients.

[0191] Results-Safety Summary: A summary of adverse events (AEs) in patients treated with fenebrutinib and placebo is provided in Table 12. [Table 12]

[0192] No adverse events (SAEs) were reported. All AEs were grade 1 or 2, with the exception of two grade 3 asymptomatic elevated liver transaminase levels. Elevated liver transaminase levels observed in patients treated with fenebrutinib were reversible and asymptomatic. Infection rates were balanced between the fenebrutinib and placebo groups. There were four AEs leading to withdrawal from the study: four cases of abnormal liver transaminase levels (which required discontinuation according to the protocol); one case of epigastric pain; nausea and headache; one case of epigastric pain; and one case of hypersensitivity.

Claims

1. A method for treating relapsing-relapsing multiple sclerosis (RMS) in a subject requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is A method comprising reducing the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks after the start of administration, as evaluated at weeks 4, 8, and 12.

2. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the total number of new gadolinium-enhanced T1 lesions at 8 weeks after the start of administration.

3. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the total number of new gadolinium-enhanced T1 lesions when evaluated at 8 and 12 weeks after the start of administration.

4. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the total number of new or expanding T2-weighted lesions over 12 weeks following the start of administration, as assessed at weeks 4, 8, and 12.

5. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the total number of new or expanding T2-weighted lesions within eight weeks of the start of administration.

6. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the total number of new or expanding T2-weighted lesions as evaluated at 8 and 12 weeks after the start of administration.

7. The method according to any one of claims 1 to 6, wherein the reduction is at least 60%.

8. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the incidence of new gadolinium-enhanced T1 lesions.

9. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method including preventing the development of new gadolinium-enhanced T1 lesions.

10. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising reducing the incidence of new or expanding T2-weighted lesions.

11. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method including preventing the development of new or expanding T2-weighted lesions.

12. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment is A method comprising increasing the likelihood that the subject does not have (a) any new gadolinium-enhanced T1 lesions, and (b) any new or expanding T2-weighted lesions.

13. The method according to claim 12, wherein the subject is at least twice as likely to have (a) no new gadolinium-enhanced T1 lesions and (b) no new or expanding T2-weighted lesions during the first 12 weeks after the start of administration.

14. The method according to any one of claims 1 to 13, wherein 200 mg of fenebrutinib is administered orally twice daily.

15. The method according to any one of claims 1 to 14, wherein 200 mg of fenebrutinib is administered orally twice daily as two tablets, each containing 200 mg of fenebrutinib.

16. The method according to any one of claims 1 to 14, wherein 200 mg of fenebrutinib is administered orally twice daily in the form of four tablets, each containing 100 mg of fenebrutinib.

17. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment for RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising reducing the total number of new gadolinium-enhanced T1 lesions in the subjects over 12 weeks following the initiation of administration, as assessed at weeks 4, 8, and 12.

18. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising reducing the total number of new gadolinium-enhanced T1 lesions at 8 weeks after the start of administration.

19. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising reducing the total number of new gadolinium-enhanced T1 lesions when evaluated at weeks 8 and 12 after the start of administration.

20. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising reducing the total number of new or expanding T2-weighted lesions over 12 weeks following the start of administration, as assessed at weeks 4, 8, and 12.

21. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising reducing the total number of new or expanding T2-weighted lesions at 8 weeks after the start of administration.

22. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising reducing the total number of new or expanding T2-weighted lesions as evaluated at weeks 8 and 12 after the start of administration.

23. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to any one of claims 17 to 22, wherein the reduction is at least 60%.

24. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, including one that reduces the incidence of new gadolinium-enhanced T1 lesions.

25. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, including the prevention of the development of new gadolinium-enhanced T1 lesions.

26. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, including one that reduces the incidence of new or expanding T2-weighted lesions.

27. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, including the prevention of the development of new or expanding T2-weighted lesions.

28. A fenebrutinib or a pharmaceutically acceptable salt thereof for use in the treatment of RMS in subjects requiring treatment of RMS, comprising administering approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of the pharmaceutically acceptable salt thereof, to the subject, wherein the treatment is Fenebrutinib or a pharmaceutically acceptable salt thereof, comprising increasing the likelihood that the subject will not have (a) any new gadolinium-enhanced T1 lesions, and (b) any new or expanding T2-weighted lesions.

29. Fenebrutinib or an equivalent amount of its pharmaceutically acceptable salt for use according to claim 28, wherein the subject is at least twice as likely to have (a) no new gadolinium-enhanced T1 lesions and (b) no new or enlarged T2-weighted lesions during the first 12 weeks following the initiation of administration.

30. Fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof for use according to any one of claims 17 to 29, wherein 200 mg of fenebrutinib is administered orally twice daily.

31. Fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof for use according to any one of claims 17 to 30, wherein 200 mg of fenebrutinib is administered orally twice daily as two tablets, each containing 200 mg of fenebrutinib.

32. Fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof for use according to any one of claims 17 to 30, wherein 200 mg of fenebrutinib is administered orally twice daily as four tablets, each containing 100 mg of fenebrutinib.

33. A compound for use in the manufacture of a pharmaceutical for the treatment of relapsing-relapsing multiple sclerosis (RMS) in subjects requiring treatment of RMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment comprises the method according to any one of claims 1 to 16.

34. A method for treating multiple sclerosis (MS) in subjects requiring treatment for MS, A method comprising orally administering to a subject an amount of a BTK inhibitor sufficient to reach a cerebrospinal fluid (CSF) concentration higher than the threshold for inhibition of activity for inhibition of B cell activation, inhibition of myeloid cell activation, inhibition of BTK, or any combination thereof.

35. The IC for inhibiting B cell activation is evaluated using an in vitro cell assay that measures B cell activation markers. ５０ The activity inhibition threshold for inhibiting myeloid cell activation is evaluated using an in vitro cell assay that measures myeloid cell activation markers. ５０ The activity inhibition threshold for BTK inhibition is evaluated using an in vitro cell assay that measures BTK activity. ５０ The method according to claim 34.

36. The method according to any one of claims 34 to 35, wherein the BTK inhibitor is orally administered to the subject in an amount sufficient to reach a CSF concentration that is 20% below (a) the maximum inhibition threshold for inhibition of B cell activation, (b) the maximum inhibition threshold for inhibition of myeloid cell activation, or (c) the maximum inhibition threshold for inhibition of BTK, or any combination thereof.

37. The method according to any one of claims 34 to 36, wherein the subject is orally administered 200 mg of the BTK inhibitor, fenebrutinib, twice daily in a total daily dose of 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt of fenebrutinib.

38. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment reduces the total number of new T1 low-signal lesions in the subject.

39. The method according to claim 38, wherein the reduction is at least 40%.

40. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment reduces the incidence of new T1 low-signal lesions.

41. A method for treating RMS in a subject requiring treatment for RMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the treatment prevents the development of new T1 low-signal lesions.

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