Treatment methods for primary progressive multiple sclerosis using Bruton's tyrosine kinase inhibitors

Abstract

The present invention provides pharmaceuticals and compositions for treating primary progressive multiple sclerosis (PPMS) using Bruton's tyrosine kinase (BTK) inhibitors. [Solution] A pharmaceutical is provided for the treatment of primary progressive multiple sclerosis (PPMS) in a subject requiring the treatment thereof, comprising approximately 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the fenebrutinib or the pharmaceutically acceptable salt thereof is administered twice daily.

Description

[Technical Field]

[0001] Related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 051,756 filed July 14, 2020 and U.S. Provisional Patent Application No. 62 / 982,872 filed February 28, 2020, the disclosures of which are incorporated herein by reference in their entirety.

[0002] Technical field

[0002] This disclosure relates to a method for treating primary progressive multiple sclerosis (PPMS) using a Bruton's tyrosine kinase (BTK) inhibitor. [Background technology]

[0003]

[0003] Bruton's tyrosine kinase (BTK): The discovery of the genetic basis of primary immunodeficiency has led to new therapeutic targets in immunomodulatory therapy. In humans, mutations in the Bruton tyrosine kinase (BTK) gene located on the X chromosome can lead to an immunodeficiency characterized by a marked absence of circulating B cells (Bruton OC. Pediatrics 1952, 9:722-8; Conley ME, et al, Immunol Rev 2005, 203:216-34) and very low immunoglobulin levels (Reth M, Nielsen P., Adv Immunol 2014, 122:129-75. doi: 10.1016 / B978-0-12-800267-4.00004-3) due to defects in B cell differentiation at the pro-B cell to pre-B cell stage, which interferes with B cell receptor (BCR) complex assembly and immunoglobulin gene expression. Affected male patients have X-linked agammaglobulinemia (XLA), a primary immunodeficiency, making them susceptible to recurrent infections from shortly after birth. Patients with XLA can lead relatively normal lives with standard treatment of intravenous (IV) immunoglobulin. This suggests that BTK can be safely inhibited, especially in individuals with an established x-immune system. IV immunoglobulin replacement therapy has reduced infection rates, decreased hospitalization rates in XLA patients, and significantly improved the long-term prognosis of these patients.

[0004]

[0004] BTK is essential for the differentiation and activation of B cells during individual development of the immune system and normal adaptive immune responses. BTK is activated by the Src family kinase Lyn through phosphatidylinositol 3-kinase-dependent plasma membrane mobilization and phosphorylation of tyrosine Y551. Autophosphorylation and activation also occur at tyrosine Y223 in a BTK-specific manner. Once activated, BTK is activated by PLCγ2 and Ca 2It induces the dependent signal transduction, leading to the activation of NF-κB- and NFAT-dependent pathways. This further leads to the activation and differentiation of cells (Niiro H, Clark EA., Nat Rev Immunol 2002, 2:945-56). Furthermore, BTK is important in FcεRI signal transduction in both basophils and mast cells. εBTK null mice impaired FcεRI signal transduction and reduced the release of histamine and inflammatory cytokines (Iyer AS, et al., J Bio Chem 201, 286:9503-13. doi: 10.1074 / jbc.M110.1656131).

[0005]

[0005] Multiple sclerosis: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease of the central nervous system (CNS) that affects approximately 900,000 people in the United States (Wallin et al. 2019) and 2.3 million people worldwide (GBD 2016 Multiple Sclerosis Collaborators 2019). MS is primarily a disease of young adults, with 70% - 80% of patients having an age of onset (i.e., the first clinical finding for a physician) between 20 and 40 years old (Anderson et al. 1992; Noonan et al. 2002), and there is a gender bias influenced by the phenotype, with approximately 64% - 70% of diagnosed patients being female (Anderson et al. 1992; Noonan et al. 2002).

[0006]

[0006] MS is classified into three clinical phenotypes, one of which is primary progressive MS (PPMS). PPMS is further subdivided into active and inactive forms based on the presence or absence of disease activity, which is defined by the presence of clinical relapse and / or gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans (T1GD+) or new / enlarged T2-weighted lesions on MRI scans.

[0007]

[0007] Although the mechanisms associated with disease progression are presumed to be present from onset (Cree et al. 2019), clinical disability progression often appears in the second half of the patient's disease course due to the degree of the patient's brain reserve. Symptomatic deterioration associated with MS disability progression results in a slow and insidious loss of the patient's motor and sensory functions, as well as cognitive decline and autonomic dysfunction (Lassmann, 2018). (Lassmann, 2018).

[0008]

[0008] Without wishing to be bound by theory, disability progression across the MS spectrum may occur as a result of two simultaneous inflammatory mechanisms: active inflammation and chronic compartmental inflammation. Chronic compartmental inflammation, caused by the activation of microglia, is associated with the accumulation of ongoing disabilities. Chronic compartmental inflammation is responsible for the increase in disabilities that occur independent of relapses and disease activity and is characterized by demyelination and axonal loss (progression biology; Lassmann et al. 2019). Progressive forms of MS (PMS), including PPMS, are associated with the chronic and slow accumulation of T cells and B cells without leakage of the blood-brain barrier, causing subcortical demyelinating lesions in the cerebral cortex and cerebellar cortex, as well as the slow expansion of pre-existing lesions in the white matter, and it is thought to spread chronic inflammation to the chronic inflammation of the normally appearing white matter and gray matter (Lassmann 2018).

[0009]

[0009] In vitro cell-based experiments suggest that antagonism of BTK with fenebrutinib results in inhibition of BCR-dependent B cell proliferation and a decrease in inflammatory cytokine production from myeloid cells (including tumor necrosis factor-α [TNF-α]). Myeloid effector functions are induced in vitro by immune complexes, and the increasing evidence suggests that B cells and myeloid / microglia may be central to the immunopathology of MS. BTK inhibition directly affects myeloid cells. As a result, there is a possibility of BTK inhibition affecting microglia, which are related to the pathological features of MS disease progression independent of relapses.

[0010]

[0010] While there are many currently available drugs that target the pathological inflammatory mechanisms related to relapse and relapse-associated exacerbations, only one is currently indicated for PPMS. As a result, the prominent features of progression of disability in all forms of MS remain unaddressed, and treatments that could halt or delay the progression of MS represent a serious unmet medical need. [Overview of the project]

[0011]

[0011] This specification provides methods and uses of fenebrutinib, a BTK inhibitor, or pharmaceutically acceptable salts of fenebrutinib, for the treatment of primary progressive multiple sclerosis (PPMS).

[0012]

[0012] E1. In a first embodiment (Embodiment 1, "E1"), the Specified provides a method for treating primary progressive multiple sclerosis (PPMS) in a subject requiring the treatment thereof, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0013]

[0013] E2. The method according to E1, further comprising evaluating the progression of the disability in the subject.

[0014]

[0014] E3. The method according to E2, wherein the progression of disability is assessed using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof.

[0015]

[0015] E4. A method according to E2 or E3, comprising evaluating the onset of complex disability progression (cCDP12) observed over 12 weeks, wherein the onset of cCDP12 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method comprising at least one progressive event selected from the group consisting of the following, wherein the progressive event is confirmed at least 12 weeks after the initial progression.

[0016]

[0016] A method for reducing the risk of experiencing cCDP12 in a subject having E4a.PPMS, comprising administering to the subject about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily.

[0017]

[0017] The method of E4a, wherein E4b.cCDP12 comprises the occurrence of a first progression event in a subject after initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, the progression event being confirmed at least 12 weeks after the first progression of disability.

[0018]

[0018] A method for reducing the time to onset of cCDP12 in a subject having E4c.PPMS, comprising administering approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof to the subject, wherein the time to onset of cCDP12 includes the period from before the commencement of administration of fenebrutinib or a pharmaceutically acceptable salt thereof to the first occurrence of a progression event, and the progression event is confirmed at least 12 weeks after the first progression of the disability.

[0019]

[0019] E4d. The following is the progression of events: (a) An increase of ≥1.0 point from baseline in the EDSS score for subjects with a baseline Total Disability Scale (EDSS) score of ≤5.5, or an increase of ≥0.5 points (confirmed disability progression [CDP]) for subjects with a baseline EDSS score of >5.5. (b) A ≥20% increase from baseline in the 25-foot walking time measurement test (T25FWT), or (c) A ≥20% increase from baseline in the time taken to complete the 9-Hole Peg Test (9-HPT). The method described in E4b or E4c, which is one of the methods described.

[0020]

[0020] E5. The method according to any one of E2 to E4d, comprising evaluating the onset of disability progression (CDP12) observed over 12 weeks in a subject, wherein the onset of CDP12 includes an increase of at least 1.0 point from baseline in the EDSS score in a subject having a baseline EDSS score of 5.5 points or less, or an increase of at least 0.5 points from baseline in the EDSS score in a subject having a baseline EDSS score greater than 5.5 points, and the progression of EDSS is observed at least 12 weeks after the first progression.

[0021]

[0021] E6. A method according to any one of E2 to E5, comprising evaluating the onset of compound disability progression (cCDP24) observed over 24 weeks, wherein the onset of cCDP24 is: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method comprising at least one progressive event selected from the group consisting of the following, wherein the progressive event is confirmed at least 24 weeks after the initial progression.

[0022]

[0022] E7. The method according to any one of E2 to E6, comprising evaluating the onset of disability progression (CDP24) observed over 24 weeks in subjects, wherein the onset of CDP24 includes an increase of at least 1.0 point from baseline in the EDSS score in subjects having a baseline EDSS score of 5.5 points or less, or an increase of at least 0.5 points from baseline in the EDSS score in subjects having a baseline EDSS score greater than 5.5 points, and the progression of EDSS is observed at least 24 weeks after the first progression.

[0023]

[0023] E8. The time until the progress event in the subject increases, and the progress event is as follows: An increase of at least 1.0 point from the baseline EDSS score in subjects with a baseline EDSS score of 5.5 points or less; or An increase of at least 0.5 points from baseline in the EDSS score in subjects with a baseline EDSS score greater than 5.5 points. The method described in any one of E1 to E7.

[0024]

[0024] E9. The method according to any one of E1 to E8, wherein the time to the progression event in the subject is increased by at least 20% from baseline in the time to the progression event to complete 9-HPT.

[0025]

[0025] E10. The method according to any one of E1 to E9, wherein the time to a progressive event in the subject is increased, and the progressive event is an increase of at least 20% from baseline in T25FWT.

[0026]

[0026] E11. A method according to any one of E1 to E10, which increases the time to the onset of CDP12.

[0027]

[0027] E12. A method according to any one of E1 to E11 that increases the time to the onset of cCDP12.

[0028]

[0028] E13. A method according to any one of E1 to E12, which increases the time to the onset of CDP24.

[0029]

[0029] E14. A method according to any one of E1 to E13 that increases the time to the onset of cCDP24.

[0030]

[0030] E15. The method according to any one of E8 to E14, wherein the increase is compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0031]

[0031] E16. The method according to any one of E8 to E15, wherein the increase is compared to a subject having PPMS administered with an anti-CD20 antibody.

[0032]

[0032] E17. The method according to any one of E8 to E16, wherein the increase is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0033]

[0033] E18. A method according to any one of E1 to E17, wherein the progress of PPMS in the subject is delayed.

[0034]

[0034] E19. The method according to any one of E1 to E18, wherein the onset of at least one progressive event in the subject is delayed.

[0035]

[0035] E20. A method according to any one of E1 to E19, wherein the risk to a subject having at least one progressive event is reduced.

[0036]

[0036] E20a. The method according to any one of E4a, E4b, E4d through E7, or E20, wherein the risk is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0037]

[0037] E20b. The method according to any one of E4a, E4b, E4d to E7, E20, or E20a, wherein the risk reduction is compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0038]

[0038] E20c. The method according to any one of E4a, E4b, E4d to E7, or E20 to E20b, wherein the risk reduction is compared with a subject having PPMS administered with an anti-CD20 antibody.

[0039]

[0039] E21. A method for slowing the progression of PPMS in a subject in need thereof, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0040]

[0040] E22. A method for delaying the onset of at least one progressive event in a subject having PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0041]

[0041] E23. A method for reducing the risk of a subject having PPMS having at least one progressive event, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0042]

[0042] E24. The method according to any one of E18 to E23, wherein the progression of PPMS is assessed using MSIS-29, Neuro-QoL Upper Extremity, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

[0043]

[0043] E25. The method according to any one of E18 to E24, wherein the progress of PPMS is evaluated using CDP12, cCDP12, CDP24, or cCDP24.

[0044]

[0044] E26. A method for use of the PPMS progression, comprising an object experiencing at least one progression event.

[0045]

[0045] E27. At least one progressing event is: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method selected from the group consisting of E19 to E26.

[0046]

[0046] E28. The method according to any one of E19, E20, or E22 to E27, wherein at least one progression event includes an increase of at least 1.0 point from baseline in the EDSS score of a subject having a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score of a subject having a baseline EDSS score greater than 5.5 points.

[0047]

[0047] E29. The method according to any one of E19, E20, or E22 to E28, wherein the progressive event is confirmed at least 12 weeks after the first progression.

[0048]

[0048] E30. The method according to any one of E19, E20, or E22 to E28, wherein the progressive event is confirmed at least 24 weeks after the first progression.

[0049]

[0049] E31. The method according to any one of E18 to E30, which results in slower progression, delayed onset, or reduced risk compared to subjects having PPMS who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0050]

[0050] E32. The method according to any one of E18 to E31, wherein the progression is slowed, the onset is delayed, or the risk is reduced compared to a subject who has been administered an anti-CD20 antibody.

[0051]

[0051] E33. The method according to any one of E1 to E32, wherein the risk of PPMS progression being delayed in the subject, or at least one progression event being delayed in the subject, or having at least one progression event in the subject is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0052]

[0052] E34. A method for reducing impairment in a subject having PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0053]

[0053] E35. Reducing the obstacles is as follows: To reduce the psychological impact of MS; To increase upper limb function; To increase walking ability; To reduce fatigue; To improve the work situation; or To reduce the overall impression of MS severity; or any combination thereof The method described in E34, including the method described in E34.

[0054]

[0054] E36. The method according to any one of E1 to E35, wherein the subject has a reduction in one or more symptoms of PPMS after initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0055]

[0055] E37. A method according to any one of E1 to E36, which reduces one or more psychological effects of multiple sclerosis on a subject.

[0056]

[0056] E38. A method for slowing the progression of PPMS in a subject in need thereof, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the progression of PPMS is slowed to the following: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method comprising at least one progressive event selected from the group consisting of the following, wherein the progressive event is confirmed at least 24 weeks after the initial progression.

[0057]

[0057] E39. The method of E38, wherein the progression event is confirmed at least 12 weeks after the initial progression.

[0058]

[0058] E40. The method according to E38 or E39, wherein at least one progression event includes an increase of at least 1.0 point from baseline in the EDSS score of a subject having a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score of a subject having a baseline EDSS score greater than 5.5 points.

[0059]

[0059] E41. The method according to any one of E38 to E40, wherein progression is delayed compared to subjects having PPMS who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0060]

[0060] E42. The method according to any one of E38 to E41, wherein progression is delayed compared to subjects who were administered an anti-CD20 antibody.

[0061]

[0061] E43. The method according to any one of E38 to E42, wherein progress is delayed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0062]

[0062] E44. The method according to any one of E1 to E43, further comprising the step of measuring one or more clinical or laboratory endpoints in a subject to evaluate the effectiveness of treatment for PPMS.

[0063]

[0063] E45. The method according to E44, wherein one or more clinical or laboratory endpoints are selected from the group consisting of MSIS-29, Neuro-QoL Upper Extremity, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

[0064]

[0064] E46. The method according to E44 or E45, wherein the clinical or laboratory endpoint is measured 2 weeks, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0065]

[0065] E47. The method according to any one of E44 to E46, wherein a clinical or laboratory endpoint is measured 120 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0066]

[0066] E48. The method according to any one of E1 to E47, wherein the occurrence of one or more novel MS-related brain lesion types in a subject is evaluated after the subject starts administration of fenebrutinib or a pharmaceutically acceptable salt thereof, and one or more lesion types are selected from the group consisting of novel gadolinium-enhanced lesions (T1Gd+) on T1-weighted MRI, novel / enlarged T2-weighted lesions detected by MRI, or T1 low-intensity lesions detected by MRI.

[0067]

[0067] E49. The method according to E48, wherein one or more novel lesions in a subject are reduced compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, or a subject that has been administered an anti-CD20 antibody, or a combination thereof.

[0068]

[0068] E50. The method according to any one of E2 to E47, wherein the evaluation period is 120 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0069]

[0069] E51. The method according to any one of E1 to E50, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0070]

[0070] E52. The method according to any one of E1 to E51, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets or capsules.

[0071]

[0071] E53. The method according to any one of E1 to E52, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered twice daily in the form of two tablets, each tablet containing about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0072]

[0072] E54. The method according to any one of E1 to E53, wherein free fenebrutinib is administered.

[0073]

[0073] E55. A compound for use in a method of treating primary progressive multiple sclerosis (PPMS) in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0074]

[0074] E56. The compound described in E55, wherein the progression of the disorder in the subject is evaluated.

[0075]

[0075] E57. Compounds for use as described in E56, wherein the progression of disability is assessed using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof.

[0076]

[0076] E58. A compound for use as described in E56 or E57, wherein the onset of complex disorder progression (cCDP12) observed over 12 weeks is evaluated, and the onset of cCDP12 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method comprising at least one progressive event selected from the group consisting of the following, wherein the progressive event is confirmed at least 12 weeks after the initial progression.

[0077]

[0077] E58a. Compounds for use in reducing the risk of experiencing cCDP12 in subjects having PPMS, comprising administering to subjects approximately 200 mg of fenebrutinib twice daily or an equivalent amount of its pharmaceutically acceptable salt.

[0078]

[0078] E58b.cCDP12 is a compound for use according to E58a, comprising the occurrence of a first progression event in a subject after initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the progression event is confirmed at least 12 weeks after the first progression of disability.

[0079]

[0079] E58c. A compound for use in reducing the time to onset of cCDP12 in subjects having PPMS, comprising administering approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof to a subject, wherein the time to onset of cCDP12 includes the period from the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof to the first occurrence of a progression event, and the progression event is confirmed at least 12 weeks after the first progression of the disability.

[0080]

[0080] E58d. The following is the progression of events: (a) An increase of ≥1.0 point from baseline in the EDSS score for subjects with a baseline Total Disability Scale (EDSS) score of ≤5.5, or an increase of ≥0.5 points (confirmed disability progression [CDP]) for subjects with a baseline EDSS score of >5.5. (b) A ≥20% increase from baseline in the 25-foot walking time measurement test (T25FWT), or (c) A ≥20% increase from baseline in the time taken to complete the 9-Hole Peg Test (9-HPT). A compound for use, as described in E58a or E58b, which is one of the compounds described above.

[0081]

[0081] E59. A compound for use according to any one of E56 to E58d, wherein the method further comprises evaluating the onset of disability progression (CDP12) observed over 12 weeks in a subject, the onset of CDP12 comprising an increase of at least 1.0 point from baseline in the EDSS score in a subject having a baseline EDSS score of 5.5 points or less, or an increase of at least 0.5 points from baseline in the EDSS score in a subject having a baseline EDSS score greater than 5.5 points, and the progression of EDSS is observed at least 12 weeks after the first progression.

[0082]

[0082] A compound for use as described in any one of E60.E56 to E59, the method further comprising evaluating the onset of complex disability progression (cCDP24) confirmed over 24 weeks, wherein the onset of cCDP24 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A compound comprising at least one progression event selected from the group consisting of the following, wherein the progression event is confirmed at least 24 weeks after the first progression.

[0083]

[0083] E61. A compound for use according to any one of E56 to E60, wherein the method further comprises evaluating the onset of disability progression (CDP24) observed over 24 weeks in a subject, the onset of CDP24 comprising an increase of at least 1.0 point from baseline in the EDSS score in a subject having a baseline EDSS score of 5.5 points or less, or an increase of at least 0.5 points from baseline in the EDSS score in a subject having a baseline EDSS score greater than 5.5 points, and the progression of EDSS is observed at least 24 weeks after the first progression.

[0084]

[0084] E62. The time until the progress event increases, and the progress event is as follows: An increase of at least 1.0 point from the baseline EDSS score in subjects with a baseline EDSS score of 5.5 points or less; or An increase of at least 0.5 points from baseline in the EDSS score in subjects with a baseline EDSS score greater than 5.5 points. A compound for use as described in any one of E55 to E61.

[0085]

[0085] E63. A compound for use according to any one of E55 to E62, wherein the time to the progression event in the subject is increased, which is at least a 20% increase from baseline in the time to the progression event to complete 9-HPT.

[0086]

[0086] E64. A compound for use according to any one of E55 to E63, wherein the time to the progression event in the subject is increased, and the progression event is an increase of at least 20% from baseline in T25FWT.

[0087]

[0087] E65. Compounds for use according to any one of E55 to E64, which increase the time to the onset of CDP12.

[0088]

[0088] E66. Compounds for use according to any one of E55 to E65, which increase the time to onset of cCDP12.

[0089]

[0089] E67. A compound for use according to any one of E55 to E66, which increases the time to the onset of CDP24.

[0090]

[0090] E68. A compound for use according to any one of E55 to E67, which increases the time to onset of cCDP24.

[0091]

[0091] E69. A compound for use according to any one of E62 to E68, wherein the increase is compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0092]

[0092] E70. Compounds for use as described in any one of E62 to E69, which are compared to a subject having PPMS administered with an anti-CD20 antibody.

[0093]

[0093] E71. A compound for use according to any one of E62 to E70, wherein the increase is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0094]

[0094] E72. A compound for use according to any one of E55 to E71, which delays the progression of PPMS in the subject.

[0095]

[0095] E73. A compound for use according to any one of E55 to E72, wherein the onset of at least one progressive event is delayed.

[0096]

[0096] E74. A compound for use according to any one of E55 to E73, wherein the risk to a subject having at least one progressive event is reduced.

[0097]

[0097] E74a. A compound for use according to any one of E58a, E58b, E58d to E61, or E74, wherein the risk is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0098]

[0098] E74b. A compound for use according to any one of E58a, E58b, E58d to E61, E74, or E74a, wherein the risk reduction is compared with a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0099]

[0099] E74c. A compound for use according to any one of E58a, E58b, E58d to E61, or E74 to E74b, wherein the risk reduction is compared with a subject having PPMS administered with an anti-CD20 antibody.

[0100]

[0100] E75. A compound for use in a method for slowing the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0101]

[0101] E76. A compound for use in a method for delaying the onset of at least one progressive event in a subject having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0102]

[0102] E77. A compound for use in a method to reduce the risk of a subject having PPMS having at least one progressive event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0103]

[0103] E78. Compounds for use as described in any one of E72 to E77, wherein the progression of PPMS is evaluated using MSIS-29, Neuro-QoL Upper Extremity, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

[0104]

[0104] E79. Compounds for use as described in any one of E72 to E78, wherein the progress of PPMS is evaluated using CDP12, cCDP12, CDP24, or cCDP24.

[0105]

[0105] E80. Compounds for use according to E79, wherein the progression of PPMS includes at least one progression event.

[0106]

[0106] E81. At least one progressing event is: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A compound for use, selected from the group consisting of, one of the compounds described in E73 to E80.

[0107]

[0107] E82. A compound for use according to any one of E73 to E81, wherein at least one progression event includes an increase of at least 1.0 point from baseline in the EDSS score in a subject having a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score in a subject having a baseline EDSS score greater than 5.5 points.

[0108]

[0108] E83. A compound for use according to any one of E76 to E82, wherein the progression event is confirmed at least 12 weeks after the first progression.

[0109]

[0109] E84. A compound for use according to any one of E76 to E82, wherein the progression event is confirmed at least 24 weeks after the first progression.

[0110]

[0110] E85. A compound for use according to any one of E76 to E84, which slows the progression of PPMS, delays the onset of the disease, or reduces the risk compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0111]

[0111] E86. A compound for use according to any one of E76 to E85, which slows progression, delays onset, or reduces risk compared to subjects treated with an anti-CD20 antibody.

[0112]

[0112] E87. A compound for use according to any one of E55 to E86, which reduces the risk of delaying the progression of PPMS in a subject, delaying at least one progression event in a subject, or having at least one progression event in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0113]

[0113] E88. A compound for use in a method for reducing impairment in subjects having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0114]

[0114] E89. Reducing the number of problems is as follows: To reduce the psychological impact of MS; To increase upper limb function; To increase walking ability; To reduce fatigue; To improve the work situation; or To reduce the overall impression of MS severity; or any combination thereof Compounds for use, including those described in E88.

[0115]

[0115] E90. A compound for use according to any one of E55 to E89, in which the subject has a reduction in one or more symptoms of PPMS after initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0116]

[0116] E91. A compound for use according to any one of E55 to E90, which reduces one or more psychological effects of multiple sclerosis on a subject.

[0117]

[0117] E92. A compound for use in a method to slow the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the progression of PPMS is slowed to the following: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method comprising at least one progressive event selected from the group consisting of the following, wherein the progressive event is confirmed at least 24 weeks after the initial progression.

[0118]

[0118] E93. Compounds for use as described in E92, wherein the progression event is confirmed at least 12 weeks after the first progression.

[0119]

[0119] E94. A compound for use according to E92 or E93, wherein at least one progression event includes an increase of at least 1.0 point from baseline in the EDSS score in a subject having a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score in a subject having a baseline EDSS score greater than 5.5 points.

[0120]

[0120] E95. A compound for use according to any one of E92 to E94, wherein the progression of PPMS is delayed compared to subjects having PPMS that have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0121]

[0121] E96. A compound for use according to any one of E92 to E95, wherein progression is delayed compared to subjects administered with an anti-CD20 antibody.

[0122]

[0122] E97. A compound for use according to any one of E92 to E96, wherein the progression is delayed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

[0123]

[0123] E98. A compound for use according to any one of E55 to E97, further comprising the step of measuring one or more clinical or laboratory endpoints in a subject to evaluate the effectiveness of treating PPMS.

[0124]

[0124] E99. One or more clinical or laboratory endpoints selected from the group consisting of MSIS-29, Neuro-QoL Upper Extremity, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels, for use as described in E98.

[0125]

[0125] E100. Compounds for use as described in E98 or E99, wherein clinical or laboratory endpoints are measured 2 weeks, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0126]

[0126] E101. A compound for use as described in any one of E98 to E100, wherein a clinical or laboratory endpoint is measured 120 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0127]

[0127] E102. The development of one or more novel MS-related brain lesion types in a subject is evaluated after the subject initiates administration of fenebrutinib or a pharmaceutically acceptable salt thereof, and one or more lesion types are selected from the group consisting of novel gadolinium-enhanced lesions (T1Gd+) on T1-weighted MRI, novel / enlarged T2-weighted lesions detected by MRI, or T1 low-intensity lesions detected by MRI, according to any one of E55 to E101 for use.

[0128]

[0128] E103. A compound for use according to E102, wherein one or more novel lesions in a subject are reduced compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, or a subject that has been administered an anti-CD20 antibody, or a combination thereof.

[0129]

[0129] E104. A compound for use according to any one of E56 to E101, wherein the evaluation period is 120 weeks after the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0130]

[0130] E105. A compound for use according to any one of E55 to E104, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0131]

[0131] E106. A compound for use according to any one of E55 to E105, in which fenebrutinib or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets or capsules.

[0132]

[0132] E107. A compound for use according to E55 to E106, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered twice daily in the form of two tablets, each tablet containing approximately 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0133]

[0133] E108. A compound for use as described in any one of E54 to E107, wherein the compound is free fenebrutinib.

[0134]

[0134] E109. The Specified herein further provides compounds for use in the manufacture of pharmaceuticals for the method described in any of E1 to E54, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof.

[0135]

[0135] E110. A compound for use according to any one of E1 to E53 or any one of E54 to E108, wherein the subject having PPMS has a progressive disease from onset and has been in a progressive stage for at least 12 months prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0136]

[0136] E111. Before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, the subject has the following conditions: (a) One or more T2 high-intensity lesions characteristic of MS in one or more of the periventricular, cortical, or near-cortical brain regions, or infratentorial brain regions, (b) Two or more T2 high-intensity lesions of the spinal cord, (c) Presence of oligoclonal bands specific to cerebrospinal fluid A compound for use having at least two of the following, according to any one of E1 to E53 or the method described in E110, or any one of E54 to E108 or the method described in E110.

[0137]

[0137] E112. A compound for use according to any one of E1 to E53, E110, or E111, or according to any one of E54 to E108, E110, or E111, in which the subject has an EDSS score of 3.0 to 6.5 prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0138]

[0138] E113. The subject having PPMS is as follows: <60mL / min / 1.73m2 Estimated glomerular filtration rate (eGFR), >2×ULN ALT or AST, Total bilirubin of 1.5+ x ULN <9.5 g / dL hemoglobin, <100×10 9 Platelet count / L, or Abnormalities in one or more liver synthesis function tests: PT, INR, PTT, or albumin levels. A compound according to the method described in E1 to E53, or any one of E110 or E112, or a compound according to any one of E54 to E108, or any one of E110 to E112, which does not have one or more of the above.

[0139]

[0139] E114. The Specified further provides the method according to any one of E1 to E54 or E110 to E113, or the compounds according to any one of E55 to E108 or E110 to E113, wherein the subject is administered about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, while no potent CYP3A4 inhibitor is administered concurrently.

[0140]

[0140] E115. A method or compound for use as described in E114, wherein the potent CYP3A4 inhibitor is boceprevir, cobicistat, clarithromycin, danoprevir / ritonavir, elvitegravir / ritonavir, indinavir / ritonavir, itraconazole, idelalisib, ketoconazole, lopinavir / ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole.

[0141]

[0141] E116. The Specified further provides the method according to any one of E1 to E54 or E110 to E114, or the compounds according to any one of E55 to E108 or E110 to E114, wherein the subject is administered about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, without concurrent administration of a potent CYP3A4 inducer.

[0142]

[0142] E117. The method or compound according to E116, wherein the potent CYP3A4 inducer is apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, or hyperforin (St. John's wort).

[0143]

[0143] E118. The Specified further provides the method according to any one of E1 to E54 or E110 to E117, or the compounds according to any one of E55 to E108 or E110 to E114, wherein the subject is administered about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, without concurrent administration of a moderate CYP3A4 inducer.

[0144]

[0144] E119. The method or compound for use according to E118, wherein the moderate CYP3A4 inducer is bosentan, dexamethasone, efavirenz, etravirine, phenobarbital, primidone, phenobarbital, or rifabutin.

[0145]

[0145] E120. The Specified herein further provides a method according to any one of E1 to E54 or E110 to E119, wherein the subject is administered about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, without being concurrently administered a CYP3A substrate having a narrow therapeutic concentration range.

[0146]

[0146] E121. The method or compound for use according to E120, wherein the CYP3A4 substrate having a narrow therapeutic concentration range is alfentanil, astemizole, cyclosporine, cisapride, dihydroergotamine, ergotamine, everolimus, fentanil, pimozide, quinidine, sirolimus, terfenadine, or tacrolimus. [Brief explanation of the drawing]

[0147] [Figure 1]

[0147] Shows the comparative kinase selectivity of fenebrutinib compared to three other BTK inhibitors.

Mode for Carrying Out the Invention

[0148]

[0148] Methods and uses of fenebrutinib, or a pharmaceutically acceptable salt of fenebrutinib, for treating primary progressive multiple sclerosis (PPMS) are provided herein.

[0149]

[0149] Fenebrutinib is a compound of the formula: TIFF2026082835000001.tif53170, Also known by 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]pyrazina-6(1,4)-piperazina-2(2,4),3(3,5),5(2,5)-tripyridina-7(3)-oxetananeheptafan-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)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4’-bipyridin]-2’-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.

[0150]

[0150] Further names of the same compound may be known, for example, using different chemical naming schemes. The R enantiomer of the compound is (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.

[0151]

[0151] Fenebrutinib is a highly selective, orally administered, reversible inhibitor of BTK. U.S. Patent No. 8,716,274 (in full text incorporated herein by reference) discloses a class of heteroarylpyridine and aza-pyridone compounds useful for inhibiting BTK. International Publication No. 2017 / 148837 (in full text incorporated herein by reference) discloses solid forms and formulations of fenebrutinib or pharmaceutically acceptable salts thereof.

[0152] I. Definition

[0152] It should be understood that the terms used herein are for the purpose of describing specific embodiments and are not intended to limit them.

[0153]

[0153] In this specification and where used, including in the attached claims, the singular forms "a," "an," and "the" include the plural form unless the context clearly refers to another. Thus, for example, a reference to "a molecule" includes, optionally, a combination of two or more such molecules.

[0154]

[0154] As used herein, the term “about” means the normal range of error for each value which is readily known to those skilled in the art. References to values ​​or parameters “about” herein include embodiments for the value or parameter itself. In some embodiments, the term “about” means a range of plus or minus 10% for each value. In some embodiments, the term “about” means a range of plus or minus 5% for each value. In some embodiments, the term “about” means a range of plus or minus 2% for each value. In some embodiments, the term “about” means a range of plus or minus 1% for each value.

[0155]

[0155] The aspects and embodiments of the Disclosure described herein include the terms “including,” “consisting of,” and “essentially consisting of.”

[0156]

[0156] The term “pharmaceutical preparation” refers to a preparation that is in a form that enables the biological activity of the active ingredient and does not contain any additional ingredients that are unacceptably toxic to the subject to which the preparation is administered. In some embodiments, such preparations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those that can be reasonably administered to the target mammal in order to provide an effective amount of the active ingredient used.

[0157]

[0157] 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 include a decrease in the rate of disease progression, reduction or mitigation of symptoms, and remission or improvement of prognosis. In some embodiments, two or more such effects are achieved. In some embodiments, an individual is successfully “treated” if one or more symptoms associated with their disease or disorder are reduced, i.e., the disease is more resistant to the subject, or the rate of degeneration or decline, or the rate of onset of the disease or disorder is slowed or stopped, or the progression of the disease or disorder is slowed or stopped, or the final point of degeneration is less debilitating. For example, an individual is successfully “treated” if one or more symptoms associated with cancer are reduced or eliminated, in which case, but not limited to, a reduction in symptoms caused by the disease, an improvement in the quality of life of the diseased person, a reduction in the dose of other drugs required to treat the disease, and / or an extension of the individual’s survival time. The treatment of a particular disease or disorder may, in some embodiments, include certain clinical endpoints or other endpoints, such as those described in the examples provided herein, but not limited to.

[0158]

[0158] Some embodiments described herein refer to providing a certain dose of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. A method for calculating the corresponding amount of the pharmaceutically acceptable salt form of fenebrutinib, taking into account the difference in molecular weight between the free form of fenebrutinib and the salt form, will be obvious to those skilled in the art. For example, in some embodiments provided herein, a subject is administered about 400 mg of fenebrutinib (as two 200 mg doses) or a pharmaceutically acceptable salt thereof per day. When the pharmaceutically acceptable salt form is administered in such embodiments, the total amount of pharmaceutically acceptable salt of fenebrutinib administered per day is greater than 400 mg, but corresponds to about 400 mg of the free form of fenebrutinib, due to the salt form having a higher molecular weight than the free form of fenebrutinib.

[0159] For therapeutic purposes, “subject” refers to any animal classified as a mammal, including humans, domesticated animals, and zoo, sports, or pet animals, such as dogs, horses, cats, and cows. In some embodiments of the methods provided herein, the subject is human. In some embodiments, the subject is a patient.

[0160]

[0160] “Before administration commencement” may include, for example, the day before the actual administration but which is the same day when the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof is administered, within one week before the first administration, or within two weeks before the first administration, or within three weeks before the first administration, or within four weeks before the first administration, or within five weeks before the first administration, or within six weeks before the first administration, or within six weeks before the first administration, or between one day and 28 days before the first administration, or between 0 and 28 days before the first administration. In some embodiments, this period may also be called “baseline.” Thus, in some embodiments, baseline may include within one week before the administration of the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof, including the same day immediately preceding administration. In other embodiments, baseline may include within one month, or between 0 and 28 days, or between 6 weeks, before the first administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0161]

[0161] As used herein, the term “biomarker” refers to an indicator that can be detected in a sample, for example, for predicting, diagnosing, and / or prognosis. A biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g., multiple sclerosis) characterized by specific molecular, pathological, histological, and / or clinical features. In some embodiments, the biomarker is a gene. Biomarkers may include, but are not limited to, polynucleotides (e.g., DNA and / or RNA), polypeptides, polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrates, and / or glycolipid-based molecular markers. The “amount” or “level” of a biomarker associated with increased clinical benefit to an individual is a level detectable in a biological sample. These are known to those skilled in the art and can be measured by the methods disclosed herein. The expression level or amount of the biomarker being evaluated can, in some embodiments, be used to determine a response to treatment. In some embodiments, the expression level or amount of one or more biomarkers is associated with a particular response to treatment.

[0162]

[0162] As used herein, the term “sample” means a composition obtained from or derived from the subject and / or individual of interest, which contains cellular entities and / or other molecular entities characterized and / or identified based on, for example, physical, biochemical, chemical and / or physiological properties. For example, the phrase “disease sample” and its variations mean any sample obtained from the subject of interest, which is expected to contain or is known to contain characterized cellular and / or molecular entities. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts, such as homogenized tissue, tumor tissue, cell extracts, and combinations thereof. In some embodiments, the sample is a blood sample. In other embodiments, the sample is cerebrospinal fluid (CSF).

[0163]

[0163] "Tissue sample" or "cell sample" means a collection of similar cells obtained from the tissue of a subject or individual. Sources of tissue samples or cell samples may be solid tissue derived from fresh, frozen, and / or preserved organs, biopsies, and / or aspirates; blood or any blood component such as plasma; body fluids such as cerebrospinal fluid, amniotic fluid, ascites, or interstitial fluid; or cells derived from any stage of the subject's pregnancy or development. Tissue or cell samples may also be primary or cultured cells or cell lines. In some cases, tissue or cell samples may be obtained from diseased tissue / organ. Tissue or cell samples may contain compounds that are not naturally mixed with tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, and antibiotics.

[0164]

[0164] As used herein, “reference sample,” “reference cells,” “reference tissue,” “control sample,” “control cells,” or “control tissue” refers to a sample, cell, tissue, standard, or level used for comparison purposes. In one embodiment, the reference sample, reference cells, reference tissue, control sample, control cells, or control tissue are obtained from healthy and / or disease-free portions of the body (e.g., tissue or cells) of the same subject or individual. For example, healthy and / or disease-free cells or tissue are adjacent to diseased cells or tissue. In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the body of the same subject or individual, for example, a sample taken from the subject or individual before the initiation of a particular treatment (e.g., before the initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof). In yet another embodiment, the reference sample, reference cells, reference tissue, control sample, control cells, or control tissue are obtained from healthy and / or disease-free portions of the body (e.g., tissue or cells) of an individual other than the subject or individual. In yet another embodiment, the reference sample, reference cells, reference tissue, control sample, control cells, or control tissue is obtained from untreated tissue and / or cells of the body of an individual that is not the subject or individual.

[0165]

[0165] The Combined Disability Scale (EDSS) is a ClinRO scale for quantifying changes in disability levels over time in individuals with MS. The EDSS is based on a standard neurological examination that incorporates functional systems (visual, brainstem, pyramidal, cerebellar, sensory, gut and bladder, brain [or mental]) (assessed and then scored as Functional Systems Scores (FSS)) and gait (scored as a gait score). Each FSS is a standard clinical assessment scale ranging from 0 to 5 or 6, and the gait score is assessed from 0 to 12. 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 (dead) in 0.5-point increments (Kurtzke 1983; Kappos 2011). In some embodiments of the methods provided herein, sexual dysfunction and fatigue are not included in the EDSS score.

[0166]

[0166] The "9-Hole Peg Test" (9-HPT) is a quantitative measure of upper limb (arm and hand) function (Goodkin et al. 1988; Fischer et al. 2001). The test device consists of a container with nine pegs and a block with nine empty holes. The subject picks up each of the nine pegs one at a time and places them into the nine holes as quickly as possible. Once all pegs are in the holes, the subject removes the pegs one at a time again and returns them to the container. The total time taken to complete the task is recorded. Both the dominant and non-dominant hands are tested twice (two successfully completed trials of the dominant hand are immediately followed by two successfully completed trials of the non-dominant hand). The two trials for each hand are averaged, converted to the reciprocal of the average time for each hand, and the reciprocals of the two times are averaged. 9-HPT can be performed as described, for example, in the Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring Manual (Fischer et al., 2001). Significant changes in upper limb function may be indicated, for example, by a 20% deterioration in mean 9-HPT time from baseline.

[0167]

[0167] The 25-foot walk time measurement test (T25FWT) is a quantitative measure of mobility and leg function based on a time-limited 25-foot walk. Participants are instructed to start from one end of a clearly marked 25-foot course and to walk 25 feet as quickly and safely as possible, and the time it takes them from the start of the walk to the end of the 25 feet is measured. In some embodiments, the task is immediately repeated by having the participant walk the same distance back, and the times of both completed trials are averaged to generate a T25FWT score. Participants may use assistive devices (e.g., canes or wheelchairs) when performing the task. The T25FWT can be performed as described, for example, in the MSFC Administration and Scoring Manual (Fischer et al., 2001). A clinically significant change in mobility and leg function may be indicated, for example, by a 20% deterioration from baseline in the mean T25FWT time.

[0168]

[0168] The Symbol-Number Modality Test (SDMT) is a test used to assess the presence of cognitive impairment and / or changes in cognitive function over time and in response to treatment. The SDMT may be particularly sensitive to the slower information processing speed commonly seen in MS (Benedict et al. 2017). The SDMT includes a substitution task. Using a reference key, subjects have 90 seconds to pair specific digits with given geometric figures. Responses can be collected orally, and the number of correct responses is considered the SDMT score. A clinically significant change in cognitive processing may be indicated, for example, by a 4-point decrease in the SDMT score from baseline.

[0169]

[0169] The Columbia Suicide Severity Rating Scale (C-SSRS) is a tool used to assess a subject's lifetime suicidal tendencies and may be used to track suicide events through treatment or part thereof. Structured interviews elicit recollections of suicidal ideation, including the intensity of suicidal thoughts, behaviors, and actual / potentially lethal attempts. A “baseline” C-SSRS may include, for example, a C-SSRS collected before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. Such a C-SSRS may be compared to a subsequent C-SSRS collected, for example, after the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. Comparisons between different assessment periods (which may occur, for example, during a clinician's consultation) may, in some embodiments, be described as a “since last consultation” C-SSRS.

[0170]

[0170] The EQ-5D-5L is a validated, self-reported health status questionnaire that can be used to calculate a health status utility score for use in health economic analysis (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013). The EQ-5D-5L has two components: one is a health status profile consisting of five items that assess mobility, self-care, usual activity, pain / discomfort, and anxiety / depression; and the other is a visual analog scale (VAS) that measures health status. The EQ-5D-5L is designed to capture the current health status of a subject. Published weighting systems may allow for the creation of a single composite score for the subject's health status.

[0171]

[0171] The Multiple Sclerosis Impact Scale 29 Version 2 (MSIS-29, Version 2) is a 29-item participant-reported scale of the physical and psychological impacts of MS (Hobart et al. 2001). Participants are asked to rate the extent to which their functioning and well-being have been affected over the past 14 days on a four-point scale from "not affected at all" (1) to "affected very much" (4). The physical score is the sum of items 1-20, which is converted to a scale from 0 to 100. The psychological score is the sum of items 21-29, which is converted to a scale from 0 to 100. A higher score may indicate a greater impact from MS. A clinically significant impact is indicated by a change of at least 7.5 points on the psychological scale in MSIS-29 Version 1. In MSIS-29 Version 2, this level of change may also indicate a significant impact.

[0172]

[0172] The Multiple Sclerosis Walking Scale (MSWS-12) is a 12-item self-report scale that measures the impact of MS on an individual's walking ability over the past two weeks. Each item is scored on a 5-point Likert scale, and the total score is converted to a scale of 0 to 100, with a higher score indicating a greater impact of MS on walking ability.

[0173]

[0173] The "Quality of Life in Neurological Disorders, Upper Extremity" (Fine Motor Skills and Activities of Daily Living; Neuro-QoL, Upper Extremity) is a 20-item questionnaire used to assess upper extremity function, involving individuals with MS at each stage (Gershon et al. 2012). Items include assessments of dressing, cooking, eating, cleaning, and writing, with individuals rating their performance on a 5-point Likert scale from "without difficulty" (5) to "unable to do" (1). The scores for the items are totaled, multiplied by 20, divided by 20, and the number of unanswered items is subtracted. The score ranges from 20 to 100, with higher scores indicating better upper extremity function. According to the NINDS User Manual (2015), the score can be calculated as long as at least 50% of the items are answered.

[0174]

[0174] The PROMIS-FatigueMS is an eight-item scale developed as a measure of fatigue in individuals with MS (Cook et al. 2012), with a recall period of the past seven days. The scale includes a 5-point Likert scale that generates a score between 1 and 5 for each scored question. The total raw score is the sum of the values ​​for each scored question. The total raw score ranges from 8 to 40. The score can also be converted to a PROMIS T-score, with a mean of 50 and a standard deviation of 10. The T-score ranges from 34.7 to 81.3. A higher score is associated with greater fatigue.

[0175]

[0175] The Patient's Overall Impression of Change (PGI-C) is a single-item assessment of the subject's impression of the change in their MS symptoms compared to six months prior. Subjects respond on a 7-point Likert scale from "very good" (1) to "very bad" (7). The PGI-C is used as an anchor to determine clinically significant change in MSIS-29.

[0176]

[0176] The Patient's Overall Severity Index (PGI-S) is a single-item assessment of the subject's perception of the severity of their MS symptoms over the past seven days. Subjects respond using a 5-point Likert scale from "none" (1) to "very severe" (5). The PGI-S is used as an anchor to determine clinically significant changes in MSIS-29.

[0177]

[0177] The "Work Productivity and Activity Impairment: Multiple Sclerosis" (WPAI:MS) is a six-item scale. Participants estimate the amount of time their work and daily activities were affected by MS in the past seven days (Reilly et al. 1993). WPAI:MS assesses habitual absenteeism and "presenteeism," which describes the amount of time participants were present at work or in their activities, but whose health was considered to have negatively impacted their ability to perform at a normal level. A higher score indicates greater impairment in productivity.

[0178]

[0178] "Confirmed disability progression" (CDP) refers to an increase in the subject's EDSS score that persists over a specified period. This can be assessed, for example, by calculating the subject's EDSS score, determining that the score has increased compared to a previous score (which may be a baseline score taken before the subject started administration of fenebrutinib or a pharmaceutically acceptable salt thereof), and then determining that the score has continued to increase after a specified period has elapsed since the initial increase (for example, by re-evaluating and recalculating the subject). For example, confirmed disability progression at 12 weeks (CDP12) refers to an EDSS score that remains increased at least 12 weeks after the initial increase (for example, confirmed by recalculating the EDSS score at least 12 weeks after the initial increase). Confirmed disability progression at 24 weeks (CDP24) refers to an EDSS score that remains increased at least 24 weeks after the initial increase (for example, confirmed by recalculating the EDSS score at least 24 weeks after the initial increase). The initial increase may be compared to the baseline EDSS score (e.g., before initiation of fenebrutinib or a pharmaceutically acceptable salt thereof) or to a previous EDSS score that remained stable over time, such as at 12, 24, 36, 48, or 60 weeks. In some embodiments, CDP refers to an increase of ≥1.0 point from the baseline EDSS score in subjects with a baseline EDSS score of ≤5.5 points, or an increase of ≥0.5 points from the baseline EDSS score in subjects with a baseline EDSS score of >5.5 points. The time to CDP (e.g., time to CDP12 or CDP24) refers to the period from when the previous EDSS score was established (e.g., baseline EDSS score before initiation of fenebrutinib or a pharmaceutically acceptable salt thereof) until a sustained increase in the EDSS score is observed.

[0179]

[0179] The "Confirmed Composite Disability Progression" (cCDP) is a composite measure of disability progression using a combination of the EDSS, 9-HPT, and T25FWT. It assesses the progression of a subject's disability over a specific period of time, determined by the first occurrence of a progression event. Progression events may include: a CDP (e.g., an increase of ≥1.0 points from the baseline EDSS score in a subject with a baseline EDSS score of ≤5.5 points, or an increase of ≥0.5 points from the baseline EDSS score in a subject with a baseline EDSS score of >5.5 points); an increase of ≥20% from baseline in the time to complete the 9-Hole Peg Test (9-HPT); or an increase of ≥20% from baseline in the 25-Foot Walk Time Measurement Test (T25FWT), where the occurrence of a progression event is confirmed after a specific period of time has elapsed since the first occurrence. For example, a compound disability progression confirmed at 12 weeks (cCDP12) refers to the occurrence of at least one progression event at the initial time point, with the same progression event confirmed at least 12 weeks later (e.g., by reassessing the subject using the same test). A compound disability progression confirmed at 24 weeks (cCDP24) refers to the occurrence of at least one progression event in the initial period, with the same progression event confirmed at least 24 weeks later. The time to onset of a cCDP (e.g., time to onset of cCDP12 or cCDP24) refers to the period from when a previous assessment score was established (e.g., baseline score before initiation of fenebrutinib or a pharmaceutically acceptable salt thereof) until the first event is observed. While we do not wish to be constrained by theory, compared to endpoints based solely on the Integrated Disability Scale (EDSS), which focuses on lower limb function, cCDP12 requires at least one of the following: 1) an increase of ≥1.0 point in the EDSS score from a baseline (BL) score of ≤5.5 points, or an increase of ≥0.5 points from a BL score of >5.5 points (confirmed disability progression); 2) a 20% increase from the BL in the time to complete the 9-hole peg test; 3) a 20% increase from the BL in the 25-foot walking time measurement test. Therefore, cCDP12 is a more sensitive assessment of disability, especially in the early stages of the disease.The use of cCDP12 as a primary outcome may provide a clearer and more complete picture of disability progression or improvement than EDSS alone.

[0180] II. Treatment Methods

[0180] While we do not wish to be bound by theory, BTK inhibition leads to decreased B cell activation and proliferation. This may explain the impact on inflammatory pathways associated with MS disease activity. BTK inhibition also directly affects myeloid cells. Consequently, BTK inhibition may affect microglia, which are associated with the pathophysiology of MS disease progression unrelated to relapse.

[0181]

[0181] This specification provides a method for treating PPMS in a subject in need of it, by administering to the subject a daily dose of about 200 mg of fenebrutinib or a corresponding amount of a pharmaceutically acceptable salt thereof, in a total daily dose of about 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Further, a compound for use in a method for treating PPMS in a subject in need of it is provided, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof. Further embodiments provide a compound for use in the manufacture of a pharmacopoeia for the treatment of PPMS in a subject in need of it, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment comprises administering to the subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, treatment of PPMS is assessed using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof. In some embodiments, treatment of PPMS is assessed based on time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP), or time to onset of confirmed composite disability progression (e.g., 12-week or 24-week cCDP). For example, in some embodiments, treating subjects with PPMS by administering approximately 200 mg of fenebrutinib twice daily or an equivalent amount of its pharmaceutically acceptable salt results in a delay in EDSS progression (e.g., an increase of 0.5, 1.0, 1.5 or more points compared to baseline), a delay in 9-HPT time progression (by more than 20% compared to baseline), a delay in T25FWT time progression (by more than 20% compared to baseline), a delay in the onset of CDP12, a delay in the onset of CDP24, a delay in the onset of cCDP12, a delay in the onset of cCDP24, a delay in the onset of at least one progressive event, a reduction in the risk of having at least one progressive event, or a reduction in disability in subjects with PPMS.In other embodiments, the treatment of PPMS includes MSIS-29, Neuro-QoL Upper Extremity, and PROMIS-Fatigue. MS The assessment is based on MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels. For example, in some embodiments, treating a subject with PPMS includes delaying the progression of PPMS, which is assessed based on MSIS-29, Neuro-QoL Upper Extremity, PROMIS-Fatigue MSThe assessment is based on MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels, or on the onset of at least one progression event which may be described as CDP12, cCDP12, CDP24, or cCDP24. In some embodiments, treating PPMS includes delaying the progression of PPMS. In some embodiments, treating PPMS includes delaying the onset of at least one progression event in a subject. In some embodiments, treating PPMS includes reducing the risk in a subject experiencing at least one progression event. In some embodiments, treating PPMS means delaying progression or delaying the onset of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% (e.g., when assessed using T25FWT time, or 9-HPT time, or EDSS score, or CDP12, or cCDP12, or CDP24, or CDP24, etc.). In some embodiments, treating PPMS means delaying progression or delaying the onset of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% compared to another subject with PPMS (e.g., a comparator), including delaying the onset of at least one progression event in which the other subject has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the delay is at least 5%. In some embodiments, the delay is at least 10%. In some embodiments, the delay is at least 15%. In some embodiments, the delay is at least 20%. In some embodiments, the delay is at least 25%. In some embodiments, the delay is at least 30%. In some embodiments, the delay is at least 35%. In some embodiments, the other subject is administered an anti-CD20 antibody (such as a CD20-targeted cell-lysing antibody).In further embodiments, treating PPMS includes reducing the risk of a subject having at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the risk is reduced over a period of time, for example, over 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, or 120 weeks. In some embodiments, the risk is reduced compared to another subject having PPMS (e.g., a comparator) that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and, in some cases, has been administered an anti-CD20 antibody. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted cell-lytic antibody). In some embodiments, the risk is reduced by at least 5%. In some embodiments, the risk is reduced by at least 10%. In some embodiments, the risk is reduced by at least 15%. In some embodiments, the risk is reduced by at least 20%. In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 30%. In some embodiments, the risk is reduced by at least 35%. In some embodiments, treating PPMS includes an improvement of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% in the same PPMS metric (e.g., T25FWT time, or 9-HPT time, or EDSS score) compared to the same metric evaluated in the same subject before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement is compared to the same metric evaluated in the same subject within one week, or within 0 to 28 days, or within 6 weeks prior to initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.In other embodiments, treatment of PPMS includes an improvement of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 40% in a PPMS metric (e.g., T25FWT time, or 9-HPT time, or EDSS score) compared to the same metric evaluated in another subject with PPMS, the other subject has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement is at least 5%. In some embodiments, the improvement is at least 10%. In some embodiments, the improvement is at least 15%. In some embodiments, the improvement is at least 20%. In some embodiments, the improvement is at least 25%. In some embodiments, the improvement is at least 30%. In some embodiments, the improvement is at least 35%. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted cell-lytic antibody).

[0182]

[0182] The Specification further provides a method for treating (e.g., delaying) the progression of PPMS in a subject in need of it by administering to the subject a dose of about 200 mg twice daily of fenebrutinib or a corresponding amount of a pharmaceutically acceptable salt thereof, in a total daily dose of about 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Thus, the Specification further provides a method for treating (delaying) the progression of PPMS in a subject in need of it by administering to the subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof. Furthermore, the Specification provides a compound for use in a method for delaying the progression of PPMS in a subject in need of it, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof. Further embodiments provide a compound for use in the manufacture of a medicament for use in a method of treating (e.g., delaying) the progression of PPMS in a subject requiring such treatment, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the progression of PPMS is assessed using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof. In some embodiments, the progression of PPMS is assessed based on the time to onset of confirmed disability progression (e.g., 12-week or 24-week CDP), or the time to onset of confirmed composite disability progression (e.g., 12-week or 24-week cCDP). In some embodiments, the progress of PPMS is delayed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the progress is delayed by at least 5%. In some embodiments, the progress is delayed by at least 10%. In some embodiments, the progress is delayed by at least 15%.In some embodiments, progression is delayed by at least 20%. In some embodiments, progression is delayed by at least 25%. In some embodiments, progression is delayed by at least 30%. In some embodiments, progression is delayed by at least 35%. In some embodiments, progression is delayed when measured by the onset of cCDP12 (e.g., by increasing the time to the onset of cCDP12) or by the risk of cCDP12 (e.g., by reducing the risk of experiencing cCDP12 for a period of time). In some embodiments, the progression of PPMS is delayed compared to another subject with PPMS (e.g., a comparator), and the other subject is not administered fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted cytolytic antibody) and not a BTK inhibitor (e.g., fenebrutinib or a pharmaceutically acceptable salt thereof). In some embodiments, the total evaluation period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks. In some embodiments, the total evaluation period is at least 120 weeks, and for example, the progression of PPMS is delayed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% when evaluated over 120 weeks compared to another subject with PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered a CD20-targeted cytolytic antibody, in some cases. In some embodiments, the other subject is administered an anti-CD20 antibody (such as a CD20-targeted cytolytic antibody).

[0183]

[0183] In further embodiments, the Specified provides a method for reducing impairment in a subject having PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, in a total daily dose of about 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, a compound for use in a method for reducing impairment in a subject having PPMS is provided, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof. Further embodiments provide a compound for use in the manufacture of a pharmacopoeia for use in a method of reducing disability in a subject having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject a daily dose of approximately 400 mg of fenebrutinib or a corresponding amount of a pharmaceutically acceptable salt thereof. Reducing disability may include reducing the psychological effects of MS; increasing upper limb function; increasing walking ability; reducing fatigue; improving work performance; or reducing the overall impression of the severity of MS; or any combination thereof. Reducing disability may further include reducing one or more symptoms of PPMS, or reducing one or more physical effects of PPMS on the subject. Reducing disability (e.g., one or more symptoms or physical effects, or other embodiments as described herein) may include, for example, MSIS-29, Neuro-QoL Upper Extremity, PROMIS-Fatigue, as described herein. MSThe assessment may be performed using MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels. In some embodiments, one or more of 9-HPT, T25FWT, or EDSS are used. In some embodiments, methods of reducing the severity of the severity include subjects who can complete the T25FWT and / or 9-HPT more quickly, or a reduction in the EDSS score (e.g., closer to "normal"). In some embodiments, the severity of MSThis includes improvements in one or more PPMS metrics, such as those assessed using MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels. In some embodiments, the improvement is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% improvement in at least one PPMS metric (e.g., T25FWT time, or 9-HPT time, or EDSS score) compared to the same metric assessed in the same subject before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, two, three, four, five, or more metrics are improved, with each improvement level being independent (e.g., one metric improves by at least 10%, and another improves by at least 20%). In some embodiments, the improvement is at least 5%. In some embodiments, the improvement is at least 10%. In some embodiments, the improvement is at least 15%. In some embodiments, the improvement is at least 20%. In some embodiments, the improvement is at least 25%. In some embodiments, the improvement is at least 30%. In some embodiments, the improvement is at least 35%. In some embodiments, the improvement is compared to the same metric evaluated in the same subject within one week, or within 0 to 28 days, or within 6 weeks prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0184]

[0184] Further embodiments provide a method for delaying the onset of at least one progressive event in a subject having PPMS, comprising administering to the subject a dose of approximately 200 mg twice daily of fenebrutinib or a pharmaceutically acceptable salt thereof, in a total daily dose of approximately 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Furthermore, a compound for use in a method for delaying the onset of at least one progressive event in a subject having PPMS is provided, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject approximately 200 mg twice daily of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof, in a total daily dose of approximately 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Further embodiments provide a compound for use in the manufacture of a pharmaceutical for a method of delaying the onset of at least one progression event in a subject having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof. Progression events may include, for example, an increase from baseline in the time required to complete a 9-HPT, or an increase from baseline in the time required to complete a T25FWT, or an increase from baseline in the EDSS score. In some embodiments, the increase from baseline in the time required to complete a 9-HPT is an increase of at least 20% (e.g., 20%, 25%, 30%, 35%, etc.). In some embodiments, the increase from baseline in the time required to complete a T25FWT is an increase of at least 20% (e.g., 20%, 25%, 30%, 35%, etc.). In further embodiments, an increase in the EDSS score from baseline is defined as an increase of at least 1.0 (where the baseline is 5.5 points or less), or an increase of at least 0.5 points for subjects with a baseline score greater than 5.5 points.In some embodiments, a progression event is confirmed after a certain period following the initial progression, for example, at least 12 weeks or at least 24 weeks. In some embodiments, the baseline used to determine the progression event is the same metric (e.g., T25FWT, 9-HPT, EDSS, or a combination thereof) evaluated in the same subject within one week prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, or within 0 to 28 days, or within 6 weeks. In some embodiments, the use of a method, a compound for use, or a compound in the manufacture of a pharmaceutical product delays the onset of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the delay is at least 5%. In some embodiments, the delay is at least 10%. In some embodiments, the delay is at least 15%. In some embodiments, the delay is at least 20%. In some embodiments, the delay is at least 25%. In some embodiments, the delay is at least 25%. In some embodiments, the delay is at least 30%. In some embodiments, the delay is at least 35%. In some embodiments, the time to onset is delayed for another subject with PPMS (e.g., a comparator), and the other subject is not administered a BTK inhibitor (e.g., fenebrutinib or a pharmaceutically acceptable salt thereof). In some embodiments, the other subject is administered an anti-CD20 antibody (e.g., a CD20-targeted cell-lytic antibody) and is not administered a BTK inhibitor (e.g., fenebrutinib or a pharmaceutically acceptable salt thereof). In some embodiments, the total evaluation period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks.In one embodiment, the total evaluation period is at least 120 weeks, and the time to the onset of at least one progression event is delayed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% when evaluated over 120 weeks compared to another subject with PPMS that has not received a BTK inhibitor (e.g., fenebrutinib or a pharmaceutically acceptable salt thereof) and possibly has received an anti-CD20 antibody (e.g., a CD20-targeted cell-lytic antibody). In some embodiments, calculating the delay in the onset of at least one progression event may include, for example, calculating the additional time to the progression event in the subject receiving fenebrutinib or a pharmaceutically acceptable salt thereof compared to the subject that has not received fenebrutinib or a pharmaceutically acceptable salt thereof (and possibly has received an anti-CD20 antibody).

[0185]

[0185] Further provided herein are methods for reducing the risk of a subject having PPMS having at least one progressive event, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, in total daily amounts of about 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Further provided herein are compounds for use in methods for reducing the risk of a subject having PPMS having at least one progressive event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof. Further embodiments provide a compound for use in the manufacture of a pharmaceutical product to reduce the risk of a subject having PPMS having at least one progression event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the subject is administered about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof. Progression events may include, for example, an increase from baseline in the time required to complete a 9-HPT, or an increase from baseline in the time required to complete a T25FWT, or an increase from baseline in the EDSS score. In some embodiments, the increase from baseline in the time required to complete a 9-HPT is an increase of at least 20% (e.g., 20%, 25%, 30%, etc.). In some embodiments, the increase from baseline in the time required to complete a T25FWT is an increase of at least 20% (e.g., 20%, 25%, 30%, etc.). In further embodiments, an increase in the EDSS score from baseline is an increase of at least 1.0 (e.g., 1.0, 1.5, 2.0, etc.) (where the baseline is 5.5 points or less), or an increase of at least 0.5 points (e.g., 0.5, 1.0, 1.5, etc.) for subjects with a baseline score greater than 5.5 points.In some embodiments, a progression event is confirmed after a certain period following the first progression, for example, at least 12 weeks or at least 24 weeks (e.g., as CDP12, cCDP12, CDP24, or cCDP24). In some embodiments, the baseline used to determine the progression event is the same metric (e.g., T25FWT, 9-HPT, EDSS, or a combination thereof) evaluated in the same subject within one week prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, or within 0 to 28 days, or within 6 weeks. In some embodiments, the use of a method, a compound for use, or a compound in the manufacture of a pharmaceutical reduces the risk to a subject having PPMS with at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%. In some embodiments, the risk is reduced by at least 5%. In some embodiments, the risk is reduced by at least 10%. In some embodiments, the risk is reduced by at least 15%. In some embodiments, the risk is reduced by at least 20%. In some embodiments, the risk is reduced by at least 25%. In some embodiments, the risk is reduced by at least 30%. In some embodiments, the risk is reduced by at least 35%. In some embodiments, the risk of having at least one progression event includes reducing the risk of experiencing cCDP12 or reducing the risk of exacerbation due to EDSS. In some embodiments, the reduction of the risk of having at least one progression event is reduced for another subject having PPMS, and the other subject is not administered a BTK inhibitor (such as fenebrutinib or a pharmaceutically acceptable salt thereof). In some embodiments, the other subject is administered an anti-CD20 antibody (such as a CD20-targeted cell-lytic antibody) and is not administered a BTK inhibitor (such as fenebrutinib or a pharmaceutically acceptable salt thereof). In one embodiment, the total evaluation period is 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, or 120 weeks.In one embodiment, the total evaluation period is at least 120 weeks, and for example, subjects with PPMS who have been administered fenebrutinib or a pharmaceutically acceptable salt thereof have at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% lower risk of having at least one progression event over 120 weeks compared to another subject with PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and, in some cases, has been administered a CD20-targeted cytolytic antibody. Such a reduction in the risk of having at least one progression event can be calculated, for example, by calculating the rate of progression events (e.g., over 60 weeks or 120 weeks) in one or more subjects with PPMS who have been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and by comparing that rate with the rate of progression events in one or more subjects with PPMS who have not been administered fenebrutinib or a pharmaceutically acceptable salt thereof, and who have been administered, in some cases, an anti-CD20 antibody (such as a CD20-targeted cell-lytic antibody).

[0186]

[0186] Further herein is provided a method for increasing mobility in subjects having PPMS who require it, comprising administering to the subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof in a total daily dose of about 400 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. Thus, herein is provided a method for increasing mobility in subjects having PPMS who require it, by administering to the subject about 200 mg of fenebrutinib twice daily or a corresponding amount of a pharmaceutically acceptable salt thereof. Increased mobility in an object may include, for example, increased ability to walk, increased ability to run, increased ability to go up and down stairs, increased ability to stand, improved balance while walking or standing, increased distance the object can walk, decreased effort required to walk, decreased reliance on support when walking indoors and / or outdoors (e.g., cane, leaning on furniture, walker, etc.), decreased concentration required to walk, or increased uniformity / smoothness of walking, or any combination thereof. In some embodiments, one, two, or more of these aspects of mobility may be improved, but one or more may not. For example, increased mobility in an object may include increased ability to walk, but one or more other elements of mobility may not be improved. Such increases in mobility may be assessed, for example, using a questionnaire for the object. In some embodiments, increases in mobility, or one or more elements of increased mobility, as described herein, may be assessed using MSWS-12. In some embodiments, the increase in mobility is evaluated by comparing it to the mobility of the subject before the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., as assessed using MSWS-12).

[0187] In some embodiments provided herein, the progression of PPMS is MSIS-29, Neuro-QoL Upper Extremity, and PROMIS-Fatigue. MSThe progression of PPMS may be assessed by one or more clinical or laboratory endpoints selected from the group consisting of MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels. For example, in some embodiments, the progression of PPMS is assessed by one or more of EDSS, T25FWT, or 9-HPT. Furthermore, in some embodiments, the progression of PPMS is assessed by a sustained increase in one or more PPMS symptoms or signs, e.g., an increase sustained for at least 12 weeks (e.g., an increase confirmed to still be increasing at least 12 weeks after the initial observed increase), or an increase sustained for at least 24 weeks (e.g., an increase confirmed to still be increasing at least 24 weeks after the initial observed increase). In some embodiments, the progression of PPMS is assessed by cCDP or CDP, for example, cCDP-12, CDP-12, cCDP24, or CDP24, or any combination thereof. In some embodiments, the progression of PPMS is assessed by cCDP12. In some embodiments, the progression of PPMS is assessed by EDSS. In some embodiments, the risk of experiencing cCDP12 is reduced, or the time to onset of cCDP12 is increased, in combination with a reduced risk of experiencing CDP12, or in combination with an increased time to onset of CDP12. In some embodiments, the risk of experiencing cCDP12 is reduced, or the time to onset of cCDP12 is increased, in combination with a reduced risk of experiencing cCDP24, or in combination with an increased time to onset of cCDP24. In further embodiments, the risk of experiencing cCDP12 is reduced by combining the reduction of the risk of experiencing CDP12 and the reduction of the risk of experiencing cCDP24. In further embodiments, the time to onset of cCDP12 is increased by combining both increasing the time to onset of CDP12 and increasing the time to onset of cCDP24.

[0188]

[0188] In some embodiments described herein, the response of a subject administered with fenebrutinib or a pharmaceutically acceptable salt thereof may be compared to that of another subject administered with an antibody against CD20 (e.g., an anti-CD20 antibody). As used herein, an anti-CD20 antibody may include an antibody that binds to CD20, a cell surface antigen present on pre-B lymphocytes and mature B lymphocytes. In some embodiments, the antibody is a humanized monoclonal antibody against CD-expressing B cells. In some embodiments, when the anti-CD20 antibody binds to the cell surface of B lymphocytes, antibody-dependent cytolysis and complement-mediated lysis may occur. In some embodiments, the anti-CD20 antibody is a CD20-targeted cytolytic antibody. An example of such an antibody may include, for example, ocrelizumab. Ocrelizumab is a recombinant, humanized, glycosylated monoclonal IgG1 antibody that selectively targets and depletes CD20-expressing B cells.

[0189]

[0189] In some embodiments of the methods, compounds for use, or uses of compounds as described herein, about 200 mg of fenebrutinib or a corresponding amount of a pharmaceutically acceptable salt thereof is administered twice daily to a subject having PPMS, the subject having PPMS having a progressive disease from onset and being in the progressive stage for at least 12 months prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject having PPMS has one or more T2 high-intensity lesions in one or more of the periventricular, cortical or pericortical or subtentorial brain regions; two or more T2 high-intensity lesions in the spine; or the presence of oligoclonal bands specific to the cerebrospinal fluid. In some embodiments, the subject having PPMS has at least two of the following: one or more T2 high-intensity lesions in one or more of the periventricular, cortical or pericortical or subtentorial brain regions; two or more T2 high-intensity lesions in the spine; or the presence of oligoclonal bands specific to the cerebrospinal fluid. In further embodiments, subjects with PPMS have a progressive disease from onset and have been in the progressive stage for at least 12 months prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. The subjects also have at least two of the following: one or more T2 high-intensity lesions in one or more of the periventricular, cortical, or pericortical or subtentorial brain regions; two or more T2 high-intensity lesions in the spine; or the presence of cerebrospinal fluid-specific oligoclonal bands. T2 high-intensity lesions can be assessed, for example, by MRI. The presence of cerebrospinal fluid-specific oligoclonal bands can be assessed, for example, by lumbar puncture. In further embodiments, subjects with PPMS may have an EDSS score of 3.0 to 6.5 prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with PPMS are neurologically stable for at least 30 days prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.In some such embodiments, a method, compound for use, or use of a compound is for treating PPMS, treating (e.g., delaying) the progression of PPMS, reducing impairment, delaying the onset of at least one progression event, reducing the risk of having at least one progression event, increasing mobility, or increasing the time to the onset of cCDP12 in a subject having PPMS requiring such treatment, comprising administering to the subject 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof twice daily.

[0190]

[0190] In some embodiments of the methods, compounds for use, or uses of compounds as described herein, about 200 mg of fenebrutinib or a corresponding amount of a pharmaceutically acceptable salt thereof is administered twice daily to a subject having PPMS, the subject having PPMS does not have progressive multifocal leukoencephalopathy or has no history of progressive multifocal leukoencephalopathy. In some embodiments, the subject having PPMS has no history of cancer within 10 years prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject having PPMS has no hematological malignancies or solid tumors within 10 years prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject having PPMS is not immunosuppressed. Immunosuppression is, for example, a CD4 number < 250 / uL, or ANC < 1.5 × 10⁻¹⁰ 3It may contain / uL or serum IgG <4.6 g / L. In further embodiments, subjects having PPMS do not have other neurological disorders. Such other neurological disorders include, for example, a history of ischemic cerebrovascular disease (e.g., stroke, transient ischemic attack, spontaneous intracranial hemorrhage, or traumatic intracranial hemorrhage) or spinal cord ischemia; a history or known presence of CNS or spinal cord tumors (e.g., meningioma or glioma); a history or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency); a history or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy); or a history of inherited progressive CNS degenerative disorders (e.g., hereditary paraplegia, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke syndrome). In some embodiments, subjects with PPMS may have a history or known presence of systemic autoimmune disorders that could cause progressive neurological diseases (e.g., lupus, antiphospholipid syndrome, Sjögren's syndrome, Behçet's disease); a history or known presence of sarcoidosis; or a history of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression). In one embodiment, subjects with PPMS do not meet the criteria for Class III and Class IV congestive heart failure as described by the New York Heart Association.In further embodiments, subjects with PPMS do not have a history of ventricular arrhythmias or risk factors for ventricular arrhythmias such as long QT syndrome or other genetic risk factors (e.g., Brugada syndrome); structural heart disease; coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic tests, previous coronary artery bypass grafting, or coronary artery lesions with a diameter stenosis of >70% that have not regenerated or are unable to regenerate); clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia); a family history of sudden death of unknown cause; or genetic mutations of cardiac ion channels (e.g., congenital long QT syndrome). In some embodiments, subjects with PPMS are not concurrently administered systemic corticosteroids or immunosuppressants while taking fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with PPMS were not administered systemic corticosteroids within 4 weeks prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with PPMS were not administered IV Ig or plasmapheresis within 12 weeks prior to the initiation of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with PPMS did not have abnormal hepatic synthesis function. In further embodiments, subjects having PPMS are not simultaneously administered one or more of the following while receiving fenebrutinib or a pharmaceutically acceptable salt thereof: CYP3A4 inhibitors, e.g., potent CYP3A4 inhibitors; or CYP3A4 inducers, e.g., potent or moderate CYP3A4 inducers; or CYP3A4 substrates; or fingolimod, siponimod, or ozanimod; or natulizumab; or dimethyl fumarate, interferon, or glatiramer acetate; or anti-CD20; or mycophenolate mofetil or methotrexate; or teriflunomide; or cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide.In other embodiments, subjects with PPMS are not administered a potent CYP3A4 inhibitor or a potent or moderate CYP3A4 inducer within 7 days or 5 drug elimination half-lives (whichever is longer) prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof; are not administered a CYP3A4 substrate with a narrow therapeutic concentration range within 7 days or 5 drug elimination half-lives (whichever is longer); are not administered anti-CD20 for 2 years; and are not administered fingolimod, siponimod, or ozanimod for 8 weeks. Not administered; natalizumab not administered within 6 months (if natalizumab has been administered for more than 1 year); dimethyl fumarate, interferon, or glatiramer acetate not administered within 4 weeks; mycophenolate mofetil or methotrexate not administered within 12 weeks; teriflunomide not administered unless the plasma concentration of teriflunomide is <0.02 mg / L; or cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide not administered. In further embodiments, subjects with PPMS have a phlegm <60 mL / min / 1.73 m. 2 Estimated glomerular filtration rate (eGFR); >2 × ULN ALT or AST; >1.5 × ULN total bilirubin; <9.5 g / dL hemoglobin; <100 × 10 9 Platelet count of ≥60 mL / L; or absence of one or more clinically significant abnormalities in one or more liver synthesis function tests (such as PT, INR, PTT, or albumin). In one embodiment, subjects with PPMS have a platelet count of ≥60 mL / min / 1.73 m². 2 Estimated glomerular filtration rate (eGFR); <2 × ULN ALT or AST; <1.5 × ULN total bilirubin; ≥9.5 g / dL hemoglobin; or >100 × 10 9Having a platelet count of / L. In some such embodiments, a method, compound for use, or use of a compound is for treating PPMS, treating (e.g., delaying) the progression of PPMS, reducing impairment, delaying the onset of at least one progression event, reducing the risk of having at least one progression event, increasing mobility, or increasing the time to the onset of cCDP12 in a subject having PPMS requiring such treatment, comprising administering to the subject 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof twice daily.

[0191] III. Pharmaceutical Compositions and Formulations

[0191] The Specified Publication also provides pharmaceutical compositions or formulations comprising fenebrutinib or a pharmaceutically acceptable salt thereof for use in the methods of treatment described herein (e.g., treating PPMS, delaying the progression of PPMS, etc.). In some embodiments, the pharmaceutical compositions and formulations further comprise one or more pharmaceutically acceptable carriers. International Publication No. 2017 / 148837 (in its entirety by reference) discloses formulations and dosage forms comprising fenebrutinib and a pharmaceutically acceptable salt thereof. In some embodiments, the formulations described in International Publication No. 2017 / 148837 are used to deliver fenebrutinib to a subject according to one or more of the methods provided herein.

[0192]

[0192] Fenebrutinib or a pharmaceutically acceptable salt thereof can be administered by any suitable means, including orally, parenterally, intrapulmonaryly, and intranasally, and can also be administered intrafocally if local treatment is desired. In some embodiments, oral administration is used.

[0193]

[0193] A pharmaceutically acceptable salt of fenebrutinib may be used in the manner described herein. As used herein, the term “pharmaceutically acceptable salt” means a salt of the active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found in the compounds described herein. When the compounds of this disclosure contain a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base in a pure or suitable inert solvent. Examples of pharmaceutically acceptable salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese triphosphate, potassium, sodium, zinc, and the like. pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, and tertiary amines, including arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, substituted amines such as triethylamine, trimethylamine, tripropylamine, tromethamine, cyclic amines, and natural amines. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in a pure or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.The present invention also includes salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galactulinic acid (see, for example, Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups that enable the compound to be converted into either a base-addition salt or an acid-addition salt.

[0194]

[0194] In some embodiments provided herein, the oral dose of fenebrutinib or a pharmaceutically acceptable salt thereof is administered as one or more tablets or capsules. For example, in some embodiments, about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily as one or more tablets, for example, as one, two, three, four, five, or six tablets twice daily. In other embodiments, about 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily as one or more capsules, for example, as one, two, three, four, five, or six capsules twice daily. Such capsules or tablets may, in some embodiments, contain approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, or approximately 225 mg of fenebrutinib or a pharmaceutically acceptable salt thereof. For example, in one embodiment, approximately 200 mg is administered twice daily to a subject requiring it, with each 200 mg dose being administered as one capsule containing approximately 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof, or as two capsules containing approximately 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In another embodiment, approximately 200 mg of fenebrutinib is administered twice daily (total dose approximately 400 mg per day), with each 200 mg being administered as two capsules containing approximately 100 mg of fenebrutinib. In other embodiments, approximately 200 mg is administered twice daily to subjects requiring it, with each 200 mg dose being administered as one tablet containing approximately 200 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof, or as two tablets containing approximately 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. In one embodiment, approximately 200 mg of fenebrutinib is administered twice daily (total dose of approximately 400 mg per day), with each 200 mg dose being administered as two tablets containing approximately 100 mg of fenebrutinib.Therefore, in some embodiments, the daily dose of fenebrutinib is approximately 400 mg per day, for example, approximately 360 mg to approximately 440 mg per day, or an equivalent amount of a pharmaceutically acceptable salt of fenebrutinib. In one embodiment, 400 mg of fenebrutinib is administered daily.

[0195]

[0195] Further embodiments provided herein offer a product or kit comprising fenebrutinib or a pharmaceutically acceptable salt thereof and a container. In some embodiments, a package insert is further provided, which includes instructions for using fenebrutinib or a pharmaceutically acceptable salt thereof. Suitable containers for the kit include, for example, bottles, boxes, blister packs, or a combination thereof (e.g., blister packs in a box). In some embodiments, the container holds the formulation, and a label on or associated with the container may display instructions for use. The product or kit may further include other materials desirable from a commercial and user standpoint, and include a package insert, which includes instructions for use.

[0196]

[0196] This specification is considered sufficient to enable those skilled in the art to carry out the invention. In addition to those shown and described herein, various modifications of the invention will be apparent to those skilled in the art from the above description and are included in the claims. All published papers, patents and patent applications referenced herein are incorporated herein by reference in their entirety for all purposes.

[0197] Enumerated embodiments

[0197] Embodiment 1. A method for treating primary progressive multiple sclerosis (PPMS) in a subject requiring the use thereof, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0198]

[0198] Embodiment 2. A method according to Embodiment 1, further comprising evaluating disability progression in a subject, wherein disability progression is evaluated using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof.

[0199]

[0199] Embodiment 3.1 further includes evaluating the onset of complex disability progression (cCDP12) observed over 12 weeks, wherein the onset of cCDP12 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline The method according to Embodiment 1 or 2, comprising at least one progression event selected from the group consisting of the following, wherein the progression event is confirmed at least 12 weeks after the first progression.

[0200]

[0200] Embodiment 4. The time to the progression event in the subject increases, and the progression event is as follows: An increase of at least 1.0 point from the baseline EDSS score in subjects with a baseline EDSS score of 5.5 points or less; or An increase of at least 0.5 points from baseline in the EDSS score in subjects with a baseline EDSS score greater than 5.5 points. The method according to any one of embodiments 1 to 3.

[0201]

[0201] Embodiment 5. The method according to any one of Embodiments 1 to 4, wherein the time to the progress event in the subject is increased, and the progress event is an increase of at least 20% from the baseline in the time to complete 9-HPT.

[0202]

[0202] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the time to the progression event in the subject is increased, and the progression event is an increase of at least 20% from the baseline in T25FWT.

[0203]

[0203] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the time to the onset of CDP12, cCDP12, CDP24, or cCDP24 is increased compared to a subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0204]

[0204] Embodiment 8. The method according to Embodiment 7, wherein a subject having PPMS who has not been administered fenebrutinib is administered an anti-CD20 antibody.

[0205]

[0205] Embodiment 9. The method according to any one of Embodiments 4 to 8, wherein the time to a progressive event or the time to the onset of symptoms is increased by at least 10%.

[0206]

[0206] Embodiment 10. A method for slowing the progression of PPMS in a subject in need thereof, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0207]

[0207] Embodiment 11. Progression of PPMS, MSIS-29, Neuro-QoL Upper Extremity, PROMIS-Fatigue MS The method according to Embodiment 10, which is evaluated using MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

[0208]

[0208] Embodiment 12. The method according to Embodiment 10 or 11, wherein the progression of PPMS includes at least one progression event.

[0209]

[0209] Embodiment 13. A method for delaying the onset of at least one progressive event in a subject having PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0210]

[0210] Embodiment 14. A method for reducing the risk of a subject having PPMS having at least one progressive event, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0211]

[0211] Embodiment 15. At least one progression event is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A method according to any one of embodiments 12 to 14, selected from the group consisting of the following.

[0212]

[0212] Embodiment 16. The method according to Embodiment 15, wherein the progression event is confirmed at least 12 weeks after the initial progression.

[0213]

[0213] Embodiment 17. The method according to any one of Embodiments 1 to 12, 15, or 16, wherein the progression of PPMS in a subject is delayed by at least 10% compared to another subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

[0214]

[0214] Embodiment 18. The method according to any one of Embodiments 13, 15, or 16, wherein the onset of at least one progressive event is delayed by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

[0215]

[0215] Embodiment 19. The method according to any one of Embodiments 1 to 16, wherein the risk to a subject having at least one progressive event is reduced by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

[0216]

[0216] Embodiment 20. A method for reducing impairment in a subject having PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0217]

[0217] Embodiment 21. Reducing the obstacles is as follows: To reduce the psychological impact of MS; To increase upper limb function; To increase walking ability; To reduce fatigue; To improve the work situation; or To reduce the overall impression of MS severity; or any combination thereof The method according to Embodiment 20, including the method described above.

[0218]

[0218] Embodiment 22. The method according to any one of Embodiments 1 to 21, wherein the subject has a reduction in one or more symptoms of PPMS after initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0219]

[0219] Embodiment 23. The method according to any one of Embodiments 1 to 22, further comprising the step of measuring one or more clinical or laboratory endpoints in a subject to evaluate the effectiveness of treatment for PPMS.

[0220]

[0220] Embodiment 24. One or more clinical or laboratory endpoints are the target MSIS-29, Neuro-QoL Upper Extremity, PROMIS-Fatigue MS The method according to Embodiment 23, selected from the group consisting of MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

[0221]

[0221] Embodiment 25. The method according to any one of Embodiments 1 to 24, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0222]

[0222] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets or capsules.

[0223]

[0223] Embodiment 27. The method according to any one of Embodiments 1 to 26, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered twice daily in the form of two tablets, each tablet containing about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0224]

[0224] Embodiment 28. The method according to any one of Embodiments 1 to 27, wherein free fenebrutinib is administered.

[0225]

[0225] Embodiment 29. A compound for use in a method for treating primary progressive multiple sclerosis (PPMS) in a subject requiring the use thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0226]

[0226] Embodiment 30. The compound for use according to Embodiment 29, wherein the method further comprises evaluating the progression of disability in a subject, the progression of disability being evaluated using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof.

[0227]

[0227] Embodiment 31.12 further includes evaluating the onset of complex disability progression (cCDP12) observed over 12 weeks, wherein the onset of cCDP12 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score for subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score for subjects with a baseline EDSS score greater than 5.5 points. (b) an increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A compound for use according to Embodiment 29 or 30, comprising at least one progression event selected from the group consisting of the following, wherein the progression event is confirmed at least 12 weeks after the first progression.

[0228]

[0228] Embodiment 32. The time until the progression event increases, and the progression event is as follows: An increase of at least 1.0 point from the baseline EDSS score in subjects with a baseline EDSS score of 5.5 points or less; or An increase of at least 0.5 points from baseline in the EDSS score in subjects with a baseline EDSS score greater than 5.5 points. A compound for use as described in any one of embodiments 29 to 31.

[0229]

[0229] Embodiment 33. A compound for use according to any one of Embodiments 29 to 32, wherein the time to the progression event is increased, and the progression event is at least a 20% increase from the baseline in the time to complete 9-HPT.

[0230]

[0230] Embodiment 34. A compound for use according to any one of Embodiments 29 to 33, wherein the time to the progression event is increased, and the progression event is an increase of at least 20% from baseline in T25FWT.

[0231]

[0231] Embodiment 35. A compound for use according to any one of Embodiments 29 to 34, which increases the time to onset of CDP12, cCDP12, CDP24, or cCDP24 compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0232]

[0232] Embodiment 36. The compound for use according to Embodiment 35, wherein a subject having PPMS who has not been administered fenebrutinib is administered an anti-CD20 antibody.

[0233]

[0233] Embodiment 37. A compound for use according to any one of Embodiments 32 to 36, wherein the time to progression or time to onset is increased by at least 10%.

[0234]

[0234] Embodiment 38. A compound for use in a method for slowing the progression of PPMS in a subject requiring it, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the compound comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0235]

[0235] Embodiment 39. The progression of PPMS is evaluated using MSIS-29, Neuro-QoL Upper Extremity, PROMIS-Fatigue MS , MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL level, and is the compound for use according to Embodiment 38

[0236]

[0236] Embodiment 40. The progression of PPMS includes at least one progression event, and is the compound for use according to Embodiment 38 or 39

[0237]

[0237] Embodiment 41. A compound for use in a method of delaying the onset of at least one progression event in a subject having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof

[0238]

[0238] Embodiment 42. A compound for use in a method of reducing the risk of a subject having PPMS with at least one progression event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof

[0239]

[0239] Embodiment 43. At least one progression event is as follows: (a) An increase of at least 1.0 point from baseline in the EDSS score in a subject having a baseline EDSS score of 5.5 or less; or an increase of at least 0.5 point from baseline in the EDSS score in a subject having a baseline EDSS score of greater than 5.5, (b) An increase of at least 20% from baseline in the time to complete 9-HPT, and (c) At least a 20% increase in T25FWT from baseline A compound for use, selected from the group consisting of, according to any one of embodiments 40 to 42.

[0240]

[0240] Embodiment 44. The compound for use according to Embodiment 43, wherein the progression event is confirmed at least 12 weeks after the first progression.

[0241]

[0241] Embodiment 45. A compound for use according to any one of Embodiments 38 to 40, 43, or 44, whose progression is delayed by at least 10% compared to another subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

[0242]

[0242] Embodiment 46. A compound for use according to any one of Embodiments 41, 43, or 44, wherein the onset of at least one progressive event is delayed by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

[0243]

[0243] Embodiment 47. A compound for use according to any one of Embodiments 42 to 44, wherein the risk of having at least one progressive event is reduced by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

[0244]

[0244] Embodiment 48. A compound for use according to any one of Embodiments 38 to 47, which slows the progression of PPMS, delays the onset of the disease, or reduces the risk compared to a subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0245]

[0245] Embodiment 49. A compound for use in a method for reducing impairment in a subject having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0246]

[0246] Embodiment 50. The following reduces the obstacles: To reduce the psychological impact of MS; To increase upper limb function; To increase walking ability; To reduce fatigue; To improve the work situation; or To reduce the overall impression of MS severity; or any combination thereof Compounds for use, including those described in Embodiment 49.

[0247]

[0247] Embodiment 51. A compound for use according to any one of Embodiments 29 to 50, wherein the subject has a reduction in one or more symptoms of PPMS after initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0248]

[0248] Embodiment 52. A compound for use according to any one of Embodiments 29 to 51, further comprising the step of measuring one or more clinical or laboratory endpoints in a subject to evaluate the effectiveness of treating PPMS.

[0249]

[0249] Embodiment 53. One or more clinical or laboratory endpoints are the target MSIS-29, Neuro-QoL Upper Extremity, PROMIS-Fatigue MS A compound for use as described in Embodiment 52, selected from the group consisting of MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL level.

[0250]

[0250] Embodiment 54. The compound for use according to any one of Embodiments 29 to 53, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0251]

[0251] Embodiment 55. The compound for use according to any one of Embodiments 29 to 54, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets or capsules.

[0252]

[0252] Embodiment 56. The compound for use according to any one of Embodiments 29 to 55, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered twice a day in the form of two tablets, and each tablet contains about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0253]

[0253] Embodiment 57. The compound for use according to any one of Embodiments 29 to 56, wherein free fenebrutinib is administered.

[0254]

[0254] Embodiment 58. The compound for use in the manufacture of a medicament for a method according to any one of Embodiments 1 to 28, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof.

Examples

[0255]

[0255] The present disclosure will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the invention. It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes may be suggested to those skilled in the art and are included within the spirit and scope of the present application and the claims.

[0256] Example 1: A multicenter, randomized, double-blind, double-dummy, parallel-group phase 3 trial to evaluate the efficacy and safety of fenebrutinib compared to ocrelizumab in adult patients with primary progressive multiple sclerosis.

[0256] This Phase 3 trial will investigate the efficacy and safety of fenebrutinib compared to ocrelizumab in adults with PPMS. The specific objectives and corresponding endpoints of this study are outlined below.

[0257] Research purpose Main efficacy objectives

[0257] The primary efficacy objective of this study is to evaluate the efficacy of fenebrutinib compared to ocrelizumab in patients with PPMS, regardless of adherence to randomized treatment, based on the following endpoints: • Time to cCDP12 onset (the time from baseline to the first occurrence of a progressive event according to one of the following three criteria, which must be confirmed at a regular check-up at least 12 weeks after the first disability progression): - An increase of ≥1.0 point from baseline in the EDSS score in patients with a baseline EDSS score of ≤5.5 points, or an increase of ≥0.5 points in patients with a baseline EDSS score of >5.5 points (confirmed disability progression [CDP]). - ≥20% increase in time to complete 9-HPT from baseline - An increase of ≥20% from baseline in T25FWT.

[0258] Second objective of effectiveness

[0258] The second efficacy objective of this study is to evaluate the efficacy of fenebrutinib treatment compared to ocrelizumab based on the following endpoint. The second endpoint does not reflect the order of statistical hierarchy: • Time to onset of complex 24-week CDP (cCDP24) • Time to onset of 12-week CDP (CDP12) (an increase of ≥1.0 point from baseline in the EDSS score for patients with a baseline EDSS score of ≤5.5 points, or an increase of ≥0.5 points for patients with a baseline EDSS score of >5.5 points) • Time to the onset of CDP (CDP24) at 24 weeks • Percentage change in total brain volume from week 24 to week 120 as assessed by MRI scans. • Changes from baseline in the physical effects of MS reported by patients at week 120 (measured by the Multiple Sclerosis Impact Scale, 29 items [MSIS-29] physical scale). • Time to the onset of a 4-point worsening of the Symbol-Number Modality Test (SDMT) score over 12 weeks.

[0259] Objectives of exploratory effectiveness

[0259] The purpose of this exploratory efficacy study is to evaluate the efficacy of fenebrutinib compared to ocrelizumab, and may include, but is not limited to, the following endpoints: • Percentage of patients whose SDMT worsened by 4 points ·below - Psychological effects of MS (MSIS-29 psychological scale) - Upper limb function (Quality of Life in Neurological Disorders [Neuro-QoL -TM ], Upper Extremity Function Form) - Walking (12-item Multiple Sclerosis Walking Scale [MSWS-12]) - Fatigue (Measurement information system of results reported by patients - Short form of fatigue in multiple sclerosis [PROMIS(registered trademark)-Fatigue) MS ]) - Work status (Work productivity and activity impairment [WPAI]: MS v2.0) - Overall impression of MS severity (Patient's overall impression of severity [PGI-S]) Patient-reported outcomes (PROs): Change from baseline and percentage of patients who experienced significant deterioration from baseline at 120 weeks. • Time to onset of a ≥20% increase in T25FWT observed within 12 weeks • Time to onset of ≥20% increase in 9-HPT observed within 12 weeks • Time to onset of a ≥20% increase in T25FWT observed within 24 weeks • Time to onset of ≥20% increase in 9-HPT observed within 24 weeks • Percentage of patients who reported a significant worsening of their MS physical effects (MSIS-29 physical scale) from baseline at week 120. • Percentage of patients who reported a significant worsening of the psychological impact of MS (MSIS-29 psychological scale) from baseline at week 120. • Brain MRI scan a Total number of new T1Gd+ lesions from baseline detected by MRI scan a Total number of new / expanding T2-weighted lesions detected by MRI scan a Total number of new T1 low-intensity lesions (black holes) detected from baseline • Percentage change in serum neurofilament light chain (NfL) levels from screening to week 120 • Percentage of patients without disability progression (cCDP12, cCDP24, CDP12, and CDP24) at week 120 and the clinical cutoff for the primary analysis. a In this study, screening MRI measurements are used as baseline measurements.

[0260] Safety objectives

[0260] The purpose of this study is to evaluate the safety of fenebrutinib compared to ocrelizumab based on the following endpoints: • Adverse events; serious adverse events; nature, frequency, timing, and severity of adverse events leading to discontinuation of research treatment. • Changes from baseline in the target vital signs • Change from baseline of the target ECG parameter • Changes from baseline in clinical laboratory results after administration of research-grade treatment. • Change from baseline on the Columbia Suicide Severity Scale (C-SSRS).

[0261] Pharmacokinetic objectives

[0261] The pharmacokinetic (PK) objective of this study is to characterize the PK profile of fenebrutinib based on the following endpoints: • Plasma concentrations of fenebrutinib at specific time points.

[0262]

[0262] Small PK samples are collected from all patients. However, to better characterize the pharmacokinetics of fenebrutinib in MS patients, more concentrated PK samples are collected from a small subset of patients.

[0263]

[0263] The objectives of this exploratory PK study are as follows: • The following endpoints: - Relationship between fenebrutinib plasma concentration and efficacy endpoints - Relationship between fenebrutinib plasma concentration and safety endpoints Based on this, evaluate the potential relationship between drug exposure and the efficacy and safety of fenebrutinib. • The following endpoints: - Relationship between selected covariates and fenebrutinib plasma concentration Based on this, evaluate the potential relationship between selected covariates and exposure to fenebrutinib.

[0264] Purpose of biomarkers

[0264] The exploratory biomarker objective of this study is to identify and / or evaluate biomarkers that can predict the response to fenebrutinib (i.e., predictive biomarkers), serve as early surrogates of efficacy, be associated with progression to more serious disease states (i.e., prognostic biomarkers), be associated with acquired resistance to fenebrutinib, be associated with susceptibility to adverse events, or potentially lead to improved monitoring or investigation of adverse events (i.e., safety biomarkers, including human leukocyte antigen [HLA] genotyping), provide evidence of fenebrutinib activity (i.e., pharmacodynamic [PD] biomarkers), or enhance knowledge and understanding of disease biology and drug safety, based on the following endpoints: • Relationship between baseline biomarkers in blood (serum and / or plasma and / or RNA) and efficacy, PK, or other biomarker endpoints • Relationship between changes in blood biomarkers (serum and / or plasma and / or RNA) from baseline to post-treatment sampling and efficacy, PK, or other biomarker endpoints • The relationship between genetics, including but not limited to HLA genotype, and efficacy, PK, or other biomarker endpoints.

[0265] The purpose of the usefulness of health status

[0265] The exploratory purpose of this study for the usefulness of health status is to evaluate the usefulness score of health status in patients treated with fenebrutinib based on the following endpoints: • Relationship between EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) index scores and clinical measurements that can support pharmacoeconomic modeling.

[0266] Detailed research design

[0266] This is a randomized, multicenter, double-blind, double-dummy, parallel-group Phase 3 trial to evaluate the efficacy and safety of fenebrutinib for disability progression in adult patients with PPMS. All eligible patients will be randomized in a 1:1 ratio through a voice-interactive system or a web-based response system to receive either daily oral fenebrutinib (or placebo) (200 mg twice daily [BID]) or IV ocrelizumab (or placebo) (600 mg every 24 weeks). Approximately 946 patients will be enrolled and recruited worldwide. Patients who discontinue the investigational drug or the trial early will not be replaced.

[0267]

[0267] This study consists of the following phases: screening (up to 4 weeks), double-blind treatment (DBT) phase, DBT safety follow-up (DBT-SFU) phase, optional open-label continued administration (OLE) phase, and OLE safety follow-up (OLE-SFU) phase.

[0268]

[0268] The study period varies from patient to patient as a result of the primary analysis triggered by the event.

[0269] Research design

[0269] This study consists of the following: • Screening phase, approximately 4 weeks • In the double-blind treatment (DBT) phase, patients are randomized in a 1:1 ratio to receive either 200 mg BID oral fenebrutinib or 600 mg IV ocrelizumab. • DBT Safety Follow-up (DBT-SFU) is available to patients who meet either of the following criteria: 1) remained in the study treatment at the end of the DBT phase but do not wish to participate in OLE, or 2) discontinued the study treatment but have less than 24 weeks of follow-up since the last ocrelizumab DBT infusion, or less than 8 weeks of follow-up since the last DBT fenebrutinib dose. Patients will be followed for safety for approximately 48 weeks. • An optional, open-label extension (OLE) phase becomes available to eligible patients if the primary analysis is positive. Patients will receive approximately 96 weeks of open-label fenebrutinib, but the OLE phase may be extended. • The OLE Safety Follow-up (OLE-SFU) phase is available to patients who discontinued OLE fenebrutinib early or who completed the OLE phase. Patients are followed for approximately 8 weeks for the OLE-SFU.

[0270]

[0270] The study period will vary from patient to patient as a result of the primary analysis triggered by the event. Patient safety will be monitored by the iDMC periodically for the initial safety assessment (iDMC-ISA) and throughout the DBT phase.

[0271] Screening stage

[0271] The screening phase will last approximately four weeks. Patients who fail the initial screening may be eligible for one re-screening opportunity (a total of two screenings per patient). The screening procedure includes collecting medical history, physical examination, complete neurological examination, EDSS score, 9-HPT, T25FWT, ECG, MRI scan, and blood and urine samples.

[0272] Double-blind treatment phase

[0272] The duration of the DBT phase is partially event-dependent. The primary analysis will be conducted when approximately 486 cCDP12 events have occurred and all patients have participated in the DBT phase for at least 120 weeks. The DBT phase will be considered complete when the results of the primary analysis are disclosed and the study becomes open-label in the field. If the predicted number of cCDP events (486) has not been reached when the last patient completes 120 weeks of the DBT phase due to a slower-than-expected rate of disability progression, the DBT phase will be extended until the required number of cCDP12 events occur to maintain statistical power for detecting differences in treatment. The DBT phase may exceed 120 weeks for the first group of patients enrolled in the study, based on the final length of the study's recruitment period.

[0273]

[0273] Patients who discontinue research treatment for any reason during the DBT phase will remain in the DBT phase but will not receive research treatment. These patients will continue to participate in DBT consultations as scheduled, but efficacy and safety evaluations will be omitted.

[0274]

[0274] Patients discontinuing research treatment during the DBT phase may, at the discretion of the patient and the investigator, initiate another disease-modifying therapy (DMT) after waiting at least 24 weeks from the last ocrelizumab / placebo DBT infusion or at least 8 weeks from the last DBT fenebrutinib / placebo dose, whichever is longer.

[0275]

[0275] Unplanned consultations to evaluate potential disease progression, new neurological symptoms, or safety events may occur at any time. Patients with new neurological symptoms suggestive of MS relapse or exacerbation should have EDSS, 9-HPT, and T25FWT performed by the principal investigator within 7 days of the onset of the new neurological symptoms.

[0276] Safety follow-up during the double-blind treatment phase

[0276] At the completion of the DBT phase, if a patient has either 1) remained in the study treatment at the end of the DBT phase but does not wish to participate in OLE, or 2) discontinued the DBT study treatment but has less than 24 weeks of follow-up since the last ocrelizumab DBT infusion or less than 8 weeks of follow-up since the last DBT fenebrutinib dose, the patient will enter a DBT-SFU for approximately 48 weeks. The patient will be followed for safety for approximately 48 weeks. If applicable, the patient may initiate another DMT at the discretion of the investigator and the patient at least 24 weeks after the last ocrelizumab DBT infusion or at least 8 weeks after the last DBT fenebrutinib dose.

[0277] Selective, open-label, and continued administration

[0277] At the end of the DBT phase (disclosure of DBT results and deblinding to the field), if the primary analysis and benefit-risk assessment of the use of fenebrutinib therapy are positive, an optional OLE phase is planned for eligible patients who have completed the DBT phase and, in the opinion of the investigator, may benefit from fenebrutinib therapy.

[0278]

[0278] Additional unscheduled consultations to evaluate potential disease progression, new neurological symptoms, or safety events may occur at any time. Patients with new neurological symptoms suggestive of MS relapse or exacerbation should have EDSS, 9-HPT, and T25FWT performed by the principal investigator (within 7 days of the onset of the new neurological symptoms).

[0279] Open-label continued administration and follow-up

[0279] Patients who discontinued OLE fenebrutinib early or completed the OLE phase will enter OLE-SFU. Patients will be followed for safety for approximately 8 weeks. During OLE-SFU, only safety evaluations will be collected. Laboratory and safety evaluations during the OLE-SFU phase will be conducted as outpatient visits at approximately 4-week intervals.

[0280] Patient group

[0280] Approximately 946 patients with PPMS will be enrolled in this study. Dynamic enrollment quotas can be added to ensure that the distribution of patients according to stratification factors is balanced across regions, screening EDSS scores, and the presence or absence of T1Gd+ at screening.

[0281] Eligibility Criteria

[0281] To be enrolled in the study, patients must meet the following criteria: • Signed informed consent form • The person must be between 18 and 65 years old when signing the informed consent form. • Ability to conform to research protocols • Diagnosis of PPMS according to the revised 2017 McDonald Criteria (Thompson et al. 2018): ○ A progressive disease from the onset. Comorbid relapses may occur due to PPMS. Therefore, clinical evidence from the principal investigator to the clinical trial sponsor is required to confirm the diagnosis of PPMS. ○ Disability progression (retroactive or predetermined) over a one-year period unrelated to clinical relapse, provided as a summary of clinical evidence from the principal investigator to the sponsor, must be confirmed over a period of at least 12 months prior to randomization.

[0282] In addition, two of the following criteria: ○ Documentary evidence (established by MRI scans of medical history) of one or more T2 high-intensity lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical, or near-cortical, or infratentorial brain regions. Documentary evidence of two or more T2 high-intensity lesions in the spinal cord (established by MRI scans in medical history) Documentary evidence of the presence of oligoclonal bands specific to cerebrospinal fluid (established by lumbar puncture during medical history). • EDSS score between 3.0 and 6.5 at the time of screening • For patients currently receiving proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs): Treatment will be administered at a stable dose during the screening period before the start of the study treatment, and this stable dose will be maintained throughout the study treatment. Patients must not initiate a PPI or H2RA within two weeks of randomization. • For patients with MS requiring symptomatic treatment (e.g., fanplidine, cannabis) and / or physiotherapy: Treatment will be conducted with a stable dose / regimen during the pre-initiation screening period for the investigational drug, and this stable dose / regimen will be maintained throughout the study treatment period. Patients must not initiate symptomatic treatment or physiotherapy for MS within four weeks of randomization. • Neurologically stable for at least 30 days prior to randomization and baseline assessment. • The ability to complete 9-HPT in 240 seconds with each hand. • Ability to perform T25FWT • For women of childbearing potential: During the treatment period and for 6 or 12 months after the last dose of the study drug (if applicable according to the local label for ocrelizumab), they must continue to practice abstinence (refrain from heterosexual intercourse) or agree to use contraception with a failure rate of <1% per year. During this same period, women must not donate eggs. Hormone contraception must be supplemented with a barrier method. For men: Continue to practice abstinence (refrain from heterosexual intercourse) or agree to use condoms and not provide sperm.

[0283] Exclusion criteria

[0282] Patients who meet any of the following criteria will be excluded from enrollment in the trial: • Known or suspected active infection at screening or baseline, or a major episode of infection requiring hospitalization or treatment with an IV antibiotic within 8 weeks prior to or during screening, or treatment with an oral antibiotic within 2 weeks prior to or during screening. • A medical history in which progressive multifocal leukoencephalopathy has been confirmed or is suspected. • A history of cancer, including hematological malignancies and solid tumors, within 10 years of screening. Basal cell carcinoma or squamous cell carcinoma of the skin that has been excised and deemed cured, and carcinoma in situ of the cervix that was treated with apparent success by curative therapy > 1 year prior to screening are not excluded. • Immunodeficiency conditions defined as one or more of the following: CD4 count <250 / μL, or <1.5 × 10⁻⁶ 3 ANC in μL, or serum IgG <4.6 g / L • Other known neurological disorders, including but not limited to the following: - A history of ischemic cerebrovascular disease (e.g., stroke, transient ischemic attack, spontaneous intracranial hemorrhage, or traumatic intracranial hemorrhage) or spinal cord ischemia. - History or known presence of CNS or spinal cord tumors (e.g., meningioma, glioma) - A history or known presence of a potential metabolic cause of myelopathy (e.g., untreated vitamin B12 deficiency) - A history or known presence of an infectious cause of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy) - History of inherited progressive CNS degenerative disorders (e.g., hereditary paraplegia, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke syndrome) - Neuromyelitis optica spectrum disorder - A history or known presence of systemic autoimmune disorders that may cause progressive neurological diseases (e.g., lupus, antiphospholipid syndrome, Sjögren's syndrome, Behçet's disease) - History or known presence of sarcoidosis - A history of severe, clinically significant brain or spinal cord injury (e.g., cerebral contusion, spinal cord compression). The principal investigator's opinion is that the patient should be excluded from participation if there is evidence of clinically significant cardiovascular (including arrhythmias or QTc prolongation), psychosis, pulmonary, renal, hepatic, endocrine (including uncontrolled diabetes, non-gallstone pancreatitis, or chronic pancreatitis), metabolic, or gastrointestinal (GI) disease. • Patients meeting the New York Heart Association Class III and Class IV criteria for congestive heart failure. • Screening of 12-lead ECGs showing clinically relevant abnormalities that could affect patient safety, or interpretation of study results including QT intervals >440ms indicated by at least two ECGs separated by >30 minutes, using Fridericia's formula. • Current treatment with drugs known to prolong the QT interval at a dose that has a clinically significant effect on QT, as determined by the principal investigator. • A history of ventricular arrhythmia or other risk factors for ventricular arrhythmia such as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome); structural heart disease; coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic tests, previous coronary artery bypass grafting, or coronary artery lesions with a diameter stenosis of >70% or less, where regeneration is not possible); clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia); family history of sudden death of unknown cause; or genetic mutations in cardiac ion channels (e.g., congenital long QT syndrome). • Comorbidities that may require chronic treatment with systemic corticosteroids or immunosuppressants during the research process • History of alcohol or other substance abuse within 12 months prior to screening • You are pregnant or breastfeeding, or you intend to become pregnant during the study or within 6 or 12 months after the last dose of the investigational drug (if applicable according to the local label of ocrelizumab). All women of childbearing age will undergo a serum pregnancy test during screening. A urine pregnancy test will be performed locally at a designated follow-up appointment. If the urine pregnancy test is positive, it will need to be confirmed by a serum pregnancy test (performed locally). • Positive screening test for active, latent, or poorly treated hepatitis B (as evidenced by any of the following): - Positive hepatitis B surface antigen - Positive hepatitis B core antibody [total HBcAb] and detectable hepatitis B virus DNA • Positive screening test for hepatitis C (positive hepatitis C antibody). Evidence of active, latent, or inadequately treated infection due to tuberculosis (TB) as defined below: - A positive QuantiFERON TB-Gold® (QFT) test is required at the time of screening or within three months prior to screening. If QFT is unavailable, a negative Mantoux purified protein derivative skin test (as defined by the Centers for Disease Control and Prevention guidelines) may be performed at the time of the screening consultation or within three months prior to screening and may be read topically. - Patients with a history of Bacille Calmette-Guerin vaccination should be screened using QFT testing only. - Uncertainty-based QFT testing needs to be repeated. - A positive QFT test or two consecutive inconclusive QFT results should be considered a definitive diagnostic TB test. - An uncertain QFT test and a subsequent negative QFT test should be considered as a negative diagnostic TB test. • Abnormalities in liver synthesis function tests (e.g., PT, INR, PTT, albumin) that the principal investigator deems clinically important. • History of hospitalization or blood transfusion for gastrointestinal bleeding • Known bleeding diathesis Symptoms that may affect oral drug absorption • A history of primary or secondary (non-drug-related) immunodeficiency, including a known history of HIV infection or IgG < 500 mg / dL, or currently active such immunodeficiency. Contraindications to essential premedication for infusion-related reactions (IRRs) (i.e., corticosteroids and antihistamines), including the following: - Uncontrolled psychosis due to corticosteroids - Antihistamine-induced angle-closure glaucoma • Inability to complete an MRI scan (including, but not limited to, pacemakers, cochlear implants, intracranial vascular clips, surgery within 6 weeks of joining the study, or coronary stents implanted within 8 weeks prior to the scheduled MRI scan time; contraindications to MRI scans), or contraindications to gadolinium administration. Lack of peripheral venous access • Previous treatments with bone marrow transplantation and hematopoietic stem cell transplantation • History of transplantation or anti-rejection therapy • Systemic corticosteroid therapy within 4 weeks prior to screening • In patients who have used systemic corticosteroids for MS prior to screening, the screening period may be extended. For a patient to be eligible, systemic corticosteroids must not be administered between screening and baseline. • Treatment with IV Ig or plasma exchange within 12 weeks prior to randomization • Sensitivity or intolerance to the components (including excipients) of fenebrutinib or ocrelizumab Influenza vaccination is permitted if a live vaccine or an inactivated live attenuated vaccine has been administered within 6 weeks prior to randomization. • The need for nonsteroidal anti-inflammatory drugs, aspirin, and other systemic anticoagulants (oral or injectable) or antiplatelet agents other than salicylates (aspirin is permitted up to 162 mg once daily). • Prior treatment with fenebrutinib or other Bruton's tyrosine kinase inhibitors for the indicated purpose. Treatment with the investigational drug (including high-dose biotin) or the investigational drug with a 5-month half-life (whichever is longer) within 24 weeks prior to screening, or treatment according to experimental procedures for MS (e.g., treatment for chronic cerebrospinal venous insufficiency). Requirements for prohibited concomitant medications • Prior use of B-cell targeted therapy (including alemtuzumab). Patients with a history of anti-CD20 therapy who have normal CD19+ B-cell levels at screening and baseline, as determined by screening and baseline results from the central laboratory of the study, may be eligible. • Prior use of fingolimod or other sphingosine-1-phosphate receptor modulators within 3 months of randomization a • Previous use of cladribine within 12 months of randomization a • Prior use of natalizumab within more than one year and within six months of randomization.a • Prior treatment with mycophenolate mofetil, methotrexate, mitoxantrone, dimethyl fumarate, glatiramer acetate, interferon, teriflunomide, or laquinimod within 3 months of randomization. a Patients previously treated with teriflunomide require an appropriate elimination protocol (follow local labeling). • Previous treatment with daclizumab, alemtuzumab, or cyclophosphamide • Prior treatment with other immunomodulatory or immunosuppressant agents not already listed above, which do not include the appropriate washout as described on the applicable local label. If the washout requirement is not described on the applicable local label, the washout period must be five times the drug's half-life. When determining the required washout time, the PD effect of previous medications should also be taken into consideration. a • Having one or more of the following test results: - <60mL / min / 1.73m 2 Estimated glomerular filtration rate (eGFR) (eGFR of 45-59 mL / min n / 1.73 m) 2 (This can be repeated in this case.) -> ALT or AST for 2×ULN (may be repeated for 2-3×ULN) - Total bilirubin levels greater than 1.5 × ULN (may be repeated in cases of 1.6-3 × ULN), except for patients with Gilbert's disease. - Hemoglobin <9.5 g / dL (may be repeated if 9-9.4 g / dL) - <100×10 9 Platelet count per L (80-100 x 10 9 (If / L, it can be repeated) - Abnormalities in liver synthesis function tests (e.g., PT, INR, PTT, albumin) that the principal investigator deems clinically important. aPatients screened for this study should not be withdrawn from treatment solely for the purpose of meeting eligibility for the trial. Patients discontinuing their current treatment for reasons other than medical ones should be specifically informed about their treatment options before deciding to participate in the study.

[0284] Eligibility Criteria for Open-Label Continued Administration

[0283] Patients who meet the following criteria will participate in the OLE stage: • Those who have completed the DBT phase of the study (remaining in the study treatment and not receiving other DMTs) and, in the opinion of the principal investigator, are likely to benefit from treatment with fenebrutinib. Those who can provide and accept written informed consent to participate in the OLE phase and conform to the research protocol. • For women of childbearing potential: During the treatment period and for at least 28 days after the last dose of fenebrutinib, they must either practice abstinence (refrain from heterosexual intercourse) or agree to use a method of contraception with a failure rate of <1% per year. During this same period, women must not donate eggs. For men: Continue to practice abstinence (refrain from heterosexual intercourse) or agree to use condoms and not provide sperm.

[0285] End of research

[0284] The end of this study is defined as the later of the date on which the last patient's last consultation (LPLV) occurred during the OLE phase, or the date on which the LPLV occurred during the OLE-SFU phase.

[0286] Length of the study

[0285] The duration of the DBT phase is approximately 225 weeks or approximately 4.7 years (assuming the last patient enrolled in the study is randomized after 122 weeks of recruitment + 120 weeks of DBT phase). The maximum duration of the study from the initial patient screening to the end of the study is expected to be approximately 370 weeks or approximately 7 years (assuming 122 weeks of recruitment + 120 weeks of DBT phase + 24 weeks of washout + 96 weeks of OLE fenebrutinib treatment + 8 weeks of OLE-SFU for the last patient enrolled in the study).

[0287]

[0286] Furthermore, the sponsor can decide at any time to terminate the research or extend the OLE period.

[0288] Investigational drug Fenebrutinib or placebo

[0287] The patient will take a total of 400 mg of fenebrutinib (or placebo) daily as two 100 mg tablets orally via BID. The patient will self-administer two 100 mg tablets in the morning and two 100 mg tablets in the evening. Fenebrutinib (or placebo) may be taken orally with or without food. Administration of the investigational drug must be staggered from the use of antacids (i.e., the investigational drug must be taken 2 hours before or 2 hours after antacid administration). The patient should be instructed not to take any missed doses with the next scheduled dose.

[0289]

[0288] For patients participating in the intensive PK sampling subgroup, the morning doses of fenebrutinib (or placebo) on days 1 and 15 are administered during the morning (mandatory) clinical examination while the patient is fasting. Patients should be instructed not to take any missed doses with the next scheduled dose.

[0290] Ocrelizumab or placebo

[0289] Patients receive 600 mg of ocrelizumab (or placebo) via IV infusion every 24 weeks. The initial dose of ocrelizumab (or placebo) is administered as two 300 mg IV infusions 14 days apart. Subsequent doses of ocrelizumab (or placebo) are administered as a single 600 mg IV infusion every 24 weeks. A minimum interval of 22 weeks must be maintained between each single infusion. Each 300 mg dose of ocrelizumab (or placebo) should be administered via IV infusion over approximately 2.5 hours. Each 600 mg dose of ocrelizumab should be administered via IV infusion over approximately 3.5 hours.

[0291]

[0290] All patients must receive mandatory prophylactic treatment with 100 mg of methylprednisolone administered by timed IV infusion, which must be completed approximately 30 minutes before the start of each ocrelizumab (or placebo) infusion. If methylprednisolone is contraindicated in a patient, an equivalent dose of an alternative steroid should be used as premedication before infusion. In addition, a mandatory oral or IV antihistamine (such as IV diphenhydramine 50 mg or an equivalent dose of an alternative) must be administered approximately 30–60 minutes before the start of each ocrelizumab (or placebo) infusion. Analgesics / antipyretics such as acetaminophen / paracetamol (1 g) may also be considered.

[0292] statistical methods Primary analysis

[0291] The primary efficacy endpoint of this clinical trial is time to the onset of cCDP12, defined as the time from baseline to the first cCDP12. Independent investigators at each study site will evaluate the components of cCDP (EDSS, 9-HPT, and T25FWT) for all patients at the site during screening, baseline, routine visits during the DBT phase, unscheduled visits, and treatment discontinuation visits. Independent investigators are not physicians responsible for patient care (i.e., researchers who treat patients).

[0293]

[0292] The time to the onset of cCDP12 in the fenebrutinib group and the ocrelizumab group will be compared and tested using a stratified log-rank test with the null and alternative hypotheses as follows. H0: There was no difference in the time to the onset of cCDP12 between the fenebrutinib group and the ocrelizumab group. H1: There is a difference in the time to the onset of cCDP12 between the fenebrutinib group and the ocrelizumab group.

[0294]

[0293] The proportion of patients with cCDP12 over time was estimated using the Kaplan-Meier method, and the overall hazard ratio was estimated using a stratified Cox proportional hazards model.

[0295]

[0294] Confirmation of cCDP requires specific complex components that resulted in an initial complex disability progression event. All assessments between the initial event and the confirmatory examination must meet the definition of the complex disability progression event to be confirmed. Assessments occurring within 30 days of relapse, as defined by the protocol, are not used to confirm initial disability progression. Patients who discontinue the investigational drug early will be asked to continue the assessments designated in the trial, and all efforts will be made to follow up on primary and secondary assessments at the next scheduled appointment. Regardless of whether the patient discontinued the investigational drug or whether the confirmatory examination occurred during the DBT phase, all initial disability progression events accompanied by a corresponding confirmatory examination at the next scheduled appointment will be considered for statistical analysis.

[0296] Determining the sample size

[0295] The purpose of this study is to estimate and test hypotheses regarding the effect of fenebrutinib on time from baseline to cCDP12 compared to ocrelizumab. Point estimates and interval estimates of the p-value and true hazard ratio are obtained.

[0297]

[0296] The sample size for this trial is based on a test of the null hypothesis that there is no difference between the control group and the experimental group. This study will enroll approximately 946 patients over an expected recruitment period of more than 122 weeks. The sample size for this study is derived from a primary efficacy analysis of cCDP12 and the following assumptions: • Two-group trial with the same duration as cCDP12 • Both sides Type I error = 0.05 • Time to cCDP12 following the exponential distribution of each group • 50% of patients in the control group experienced 12 cCDP events by week 120. The final analysis is based on approximately 486 cCDP12 events. When the true risk reduction rate is 25% (i.e., hazard ratio = 0.75), the detection power is approximately 89%. • By week 120, 20% of each group had discontinued the program.

[0298] Example 2: A multicenter, randomized, double-blind, double-dummy, parallel-group phase 3 trial to evaluate the efficacy and safety of fenebrutinib compared to ocrelizumab in adult patients with primary progressive multiple sclerosis.

[0297] This Phase 3 trial investigates the efficacy and safety of fenebrutinib compared to ocrelizumab in adults with PPMS. The specific objectives, corresponding endpoints, eligibility criteria, exclusion criteria, and other aspects of this study are as described in Example 1 above, with the following additions and / or modifications. • Primary efficacy objective: In evaluating the time to onset of cCDP12: All evaluations between the initial event and the confirmatory examination must meet the definition of a complex disability progression event to be confirmed. Evaluations occurring within 90 days of relapse, as defined by the protocol, are not used to confirm the initial disability progression. • Second objective of effectiveness: - Percentage change in total brain volume from week 24 as assessed by MRI scan - Changes from baseline in the physical effects of MS as reported by patients (measured by the Multiple Sclerosis Impact Scale, 29 items [MSIS29] physical scale). • Exploratory endpoints will be added: change from baseline and the percentage of patients who experienced significant worsening from baseline at week 120; and the overall impression of MS change (patient's impression of overall change). • For safety purposes, the change from baseline in the Columbia Suicide Severity Scale will be changed to the percentage of patients with suicidal ideation or suicidal behavior as assessed by the Columbia Suicide Severity Scale. Randomization is stratified according to the following criteria: - Global domain (US vs. non-US) - EDSS score (≤5.0 vs. >5.0) - MRI T1Gd+ (present or absent) at screening • Criteria for eligibility: - The patient may provide a signed informed consent form to participate, and this must be accepted. - Use a pre-baseline disability progression questionnaire to assess disability progression over one year, regardless of clinical relapse. ·Exclusion criteria: - Patients with a history of severe IRR (general terminology criteria for adverse event grade ≥ 4) and / or hypersensitivity reaction to ocrelizumab. - Gilbert's syndrome is a clinically important liver disease, and in the opinion of the principal investigator, it may deter patient participation. • A man who intends to have children during the study or 6 or 12 months after the last dose of the investigational drug (if applicable according to the local label of ocrelizumab) • The exclusion criteria for concomitant medications and / or previously administered medications have been updated to include the following: - Treatment with a potent CYP3A4 inhibitor, potent CYP3A4 inducer, 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 concentration range, within 7 days prior to randomization or with 5 drug elimination half-lives (whichever is longer). - Prior use of anti-CD20 drugs, including ocrelizumab, and discontinuation of treatment within 6 months of randomization were not motivated by safety concerns or lack of efficacy. - Prior use of fingolimod, siponimod, or ozanimod within 8 weeks of randomization. - Prior use of natalizumab more than one year ago and within six months of randomization - Prior treatment with dimethyl fumarate, interferon, or glatiramer acetate within 4 weeks of randomization. - Prior treatment with mycophenolate mofetil or methotrexate within 12 weeks of randomization - Prior treatment with teriflunomide, except for cases where it has been more than 24 months since screening or where the plasma concentration of teriflunomide was <0.02 mg / L at the time of screening. - Previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide • Pregnancy Testing: Before the 12th week, pregnancy tests will be performed at each scheduled clinic appointment. After the 12th week, women who may give birth will need to perform monthly home urine pregnancy tests in addition to the urine pregnancy tests performed at each scheduled clinic appointment. Urine pregnancy test kits will be provided to female patients at each scheduled clinic appointment. If a patient becomes pregnant during the study, the patient must immediately discontinue the investigational drug, inform the principal investigator, and be instructed to seek a scheduled consultation within 5 days of discovering the pregnancy. If a home urine pregnancy test is positive, it should preferably be confirmed by a serum pregnancy test from a central laboratory. Home pregnancy tests are not required more than 28 days after permanent discontinuation of the study treatment. If pregnancy is detected, it must be confirmed by a serum pregnancy test. If pregnancy is confirmed, the patient must permanently discontinue the investigational drug. • In the double-blind treatment (DBT) phase, patients are randomized in a 1:1 ratio to receive either 200 mg BID oral fenebrutinib (or placebo) or 600 mg IV ocrelizumab (or placebo). • During the DBT phase, semi-structured telephone interviews will be conducted every 6 weeks (±3 days) between study consultations starting from week 24. • Between study consultations from week 24 onward, semi-structured telephone interviews are conducted every 6 weeks (±3 days) during the OLE phase.

[0299] Prohibited treatments

[0298] Medication in the following categories must be prohibited for the longer of 7 days or 5 half-lives, from before the first dose of the investigational drug to the last dose of the investigational drug. • A potent CYP3A4 inhibitor • Strong or moderate CYP3A inducers

[0300]

[0299] The following medications should be prohibited during research treatment: • A CYP3A4 substrate with a narrow therapeutic concentration range.

[0301] Table 1 lists prohibited medications. This list is not exhaustive. TIFF2026082835000002.tif94170

[0302] Other prohibited treatments

[0300] As explained below, the following combination therapies are prohibited for patients in the DBT stage, OLE stage, and OLE-SFU stage who are continuing research treatment. • Clinical trial therapy (other than research treatments mandated by the protocol) • Any B-cell targeted therapy (e.g., rituximab, alemtuzumab, atacicept, belimumab, ofatumumab, or commercially available ocrelizumab) • BTK inhibitors (other than fenebrutinib) • Any other DMT for MS (including, but not limited to, high-dose biotin, cladribine, mitoxantrone, interferon, dimethyl fumarate and other fumarates, as well as fingolimod and other sphingosine-1-phosphate receptor modulators) • Nonsteroidal anti-inflammatory drugs, aspirin, and other systemic anticoagulants other than salicylates (oral or injectable) or antiplatelet agents (aspirin is permitted up to 162 mg once daily). • In examinations requiring PK sampling, the use of independent doses of acid-reducing agents (e.g., PPIs, H2RAs) is prohibited.

[0303]

[0301] For patients who have discontinued DBT treatment and DBT-SFU, the use of the following combination therapies during the DBT phase is prohibited, as described below: • Clinical trial therapy (other than research treatments mandated by the protocol).

[0304]

[0302] Caution is required when administering DMT after using fenebrutinib. There is insufficient available data regarding the risks associated with switching from fenebrutinib to other products.

[0305] Table 2 lists medications that may be administered concomitantly, but such administrations may involve specific precautions. This list is not exhaustive. TIFF2026082835000003.tif135170

[0306] Recurrence assessment

[0303] In this study, a relapse is defined as the occurrence of new or worsening neurological symptoms attributable to MS, preceded by at least 90 days of relatively stable neurological improvement. Symptoms must last for >24 hours and must not be attributable to confounding clinical factors (e.g., fever, infection, injury, side effects of concomitant medications). New or worsening neurological symptoms must be accompanied by objective neurological deterioration consistent with at least one increase: • Half a step (0.5 points) on the EDSS • 2 points for one of the selected FSS listed below • 1 point for every two or more of the selected FSS listed below.

[0307]

[0304] The change must affect one of the following selected FSS: pyramidal, gait, cerebellar, brainstem, sensation, or vision. Transient seizures, sexual dysfunction, fatigue, mood changes, or bladder or bowel emergency or incontinence are not sufficient to establish a relapse. Note that the following items do not need to be scored: sexual dysfunction and fatigue.

[0308] Example 3: Comparison of in vitro properties of BTK inhibitors

[0305] The in vitro characteristics of the three BTK inhibitors, fenebrutinib, evobrutinib, and trebrutinib, are summarized in Table 3. Evobrutinib and trebrutinib are covalent inhibitors, while fenebrutinib is a non-covalent inhibitor. The kinase selectivity of fenebrutinib, evobrutinib, and trebrutinib, as well as ibrutinib, a covalent BTK inhibitor, are shown in Figure 1.

[0309]

[0306] BTK Inhibition Ability (IC 50 The kinase selectivity of fenebrutinib (FEN), evobrutinib (EVO), and trebrutinib (TOL) was evaluated internally or using a commercially available panel of over 200 human kinases. FEN, TOL, and EVO were screened at 1 μM, and EVO was further screened at 10 μM. This was because EVO showed weaker BTK IC50 than FEN and TOL. 50 This is because it has the following properties. For all kinases that were inhibited by at least 50% in the initial screening at 1 or 10 μM, IC 50 The value was determined. IC 50 To demonstrate that the selectivity values ​​determined using these values ​​are related to the covalent inhibitors EVO and TOL, their covalent reactivity (or k inact / K iThe inactivation efficiency was measured by biochemical assays by monitoring in real time the competition between BTK and BMX and covalent inhibitors with fluorescent active site ligands. FEN's ability to block the activation of B cells (CD69) and basophils (CD63) was also tested in human whole blood. The rate of FEN release from the BTK-FEN complex was quantified by biochemical pre-incubation-dilution experiments. In this experiment, the rate constant k was used. off and residence time 1 / k off BTK activity was restored.

[0310]

[0307] FEN strongly inhibits BTK (IC 50 =2.3nM), TOL is IC 50 While BTK is inhibited at =1.5nM, EVO is far less effective (IC 50 (=32nM). In whole blood, FEN is found in B cells (CD69 IC). 50 =8nM) and basophils (CD63 IC) 50 It strongly blocks the activation of kinase IC50 (=31nM). In a kinase panel, FEN (1μM) inhibits only 3 / 286 off-target kinases by >50%, while TOL (1μM) inhibits 19 / 218 off-target kinases. EVO inhibits 3 / 221 off-target kinases at 1μM, but inhibits 18 / 218 kinases at 10μM. Kinase IC50 50 Based on the values, FEN is >130-fold selective for all 286 kinases tested, while EVO is <75-fold selective for Bmx (0.5×), TEC (2×), ErbB4 (10×), Blk (23×), and Flt3 (71×). TOL is <10-fold selective for BMX, BLK, ERBB4, TXK, and LCK, and inhibits 11 additional kinases (Src, Fgr, TEC, RIPK2, BRK, CSK, YES, ERBB2, EGFR, HCK, and SRM) with <100-fold selectivity. The differences in kinase selectivity between the tested compounds are further shown in Figure 1. Furthermore, the k of BMX vs BTK inact / K iThe covalent rate selectivity of EVO and TOL, as evaluated by their ratio (EVO=0.5, TOL=1), is the IC50 of these inhibitors against these kinases. 50 The selectivity (EVO=0.5, TOL=2) was found to be nearly equal. Finally, in the pre-incubation-dilution assay, the BTK·FEN complex showed high stability. FEN slowly dissociated from BTK and remained bound to BTK for 18.3 hours.

[0311] Table 3 summarizes the in vitro characteristics of fenebrutinib, evobrutinib, and trebrutinib. JPEG2026082835000004.jpg248170JPEG2026082835000005.jpg255170JPEG2026082835000006.jpg109170

[0312]

[0308] Unpublished kinase selectivity data were generally obtained following the procedure in Crawford, et al., J Med Chem 2018, 61: 2227-2245 (SI pp S31-S32). Unpublished covalent reaction (k inact / K i Data for BTK residence time were generally obtained using N-terminally His-tagged full-length recombinant human BTK, following the procedure of Schnute, et al., ACS Med Chem Lett 2018, 10: 80-85 (SI pp S29-S31). Data for BTK residence time were obtained following the procedure of Crawford, et al., J Med Chem 2018, 61: 2227-2245 (SI pp S43). Data for unpublished competitive binding kinetics were generally obtained using N-terminally His-tagged full-length recombinant human BTK, following the procedure of Schnute, et al., ACS Med Chem Lett 2018, 10: 80-85 (SI pp S29-S31). The effects of ibrutinib (another covalent BTK inhibitor) on B cell and basophil activation in human whole blood were also evaluated (CD63 IC). 50 nM = 171; CD69 IC 50nM = 12; Crawford, et al., J Med Chem 2018, 61: 2227-2245)。

Claims

1. A method for treating primary progressive multiple sclerosis (PPMS) in a subject requiring the treatment, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, further comprising evaluating disability progression in a subject, wherein disability progression is evaluated using the Total Disability Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof.

3. Further including the assessment of the onset of complex disability progression (cCDP12) observed over 12 weeks, the onset of cCDP12 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score of subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score of subjects with a baseline EDSS score greater than 5.5 points. (b) 9- An increase of at least 20% from baseline in the time to complete the HPT, (c) At least a 20% increase from baseline in T25FWT It includes at least one progressive event selected from the group consisting of, The method according to claim 1 or 2, wherein the progression event is confirmed at least 12 weeks after the initial progression.

4. The time to the progression event in the subject increases, and the progression event is as follows: An increase of at least 1.0 point in the EDSS score from baseline in subjects with a baseline EDSS score of 5.5 points or less; or An increase of at least 0.5 points from baseline in the EDSS score of subjects with a baseline EDSS score greater than 5.5 points. The method according to any one of claims 1 to 3.

5. The method according to any one of claims 1 to 4, wherein the time to the progress event in the subject is increased, and the progress event is at least a 20% increase from the baseline in the time to complete 9-HPT.

6. The method according to any one of claims 1 to 5, wherein the time to the progression event in the subject is increased, and the progression event is an increase of at least 20% from the baseline at T25FWT.

7. The method according to any one of claims 1 to 6, wherein the time to the onset of CDP12, cCDP12, CDP24, or cCDP24 is increased compared to a subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7, wherein a subject having PPMS who has not been administered fenebrutinib is administered an anti-CD20 antibody.

9. The method according to any one of claims 4 to 8, wherein the time to a progressive event or the time to the onset of symptoms is increased by at least 10%.

10. A method for slowing the progression of PPMS in a subject requiring it, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

11. The progression of PPMS is MSIS-29, Neuro-QoL Upper Extreme, and PROMIS-Fatigue. ＭＳ The method according to claim 10, which is evaluated using MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

12. The method according to claim 10 or 11, wherein the progression of PPMS includes at least one progression event.

13. A method for delaying the onset of at least one progressive event in a subject with PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

14. A method for reducing the risk of PPMS in a subject having at least one progressive event, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

15. At least one ongoing event is: (a) an increase of at least 1.0 point from baseline in the EDSS score of subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score of subjects with a baseline EDSS score greater than 5.5 points. (b) 9- An increase of at least 20% from baseline in the time to complete the HPT, (c) At least a 20% increase from baseline in T25FWT A method according to any one of claims 12 to 14, selected from the group consisting of the following.

16. The method according to claim 15, wherein the progression event is confirmed at least 12 weeks after the initial progression.

17. The method according to any one of claims 1 to 12, 15, or 16, wherein the progression of PPMS in a subject is delayed by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

18. The method according to any one of claims 13, 15, or 16, wherein the onset of at least one progressive event is delayed by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

19. The method according to any one of claims 1 to 16, wherein the risk for a subject having at least one progressive event is reduced by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

20. A method for reducing impairment in a subject with PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

21. Reducing the number of obstacles is as follows: Reducing the psychological impact of MS; To increase upper limb function; To increase walking ability; To reduce fatigue; To improve the work situation; Alternatively, reducing the overall impression of the severity of MS; or any combination thereof The method according to claim 20, including the method described in claim 20.

22. The method according to any one of claims 1 to 21, wherein the subject has a reduction in one or more symptoms of PPMS after initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

23. The method according to any one of claims 1 to 22, further comprising the step of measuring one or more clinical or laboratory endpoints in a subject to evaluate the effectiveness of treatment for PPMS.

24. One or more clinical or laboratory endpoints are included in the target MSIS-29, Neuro-QoL Upper Extremity, and PROMIS-Fatigue. ＭＳ The method according to claim 23, selected from the group consisting of MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

25. The method according to any one of claims 1 to 24, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

26. The method according to any one of claims 1 to 25, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets or capsules.

27. The method according to any one of claims 1 to 26, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered twice daily in the form of two tablets, each tablet comprising about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

28. The method according to any one of claims 1 to 27, wherein free fenebrutinib is administered.

29. A compound for use in a method of treating primary progressive multiple sclerosis (PPMS) in a subject requiring such treatment, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

30. The compound for use according to claim 29, wherein the method further comprises evaluating the progression of disability in a subject, the progression of disability being evaluated using the Total Disability Severity Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Walk Time Measurement Test (T25FWT), or any combination thereof.

31. Further including the assessment of the onset of complex disability progression (cCDP12) observed over 12 weeks, the onset of cCDP12 is as follows: (a) an increase of at least 1.0 point from baseline in the EDSS score of subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score of subjects with a baseline EDSS score greater than 5.5 points. (b) 9- An increase of at least 20% from baseline in the time to complete the HPT, (c) At least a 20% increase from baseline in T25FWT It includes at least one progressive event selected from the group consisting of, A compound for use according to claim 29 or 30, wherein the progression event is confirmed at least 12 weeks after the initial progression.

32. The time until the progress event increases, and the progress event is as follows: An increase of at least 1.0 point in the EDSS score from baseline in subjects with a baseline EDSS score of 5.5 points or less; or An increase of at least 0.5 points from baseline in the EDSS score of subjects with a baseline EDSS score greater than 5.5 points. A compound for use according to any one of claims 29 to 31.

33. A compound for use according to any one of claims 29 to 32, wherein the time to the progression event is increased, and the progression event is at least a 20% increase from the baseline in the time to complete 9-HPT.

34. A compound for use according to any one of claims 29 to 33, wherein the time to the progression event is increased, and the progression event is an increase of at least 20% from the baseline at T25FWT.

35. A compound for use according to any one of claims 29 to 34, which increases the time to onset of CDP12, cCDP12, CDP24, or cCDP24 compared to a subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

36. The compound for use according to claim 35, wherein a subject having PPMS who has not been administered fenebrutinib is administered an anti-CD20 antibody.

37. A compound for use according to any one of claims 32 to 36, which increases the time to progression or the time to onset of an event by at least 10%.

38. A compound for use in a method for slowing the progression of PPMS in subjects requiring it, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the compound comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

39. The progression of PPMS is MSIS-29, Neuro-QoL Upper Extreme, and PROMIS-Fatigue. ＭＳ A compound for use according to claim 38, which is evaluated using MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

40. A compound for use according to claim 38 or 39, wherein the progression of PPMS comprises at least one progression event.

41. A compound for use in a method for delaying the onset of at least one progressive event in a subject having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

42. A compound for use in a method to reduce the risk of a subject having PPMS with at least one progressive event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

43. At least one ongoing event is: (a) an increase of at least 1.0 point from baseline in the EDSS score of subjects with a baseline EDSS score of 5.5 points or less; or an increase of at least 0.5 points from baseline in the EDSS score of subjects with a baseline EDSS score greater than 5.5 points. (b) 9- An increase of at least 20% from baseline in the time to complete the HPT, (c) At least a 20% increase from baseline in T25FWT A compound for use according to any one of claims 40 to 42, selected from the group consisting of the following.

44. A compound for use according to claim 43, wherein the progression event is confirmed at least 12 weeks after the initial progression.

45. A compound for use according to any one of claims 38 to 40, 43, or 44, wherein the progression of the disease is delayed by at least 10% compared to another subject having PPMS that has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

46. A compound for use according to any one of claims 41, 43, or 44, wherein the onset of at least one progressive event is delayed by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

47. A compound for use according to any one of claims 42 to 44, wherein the risk of having at least one progressive event is reduced by at least 10% compared to another subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof and has been administered an anti-CD20 antibody.

48. A compound for use according to any one of claims 38 to 47, which slows the progression of PPMS, delays the onset of the disease, or reduces the risk compared to a subject having PPMS who has not been administered fenebrutinib or a pharmaceutically acceptable salt thereof.

49. A compound for use in a method for reducing impairment in subjects having PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to a subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

50. Reducing the number of obstacles is as follows: Reducing the psychological impact of MS; To increase upper limb function; To increase walking ability; To reduce fatigue; To improve the work situation; Alternatively, reducing the overall impression of the severity of MS; or any combination thereof A compound for use according to claim 49, comprising:

51. A compound for use according to any one of claims 29 to 50, wherein the subject has a reduction in one or more symptoms of PPMS after initiation of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

52. A compound for use according to any one of claims 29 to 51, further comprising the step of measuring one or more clinical or laboratory endpoints in a subject to evaluate the effectiveness of treating PPMS.

53. One or more clinical or laboratory endpoints are included in the target MSIS-29, Neuro-QoL Upper Extremity, and PROMIS-Fatigue. ＭＳ A compound for use according to claim 52, selected from the group consisting of MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels.

54. A compound for use according to any one of claims 29 to 53, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

55. A compound for use according to any one of claims 29 to 54, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in the form of one or more tablets or capsules.

56. A compound for use according to any one of claims 29 to 55, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered twice daily in the form of two tablets, each tablet containing about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

57. A compound for use according to any one of claims 29 to 56, wherein free fenebrutinib is administered.

58. A compound for use according to any one of claims 1 to 28, or according to any one of claims 29 to 57, wherein the subject having PPMS has a progressive disease from the onset and has been in a progressive stage for at least 12 months prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

59. Before initiating administration of fenebrutinib or a pharmaceutically acceptable salt thereof, the subject must meet the following criteria: (a) One or more T2 high-intensity lesions characteristic of MS in one or more of the periventricular, cortical or near-cortical brain regions, or infratentorial brain regions, (b) Two or more T2 high-intensity lesions of the spinal cord, (c) Presence of oligoclonal bands specific to cerebrospinal fluid A compound for use according to any one of claims 1 to 28 or 58, having at least two of the above.

60. A compound for use according to any one of claims 1 to 28, 58, or 59, or any one of claims 29 to 59, wherein the subject has an EDSS score of 3.0 to 6.5 prior to the initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

61. The subjects that have PPMS are as follows: <60mL / min / 1.73m ２ Estimated glomerular filtration rate (eGFR), > 2x ULN ALT or AST, Total bilirubin of 1.5 ULN <9.5 g / dL hemoglobin, <100 x 10 ９ / L platelet count, or Abnormalities in one or more liver synthesis function tests: PT, INR, PTT, or albumin levels. A compound for use according to any one of claims 1 to 28 or 58 to 60, which does not have one or more of the above.

62. A compound for use according to any one of claims 1 to 28 or 58 to 61, wherein the subject is administered approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, while no potent CYP3A4 inhibitor is administered concurrently.

63. A compound for use according to any one of claims 1 to 28 or 58 to 62, wherein the subject is administered approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, without concurrent administration of a potent CYP3A4 inducer.

64. A compound for use according to any one of claims 1 to 28 or 58 to 63, wherein the subject is administered approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, without concurrent administration of a moderate CYP3A4 inducer.

65. A compound for use according to any one of claims 1 to 28 or 58 to 64, wherein the subject is administered approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, without being simultaneously administered a CYP3A4 substrate having a narrow therapeutic concentration range.

66. A compound for use in the manufacture of a pharmaceutical product for the method of any one of claims 1 to 28 or 58 to 65, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof.

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