METHODS FOR TREATING PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS USING A BRUTON TYROSINE KINASE INHIBITOR

Abstract

Methods are provided herein for treating primary progressive multiple sclerosis (PPMS) in a subject in need, by administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

Description

METHODS FOR TREATING PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS USING A BRUTON TYROSINE KINASE INHIBITOR CROSS REFERENCE TO RELATED REQUESTS

[0001] The present application claims the benefit of the priority of US Provisional Application No. 63 / 051,756 filed on July 14, 2020, and US Provisional Application No. 62 / 982,872, filed on February 28, 2020 , the disclosures of which are incorporated herein by reference in their entirety. FIELD

[0002] The present disclosure relates to methods of treating primary progressive multiple sclerosis (PPMS) using a Bruton's tyrosine kinase (BTK) inhibitor. BACKGROUND

[0003] Bruton's Tyrosine Kinase (BTK): The discovery of the genetic basis for primary immunodeficiencies has been the source of new therapeutic targets in immunomodulatory treatments. In humans, mutations in the gene for Bruton's tyrosine kinase (BTK), which is located on the , 9:722-8; Conley ME, et al, Immunol Rev 2005, 203:216-34), and very low immunoglobulin levels due to a defect in B cell differentiation at the pro-B cell stage to pre -B that prevents the assembly of the B cell receptor complex (BCR) and immunoglobulin gene expression (Reth M, Nielsen P„ Adv Immunol 2014, 122:129-75. doi: 10.1016 / B978-0-12-800267- 4.00004-3). Affected male patients have a primary immune deficiency, X-linked agammaglobulinemia (XLA), and are susceptible to recurrent infections that begin shortly after birth. Patients with XLA can live relatively normal lives on standard intravenous (IV) immunoglobulin treatment, suggesting that BTK can be safely inhibited, especially in humans with established immune systems. IV immunoglobulin replacement therapy decreases the rate of infection, reduces hospitalization rates for patients with XLA, and significantly improved the long-term prognosis of these patients.

[0004] BTK is essential for the differentiation and activity of B lymphocytes during immune system ontogeny and normal adaptive immune responses. BTK is activated by phosphatidylinositol 3-kinase-dependent plasma membrane recruitment and phosphorylation on tyrosine Y551 by the Src family kinase Lyn. Autophosphorylation and activation also occurs at tyrosine Y223 in a BTK-specific manner. Once activated, BTK induces PLCy2- and Ca2+-dependent signaling, resulting in the activation of NF-κΒ- and NFAT-dependent pathways; this in turn produces cell activation and differentiation (Niiro H, Clark EA., Nat Rev Immunol 2002, 2:945-56). Furthermore, BTK is important in FceRI signaling in basophils and mast cells. BTK null mice have altered FccRI signaling, resulting in decreased histamine and inflammatory cytokine release (lyer AS, etal., J Bio Chem 2011,286:9503-13. doi: 10.1074 / jbc. M110.1656131).

[0005] Multiple sclerosis: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease of the CNS that affects approximately 900,000 people in the United States of America (Wallin et al. 2019) and 2.3 million worldwide (GBD 2016 Multiple Sclerosis Collaborators 2019). Primarily, it is a disease of young adults, with 70%-80% of patients having an age of onset (i.e., initial clinical presentation to a physician) between 20 and 40 years (Anderson et al. 1992; Noonan et al. . 2002), and has a sex bias influenced by the phenotype, where approximately up to 64%-70% of diagnosed patients are women (Anderson etal. 1992; Noonan etal. 2002).

[0006] MS is classified into three clinical phenotypes, one of which is primary progressive (PPMS). PPMS is further subdivided into active and non-active forms based on the presence or absence of disease activity, defined by the presence of clinical relapses and / or gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans. (T1Gd+) or new / enlarging T2-weighted lesions on MRI scan.

[0007] Although the mechanisms associated with disease progression are assumed to be present from the onset of the disease (Cree et al. 2019), the progression of clinical disability generally manifests later during the illness of a very probably due to the patient's degree of cognitive reserve. The symptomatic worsening associated with MS disability progression produces a slow and insidious loss of a patient's motor and sensory function, as well as cognitive decline and autonomic dysfunction (Lassmann, 2018).

[0008] Without wishing to be limited to one theory, the progression of disability across the MS spectrum may occur as a result of two concurrent inflammatory mechanisms: active inflammation and chronic compartmentalized inflammation. Chronic compartmentalized inflammation, which is driven by microglial activation, is associated with ongoing disability accumulation. Chronic compartmental inflammation is responsible for an increase in disability that occurs independently of relapses or disease activity and is characterized by demyelination and axonal loss (progression biology; Lassmann et al. 2019). Progressive forms of MS (PMS), which include PPMS, are associated with a slow, chronic accumulation of T cells and B cells without filtration of the blood-brain barrier, and are believed to create subpial demyelinated lesions in the cerebral and cerebellar cortex, as well as such as a slow expansion of pre-existing white matter lesions and diffuse chronic inflammation in normal-looking white and gray matter (Lassmann 2018).

[0009] In vitro cell-based experiments suggest that BTK antagonism with fenebrutinib results in inhibition of BCR-dependent B cell proliferation and a reduction in myeloid cell inflammatory cytokine production (including a necrosis factor tumor a [TNF-a]). Myeloid effector functions are triggered by immune complexes in vitro and increasing evidence suggests that B cells and myeloid / microglia may be central to MS immunopathology. Inhibition of BTK has direct effects on cells of the myeloid lineage. As a result, there is a potential for the inhibition of BTK affects microglia which is associated with the pathological hallmark of MS disease progression independent of relapse.

[0010] Although there are many drugs currently available that act on the pathological inflammatory mechanisms associated with relapses and worsening associated with relapse, only one is currently indicated for PPMS. As a result, the main feature of disability progression in all forms of MS remains to be fully addressed, and treatments that can stop or slow MS disease progression represent a serious unmet medical need. BRIEF DESCRIPTION OF THE DISCLOSURE

[0011] Provided herein are methods and uses of a BTK inhibitor, fenebrutinib or a pharmaceutically acceptable salt of fenebrutinib, for treating primary progressive multiple sclerosis (PPMS).

[0012] E1. In a first embodiment (embodiment 1, "The"), provided herein is a method of treating primary progressive multiple sclerosis (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.

[0013] E2. The E1 method, which also includes evaluating the progression of disability in the subject.

[0014] E3. The E2 method, where disability progression is assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT) or any combination of these.

[0015] E4. The method of E2 or E3, which comprises evaluating the occurrence of the composite 12-week confirmed disability progression (cCDP12), wherein the occurrence of cCDP12 comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT, and where the progression event is confirmed at least 12 weeks after initial progression.

[0016] E4a. A method of reducing the risk of experiencing cCDP12 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.

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

[0018] E4c. A method of reducing the time to the appearance of cCDP12 in a subject with PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice a day or an equivalent amount of a pharmaceutically acceptable salt thereof, wherein the time to the appearance cCDP12 occurrence comprises the period from before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof until the first occurrence of a progression event, where the progression event is confirmed at least 12 weeks after the initial disability progression .

[0019] E4d. The E4b or E4c method, where the progression event is one of: (a) an increase from baseline in the Expanded Disability Status Scale (EDSS) score of >1.0 point in a subject with a baseline EDSS score of <5.5 or an increase of >0.5 points in a subject with a baseline EDSS score of >5.5 (confirmed disability progression [CDP]); (b) >20% increase from baseline in the timed 25-foot walk test (T25FWT); or (c) >20% increase from baseline over time to completion of the 9-hole peg test (9-HPT).

[0020] E5. The method of any of E2 to E4d, comprising evaluating the onset of confirmed 12-week disability progression (CDP12) in the subject, wherein the onset of CDP12 comprises an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; and wherein EDSS progression is confirmed at least 12 weeks after initial progression.

[0021] E6. The method of any of E2 to E5, comprising evaluating the occurrence of composite 24-week confirmed disability progression (cCDP24), wherein the occurrence of cCDP24 comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 24 weeks after the initial progression.

[0022] E7. The method of any of E2 to E6, comprising evaluating the onset of confirmed 24-week disability progression (CDP24) in the subject, wherein the onset of CDP24 comprises an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; and wherein EDSS progression is confirmed at least 24 weeks after initial progression.

[0023] E8. The method of any of E1 to E7, wherein the time until a progression event in the subject increases, wherein the progression event is: an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

[0024] E9. The method of any of E1 to E8, wherein the time to a progression event in the subject is increased, wherein the progression event is an increase from baseline of at least 20% in the time to completion of the 9- HPT.

[0025] E10. The method of any of El to E9, wherein the time to a progression event in the subject is increased, wherein the progression event is an increase from baseline of at least 20% in T25FWT. ινΐΛ / a / zuzz / u i uo i □

[0026] E11. The method is any from E1 to E10, where the time until the appearance of CDP12 increases.

[0027] increases. E12. The method of any from E1 to E11, where the time until the appearance of cCDP12

[0028] increases. E13. The method of any from E1 to E12, where the time until the appearance of CDP24

[0029] increases. E14. The method of any from E1 to E13, where the time until the appearance of cCDP24

[0030] E15. The method of any of E8 to E14, wherein the increase is in comparison to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0031] E16. The method of any from E8 to E15, where the increase is in comparison to a subject with PPMS who is administered an anti-CD20 antibody.

[0032] E17. The method of any 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] E18. The method is from any of E1 to E17, where the progression of PPMS in the subject is slowed down.

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

[0035] E20. The method is any of E1 to E19, where the risk of the subject having at least one progression event is reduced.

[0036] E20a. The method of any of E4a, E4b, E4d to 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] E20b. The method of any of E4a, E4b, E4d to E7, E20, or E20a, wherein the risk reduction is compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0038] E20c. The method of any of E4a, E4b, E4d to E7 or E20 to E20b, where the risk reduction is in comparison to a subject with PPMS who is administered an anti-CD20 antibody.

[0039] E21. A method of 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] E22. A method of delaying the onset of at least one progression event in a subject with PPMS, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice per day or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0041] E23. A method of reducing the risk of a subject with PPMS having at least one progression event, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice per day or an equivalent amount of a pharmaceutically acceptable salt thereof.

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

[0043] E25. The method of any from E18 to E24, wherein the progression of PPMS is evaluated using the CDP12, CCDP12, CDP24 or cCDP24.

[0044] E26. The method of E21, wherein the progression of PPMS comprises the subject experiencing at least one progression event.

[0045] E27. The method is any of E19 to E26, wherein the at least one progression event is selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT.

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

[0047] E29. The method is any of E19, E20 or E22 to E28, wherein the progression event is confirmed at least 12 weeks after initial progression. ινΐΛ / a / zuzz / u i uo i □

[0048] Ε30. The method is any of E19, E20 or E22 to E28, wherein the progression event is confirmed at least 24 weeks after initial progression.

[0049] E31. The method of any from E18 to E30, where progression is slowed, or onset is delayed, or risk is decreased, compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0050] E32. The method of any of E18 to E31, where the progression is slowed, or the onset is delayed or the risk is decreased compared to a subject who is administered an anti-CD20 antibody.

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

[0052] E34. A method of reducing disability in a subject with PPMS, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice per day or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0053] E35. The E34 method, where the reduction of disability includes: reduce the psychological impact of MS; increase the function of the upper limbs; increase walking ability; reduce fatigue; improve employment status; or decrease the overall impression of MS severity; or any combination of these.

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

[0055] E37. The method of any of E1 to E36, wherein one or more physical effects of multiple sclerosis in the subject are diminished.

[0056] E38. A method of 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 comprises minus one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 24 weeks after the initial progression.

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

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

[0059] E41. The method of any from E38 to E40, where progression is slowed compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0060] E42. The method is any of E38 to E41, where progression is slowed compared to a subject administered an anti-CD20 antibody.

[0061] E43. The method of any from E38 to E42, where the progression is slowed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or at least 35% .

[0062] E44. The method of any of E1 to E43, wherein the method further comprises the step of measuring one or more clinical or laboratory endpoints in the subject in order to evaluate the efficacy for treating PPMS.

[0063] E45. The E44 method, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMS, MSWS12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or subject's NfL levels.

[0064] E46. The E44 or E45 method, where 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, or any combination thereof, after starting administration of fenebrutinib, or a pharmaceutically acceptable salt thereof.

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

[0066] E48. The method of any of E1 to E47, wherein the development of one or more new types of MS-related brain lesions in the subject is evaluated after the subject begins administration of fenebrutinib or a pharmaceutically acceptable salt thereof, in wherein the one or more types of lesions are selected from the group consisting of new gadolinium-enhancing lesions on T1-weighted MRI (T1Gd+), new / enlarged T2-weighted lesions detected by MRI, or new T1 hypointense lesions detected by MRI.

[0067] E49. The method of E48, wherein the development of one or more new lesions in the subject is reduced compared to a subject with PPMS who is not administered fenebrutinib or a salt thereof ινΐΛ / a / zuzz / u i uo i □ pharmaceutically acceptable, or a subject administered an anti-CD20 antibody or a combination thereof.

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

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

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

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

[0072] E54. The method of any from E1 to E53, where the free form of fenebrutinib is administered.

[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 wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0074] E56. The compound for use is E55, where the progression of disability in the subject is evaluated.

[0075] E57. The composite for use of E56, where disability progression is assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-foot Timed Walk Test ( T25FWT) or any combination of these.

[0076] E58. The compound for use of E56 or E57, wherein the occurrence of the composite 12-week confirmed disability progression (cCDP12) is evaluated, wherein the occurrence of the cCDP12 comprises at least one progression event selected from the group consisting of : (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 12 weeks after the initial progression.

[0077] E58a. A compound for use to reduce the risk of experiencing cCDP12 in a subject with PPMS, which comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

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

[0079] E58c. A compound for use in reducing the time to the appearance of cCDP12 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, wherein the time to occurrence of cCDP12 comprises the period from before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof until the first occurrence of a progression event, where the progression event is confirmed at least 12 weeks after progression of initial disability.

[0080] E58d. The compound for use of E58a or E58b, wherein the progression event is one of: (a) an increase from baseline in the Expanded Disability Status Scale (EDSS) score of >1.0 point in a subject with a baseline EDSS score of <5.5 or an increase of >0.5 points in a subject with a baseline EDSS score of >5.5 (confirmed disability progression [CDR]); (b) >20% increase from baseline in the timed 25-foot walk test (T25FWT); or (c) >20% increase from baseline over time to completion of the 9-hole peg test (9-HPT).

[0081] E59. The compound for use is any of E56 to E58d, wherein the method further comprises evaluating the occurrence of confirmed 12-week disability progression (CDP12) in the subject, wherein the occurrence of CDP12 comprises an increase with respect to the value baseline EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; and wherein EDSS progression is confirmed at least 12 weeks after initial progression.

[0082] E60. The compound for use is any of E56 to E59, wherein the method further comprises evaluating the occurrence of composite 24-week confirmed disability progression (cCDP24), wherein the occurrence of cCDP24 comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 24 weeks after the initial progression.

[0083] E61. The compound for use is any of E56 to E60, wherein the method further comprises evaluating the occurrence of confirmed 24-week disability progression (CDP24) in the subject, wherein the occurrence of CDP24 comprises an increase with respect to the value baseline EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; and wherein EDSS progression is confirmed at least 24 weeks after Initial progression.

[0084] E62. The compound for use is any of E55 to E61, wherein the time until a progression event increases, wherein the progression event is: an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

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

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

[0087] E65. The compound for use is any from E55 to E64, where the time until the appearance of CDP12 increases.

[0088] E66. The compound for use is any from E55 to E65, where the time to the appearance of cCDP12 increases.

[0089] E67. The compound for use is any from E55 to E66, where the time until the appearance of CDP24 increases.

[0090] E68. The compound for use is any from E55 to E67, where the time to the appearance of cCDP24 increases.

[0091] E69. The compound for use is any of E62 to E68, where the increase is in comparison to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0092] E70. The compound for use is any of E62 to E69, where the increase is in comparison to a subject with PPMS who is administered an anti-CD20 antibody.

[0093] E71. The compound for use is any 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] E72. The compound for use is any from E55 to E71, where it slows down the progression of PPMS in the subject.

[0095] E73. The compound for use is any from E55 to E72, where the onset of at least one progression event is delayed.

[0096] E74. The compound for use is any of E55 to E73, where the risk of the subject having at least one progression event is reduced.

[0097] E74a. The compound for use is any 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] E74b. The compound for use is any of E58a, E58b, E58d to E61, E74, or E74a, wherein the risk reduction is in comparison to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[0099] E74c. The compound for use is any of E58a, E58b, E58d to E61 or E74 to E74b, wherein the risk reduction is in comparison to a subject with PPMS who is administered an anti-CD20 antibody.

[00100] E75. A compound for use in a method of slowing the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00101] E76. A compound for use in a method of delaying the occurrence of at least one progression event in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00102] E77. A compound for use in a method of reducing the risk of a subject with PPMS having at least one progression event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject about of 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00103] E78. The compound for use is any of E72 to E77, wherein PPMS progression is assessed using MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAkMS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or NfL levels

[00104] E79. The compound for use is any of E72 to E78, where the progression of PPMS is evaluated using CDP12, cCDP12, CDP24 or cCDP24.

[00105] E80. The compound for use is E79, wherein the progression of PPMS comprises at least one progression event.

[00106] E81. The compound for use is any of E73 to E80, wherein the at least one progression event is selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT.

[00107] E82. The compound for use of any of E73 or E81, wherein the at least one progression event comprises an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less of or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

[00108] E83. The compound for use is any of E76 to E82, wherein the progression event is confirmed at least 12 weeks after initial progression.

[00109] E84. The compound for use is any of E76 to E82, wherein the progression event is confirmed at least 24 weeks after initial progression.

[00110] E85. The compound for use from any of E76 to E84, where progression is slowed, or onset is delayed, or risk is decreased, compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof .

[00111] E86. The compound for use is any from E76 to E85, where progression is slowed, or onset is delayed, or risk is decreased compared to a subject administered an anti-CD20 antibody.

[00112] E87. The compound for use is any of E55 to E86, wherein the progression of PPMS in the subject is slowed, or the occurrence of at least one progression event in the subject is delayed, or the risk of having at least one progression event. progression in the subject decreases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or at least 35%.

[00113] E88. A compound for use in a method of reducing disability in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice a day. day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00114] E89. The compound for use of E88, wherein the reduction of disability comprises: reduce the psychological impact of MS; increase the function of the upper limbs; increase walking ability; reduce fatigue; improve employment status; or decrease the overall impression of MS severity; or any combination of these.

[00115] E90. The compound for use is any of E55 to E89, wherein the subject has a reduction in one or more symptoms of PPMS after beginning treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[00116] E91. The compound for use is any of E55 to E90, wherein one or more physical effects of multiple sclerosis in the subject are diminished.

[00117] Ε92. A compound for use in a method of slowing the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein 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 PPMS progression comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 24 weeks after the initial progression.

[00118] E93. The compound for use is E92, wherein the progression event is confirmed at least 12 weeks after initial progression.

[00119] E94. The compound for use of E92 or E93, wherein the at least one progression event comprises an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

[00120] E95. The compound for use is from any of E92 to E94, where progression is slowed compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[00121] E96. The compound for use is from any of E92 to E95, where progression is slowed compared to a subject administered an anti-CD20 antibody.

[00122] E97. The compound for use is any of E92 to E96, wherein the progression is slowed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or at minus 35%.

[00123] E98. The compound for use is any of E55 to E97, wherein the method further comprises the step of measuring one or more clinical or laboratory endpoints in the subject in order to evaluate the efficacy for treating PPMS.

[00124] E99. The compound for use of E98, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of MSIS-29, Upper Extremity Neuro-QoL, PROMISFatigueMS, MSWS-12, PGI-S, WPAkMS , PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or subject's NfL levels.

[00125] E100. The compound for use of E98 or E99, 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, or any combination thereof, after starting administration of fenebrutinib, or a pharmaceutically acceptable salt thereof.

[00126] Ε101. The compound for use is any from E98 to E100, wherein the clinical or laboratory endpoint is measured 120 weeks after starting administration of fenebrutinib, or a pharmaceutically acceptable salt thereof.

[00127] E102. The compound for use is any of E55 to E101, wherein the development of one or more new types of MS-related brain lesions in the subject is evaluated after the subject begins administration of fenebrutinib or a salt thereof pharmaceutically acceptable, wherein the one or more types of lesions are selected from the group consisting of new gadolinium-enhancing lesions on T1-weighted MRI (T1Gd+), new / enlarged T2-weighted lesions detected by MRI, or hypointense lesions in new T1 detected by MRI.

[00128] E103. The compound for use of E102, wherein the development of one or more new lesions in the subject is reduced compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof, or a subject to whom You are given an anti-CD20 antibody or a combination of these.

[00129] E104. The compound for use is any of E56 to E101, wherein the evaluation period is 120 weeks after beginning administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[00130] E105. The compound for use is any of E55 to E104, wherein fenebrutinib, or pharmaceutically acceptable salt thereof, is administered orally.

[00131] E106. The compound for use is any of E55 to E105, wherein the fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered in the form of one or more tablets or capsules.

[00132] E107. The compound for use is any of E55 to E106, wherein the fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered in the form of two tablets twice a day, wherein each tablet comprises about 100 mg of fenebrutinib or a equivalent amount of a pharmaceutically acceptable salt thereof.

[00133] E108. The compound for use is any of E54 to E107, wherein the compound is the free form of fenebrutinib.

[00134] E109. Furthermore, provided herein is a compound for use in the preparation of a medicament for any of methods E1 to E54, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof.

[00135] E110. The method of any of E1 to E53, or the compound for use of any of E54 to E108, wherein the subject with PPMS had progressive disease since onset, and was in a progressive stage for at least 12 months before starting the administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[00136] E111. The method of any of E1 to E53 or E110, or the compound for use of any of E54 to E108 or E110, wherein, before commencing administration of fenebrutinib, or a pharmaceutically acceptable salt thereof, the subject has at least two of: (a) one or more T2 hyperintense lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical or infratentorial; (b) two or more T2 hyperintense lesions in the spinal cord; and (c) the presence of cerebrospinal fluid-specific oligoclonal bands.

[00137] E112. The method of any of E1 to E53, E110 or E111, or the compound for use of any of E54 to E108, E110 or E111, wherein the subject has an EDSS score of 3.0 to 6.5 before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[00138] E113. The method of any of E1 to E53 or E110 to E112, or the compound for use of any of E54 to E108 or E110 to E112, wherein the subject with PPMS does not have one or more of: estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2; ALT or AST > 2 x ULN; total bilirubin greater than 1.5 χ ULN; hemoglobin < 9.5 g / dL; platelet count < 100 χ 109 / L; or abnormalities in one or more of the liver synthetic function tests (PT, INR, PTT, or albumin).

[00139] E114. Further provided herein is a method of any of E1 to E54 or E110 to E113, or compound for use of any of E55 to E108 or E110 to E113, wherein the subject is not concomitantly administered a CYP3A4 inhibitor. strong while being administered about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00140] E115. The method or compound for use of E114, wherein the strong 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.

[00141] E116. Further provided herein is a method of any of E1 to E54 or E110 to E114, or compound for use of any of E55 to E108 or E110 to E114, wherein the subject is not concomitantly administered a CYP3A4 inducer. strong while being administered about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00142] E117. The method or compound for use of E116, wherein the strong CYP3A4 inducer is apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampicin or hyperforin (St. John's wort).

[00143] E118. Further provided herein is a method of any of E1 to E54 or E110 to E117, or compound for use of any of E55 to E108 or E110 to E114, wherein the subject is not concomitantly administered a CYP3A4 inducer. moderate while being administered about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00144] E119. The method or compound for use of E118, wherein the moderate CYP3A4 inducer is bosentan, dexamethasone, efavirenz, etravirine, phenobarbital, pidone, phenobarbital or rifabutin.

[00145] E120. Further provided herein is a method of any of E1 to E54 or E110 to Ε119, or compound for use of any of E55 to E108 or E110 to E119, wherein the subject is not concomitantly administered a CYP3A4 substrate with a narrow therapeutic window while being administered about 200 mg of fenebrutinib twice per day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00146] E121. The method or compound for use of E120, wherein the CYP3A4 substrate with a narrow therapeutic window is alfentanil, astemizole, cyclosporine, cisapride, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, if roli mus, terfenadine or tacrolimus. BRIEF DESCRIPTION OF THE DRAWINGS

[00147] Figure 1A-1B shows the comparative kinase selectivity of fenebrutinib compared to three different BTK inhibitors. DETAILED DESCRIPTION

[00148] Provided herein are methods and uses of fenebrutinib, or a pharmaceutically acceptable salt of fenebrutinib, for treating primary progressive multiple sclerosis (PPMS).

[00149] Fenebrutinib is a compound of the formula: and also known by the following names: GDC-0853; (62S)-23-(hydroxymethyl)-17,17,31,62-tetramethyl-13,14,17,18-tetrahydro-4-aza-1 (2)-cyclopenta[4,5]pyrrolo[1 ,2a]pyrazine-6(1,4)-p¡peraz¡ne-2(2,4),3(3,5),5(2,5)-tryp¡r¡dina-7(3 )-oxetanaheptaphane-11(16H),36(31H)-dione; and (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1- il)pyridin-2-¡l)am¡no)-6-oxo-1,6d¡hydro-[3,4'-b¡p¡r¡d¡n]-2'-¡l)-7, 7-dimethyl-2,3,4,6,7,8-hexahydro-1 H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.

[00150] Additional names for the same compound may be known, for example, by using different chemical nomenclature schemes. The R enantiomer of the compound is: (R)-2-(3'-(hydroxymethyl)-1 methyl-5-((5-(2-methyl-4-(oxetan-3-yl) piperazin-1-¡l)pir¡din-2-¡l)amino)-6-oxo-1,6-d¡hydro-[3,4,-b¡pyrid¡n]- 2'-¡l)-7,7-dimethyl2,3,4,6,7,8-hexahydro-1 H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.

[00151] Fenebrutinib is a highly selective, orally administered, reversible BTK inhibitor. U.S. Patent No. 8,716,274, which is incorporated herein by reference in its entirety, discloses the classes of heteroaryl pyridine and aza-pyridone compounds useful for inhibiting Btk, including fenebrutinib. WO 2017 / 148837, which is incorporated herein by reference in its entirety, discloses solid forms and formulations of fenebrutinib and pharmaceutically acceptable salts thereof. I. Definitions

[00152] It should be noted that the terminology used herein is intended to describe only particular embodiments and is not intended to limit them.

[00153] As used herein, including the appended claims, the singular forms “a”, “an / an” and “the / the” include plural references unless the context clearly indicates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[00154] As used herein, the expression about refers to the usual error range for the respective value readily known to the mid-level skilled person in this technical field. Reference to about a value or parameter herein includes (and describes) embodiments that refer to that value or parameter itself. In some embodiments, the term “about” refers to a range of plus or minus 10% for the respective value. In some embodiments, the term “about” refers to a range of plus or minus 5% for the respective value. In some embodiments, the term “about” refers to a range of plus or minus 2% for the respective value. In some embodiments, the term “about” refers to a range of plus or minus 1% for the respective value.

[00155] It should be noted that aspects and embodiments of the disclosure described herein include “comprising”, “consisting of” and “consisting essentially of” aspects and embodiments.

[00156] The term "pharmaceutical formulation" refers to a preparation that is in such a form as to allow the biological activity of the active ingredient to be effective, and that does not contain additional components that are unacceptably toxic to a subject to whom it would be administered. the formulation. In some embodiments, such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those that can reasonably be administered to a mammalian subject to provide an effective dose of the active ingredient used.

[00157] As used herein, the term treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of a clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, improvement or alleviation of the disease state, and remission or improved 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 the disease or disorder decrease; the disease is more tolerable for the subject; the rate of degeneration or decline, or rate of development of the disease or disorder is slowed or stopped; the progression of the disease or disorder is slowed or stopped; or the end point of degeneration is less debilitating. For example, an individual is successfully “treated” if one or more symptoms associated with a type of cancer are mitigated or eliminated, which includes, but is not limited to, reducing the symptoms resulting from the disease, increasing the quality of life of those who have the disease, reduce the dose of other medications required to treat the disease and / or prolong the survival of the individuals. Treatment of certain diseases or disorders may, in some embodiments, include, but is not limited to, specific clinical or other endpoints such as those described in the examples provided herein.

[00158] Some embodiments described herein relate to providing a dose of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. It will be apparent to a person of mid-level skill how to calculate a corresponding amount of a pharmaceutical salt form of fenebrutinib, taking into account the difference in molecular weight between the free form of fenebrutinib and a salt form. For example, in some embodiments provided herein, a subject is administered about 400 mg daily of fenebrutinib (as two 200 mg doses), or a pharmaceutically acceptable salt thereof. If a pharmaceutically acceptable salt form is administered in such embodiments, because the salt form has a higher molecular weight than the free form of fenebrutinib, the total weight of the pharmaceutically acceptable salt of fenebrutinib administered daily is more of 400 mg, but corresponds to around 400 mg of the free form of fenebrutinib.

[00159] A “subject, for purposes of treatment, refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports or pet animals, such as dogs, horses, cats , cows, etc. In some embodiments of the methods provided herein, the subject is a human being. In some embodiments, the subject is a patient.

[00160] “Before starting administration” may include, for example, on the same day as, but before the actual administration of, the first dose of fenebrutinib or pharmaceutically acceptable salt thereof; or within one week before the first dose; or within two weeks before the first dose; or within three weeks before the first dose; or within four weeks before the first dose; or within five weeks before the first dose; or within six weeks before the first dose; or within more than six weeks before the first dose; or between 1 and 28 days before the first dose; or within 0 to 28 days before the first dose. In some embodiments, this period may also be referred to as “baseline.” Thus, in some embodiments, the baseline time may include within one week before administering the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof, including the day prior to administration. In other embodiments, the baseline time includes within one month, or within 0 to 28 days, or within six weeks before the first dose of fenebrutinib or a pharmaceutically acceptable salt thereof.

[00161] As used herein, the term “biomarker” refers to an indicator, e.g., predictive, diagnostic and / or prognostic, that can be detected in a sample. The biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g., multiple sclerosis) characterized by certain 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), 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 greater clinical benefit for an individual is a detectable level in a biological sample. They can be measured by methods known to the person of the mid-level trade and also disclosed herein. The level of expression or amount of biomarker assessed can, in some embodiments, be used to determine response to treatment. In some embodiments, the level of expression or amount of one or more biomarkers is associated with a particular response to treatment.

[00162] The term “sample,” as used herein, refers to a composition that is obtained or derived from a subject and / or individual of interest that contains a cellular and / or molecular entity to be characterized and / or will identify, for example, based on physical, biochemical, chemical and / or physiological characteristics. For example, the phrase “disease sample” and its variations refer to any sample obtained from a subject of interest that is expected or known to contain the cellular and / or molecular entity that is desired to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell waste, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, blood, cells derived from blood, urine, cerebrospinal fluid, saliva, sputum, tears, perspiration, mucus, Used from tumors and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cell extracts and combinations of these. In some embodiments, the sample is a blood sample. In other embodiments, the sample is cerebrospinal fluid (CSF).

[00163] “Tissue sample” or “cell sample” means a collection of similar cells that are obtained from tissue of a subject or individual. The source of the tissue or cellular sample can be a solid tissue such as from a fresh, frozen and / or preserved organ, biopsy, and / or aspirate; blood or any constituent of blood, such as plasma; body fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid or interstitial fluid; cells from any time in the gestation or development of the subject. The tissue or cellular sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a diseased tissue / organ. The tissue or cell sample may contain compounds that mix naturally with the tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics or the like.

[00164] As used herein, a “reference sample”, “reference cell”, “reference tissue”, “control sample”, “control cell” or “control tissue” refers to a sample, cell, tissue, standard or level used for comparative purposes. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell or control tissue is obtained from a healthy and / or non-diseased body part (for example, tissue or cells) of the same subject or individual. For example, healthy and / or non-diseased cells or tissues adjacent to diseased cells or tissue. In another embodiment, a reference sample is obtained from an untreated tissue and / or cell from the body of the same subject or individual, for example, a sample taken from the subject or individual before beginning a particular treatment (for example, before starting treatment with fenebrutinib or a pharmaceutically acceptable salt thereof). In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased body part (e.g. , tissues or cells) of an individual who is not the subject or individual. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell or control tissue is obtained from an untreated tissue and / or cell from the body of an individual who It is not the subject or individual.

[00165] The “Expanded Disability Status Scale” (EDSS) is a ClinRO measure to quantify changes in the level of disability of a subject with MS over time. The EDSS is based on a standard neurological examination, which incorporates functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral [or mental]) that are classified and then scored as a functional scoring system. (FSS), and ambulation, which is scored as ambulation score. Each FSS is an ordinal clinical rating scale that ranges from 0 to 5 or 6, and an ambulation score that is rated from 0 to 12. These scores can then be used in conjunction with observations as well as information regarding the ambulation and use of assistive devices to determine total EDSS score. The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10.0 (death) (Kurtzke 1983; Kappos 2011). In some embodiments of the methods provided herein, the item sexual dysfunction and fatigue are not included in the EDSS score.

[00166] The “9-hole peg test” (9-HPT) is a quantitative measurement of upper extremity (arm and hand) function (Goodkin et al. 1988; Fischer et al. 2001). The test device consists of a container with nine pins and a block containing nine empty holes. The subject must lift each of the nine pegs one at a time and place them as quickly as possible into the nine holes. Once all the pegs are in the holes, the subject must remove them again one at a time as quickly as possible and place them back in the container. The total time to complete the task is recorded. The dominant and non-dominant hands are tested twice (two successfully completed trials of the dominant hand, immediately followed by two successfully completed trials of the non-dominant hand). The two trials for each hand are averaged, converted to reciprocals of the time mean for each hand, and the two reciprocals are averaged. 9-HPT can be administered, for example, as described in the Manual of Multiple Sclerosis Functional Compound Classification and Administration (MSFC) (Fischer et al., 2001). A significant change in upper extremity function may, for example, be indicated by a 20% worsening from baseline of averaged 9-HPT periods.

[00167] The “25-foot timed walk test” (T25FWT) is a quantitative measurement of leg mobility and function, based on a 25-foot timed walk. The subject is asked to start at the end of a clearly marked 25-foot path and is instructed to walk 25 feet as quickly and safely as possible, and is timed how long it takes the subject to go from the start of the walk to the end. end of the 25 feet. In some embodiments, the task is immediately administered again by having the subject walk back the same distance, and the time of both completed trials is averaged to produce the T25FWT score. Subjects may use assistive devices (e.g., cane or wheelchair) when performing the task. T25FWT can be administered, for example, as described in the MSFC Classification and Administration Manual (Fischer et al., 2001). A clinically significant change in leg mobility and function may, for example, be indicated by a 20% worsening from baseline of period averaged T25FWT.

[00168] The “Symbol Digit Modalities Test” (SDMT) is a test used to assess the presence of cognitive impairment and / or changes in cognitive functioning over time and in response to treatment. SDMT may be particularly sensitive to slowed information processing commonly observed in MS (Benedict et a / .2O17). The SDMT comprises a substitution task. Using a reference key, the subject has 90 seconds to match specific numbers with specific geometric figures. Responses can be collected orally, and the number of correct responses indicates the SDMT score. A clinically significant change in cognitive processing may, for example, be indicated by a 4-point decrease in the SDMT score from baseline.

[00169] The “Columbla Suicidal Ideation Severity Scale” (C-SSRS) is a tool used to assess a subject's suicidal ideation over their lifetime, and can be used to track the suicidal events through treatment or a portion of it. The structured interview asks for recall of suicidal ideation, including intensity of ideation, behavior, and attempts with actual / potential lethality. A “baseline” C-SSRS may include, for example, C-SSRS collected before beginning administration of fenebrutinib or a pharmaceutically acceptable salt thereof. Such a score can be compared, for example, with subsequent C-SSRS collected after starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof. Comparisons between different assessment periods (which may, for example, occur during visits to a doctor) may be described, in some embodiments, as C-SSRS “since last visit.”

[00170] EQ-5D-5L is a validated self-reported health status questionnaire used to calculate a health state utility score for use in health economic analyzes (EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013). There are two components to EQ-5D-5L: a five-item health status profile that assesses mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, as well as visual analogue scale (VAS) that measures health status. health. EQ-5D-5L was designed to record the subject's current health status. Published weighting systems may allow the creation of a single composite score of the subject's health status.

[00171] The “Multiple Sclerosis Impact Scale 29 version 2” (MSIS-29, version 2) is a 29-item, subject-reported measure of the physical and psychological effects of MS (Hobart et al. 2001). Subjects are asked to rate how much their functioning and well-being was affected in the past 14 days on a 4-point scale, from “Not at all” (1) to “Extremely” (4). The physical score is the sum of items 1-20, which are then transformed into a scale of 0-100. The psychological score is the sum of items 21-29, transformed into a scale of 0-100. Higher scores may indicate greater impact of MS. A clinically significant impact is indicated by a change of at least 7.5 points on the physical scale in version 1 of the MSIS-29. In MSIS-29 version 2, this level of change may also indicate a significant impact.

[00172] The “12-item Multiple Sclerosis Walking Scale” (MSWS-12) is a 12-item self-report measure of the impact of MS on the Individual's ability to walk over the past 2 weeks. Each item is rated on a 5-point Likert scale, and total scores are converted to a 0-100 scale with higher scores indicating a greater impact of MS on walking ability.

[00173] “Quality of life in neurological disorders, upper extremities” (fine motor skills and activities of daily living; Neuro-QoL, upper extremities) is a 20-item questionnaire used to assess upper extremity function, which includes subjects with MS through each stage of this development (Gershon et al. 2012). Items include assessments of dressing, cooking, eating, cleaning, and writing in which the subject uses a 5-point Likert scale to rate performance ranging from “without any difficulty” (5) to “unable to do” (1). ). Item scores are added, multiplied by 20, and divided by 20 minus the number of unanswered items. Scores range from 20-100, with a higher score indicating better upper limb function. According to the NINDS User Manual (2015), scores can be calculated as long as at least 50% of the items have been answered.

[00174] “PROMIS-FatigueMS” is an 8-item scale developed as a measure of fatigue for subjects with MS (Cook et al. 2012) with a recall period of 7 days prior. It comprises a 5-point Likert-type scale that produces a score between 1 and 5 for each rated question. The total raw score is the sum of the values ​​for each graded question. The total raw score ranges from 8-40. Scores can also be transformed into a PROMIS T-score where the mean is 50 and a standard deviation of 10. T-scores range from 34.7-81.3. A higher score is associated with worse fatigue.

[00175] The “Patient's Global Impression of Change” (PGI-C) is a single-item assessment of a subject's impression of his or her change in MS symptoms compared to a previous 6-month point. Subjects respond on a 1-point Likert scale ranging from “much better” (1) to “much worse” (7). PGI-C is used as an anchor to determine a clinically significant change in MSIS-29.

[00176] The “patient global impression of severity” (PGI-S) is a single-item assessment of a subject's impression of the severity of their MS symptoms from the previous 7 days. A subject responds on a 5-point Likert scale ranging from “none” (1) to “very severe” (5). PGI-C is used as an anchor to determine a clinically significant change in MSIS-29.

[00177] The “alteration in work activity and productivity: multiple sclerosis” (WPALMS) is a 6-item scale. A subject estimates the amount of time his work and daily activities were affected by her MS during the previous 7 days (Reilly et al. 1993). WPALMS assesses absence as well as “presenteeism,” which indicates the period when a subject was present for work or activities, but believed that her health had a negative effect on her ability to perform them at the usual level. . A higher score represents a greater alteration in productivity.

[00178] “Confirmed Disability Progression” (CDP) refers to an increase in the subject's EDSS score that is maintained over a particular period. This can be assessed, for example, by calculating the subject's EDSS score, which determines that the score increases from a previous score (such as a baseline score, which may be a score taken before the subject began administration of fenebrutinib or a pharmaceutically acceptable salt thereof), and then confirms that the score increased even after a specified period has elapsed since the initial increase (for example, by retesting the subject and recalculating it). For example, a confirmed 12-week disability progression (CDP12) refers to an EDSS score that remains increased at least 12 weeks after the initial increase (e.g., as confirmed by recalculating the EDSS score at least 12 weeks). after the initial increase). A confirmed 24-week disability progression (CDP24) refers to an EDSS score that remains increased at least 24 weeks after the initial increase (for example, as confirmed by recalculating the EDSS score at least 24 weeks after the increase initial). The initial increase can be compared to a baseline EDSS score (such as before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof), or can be compared to a previous EDSS score that was stable over time, such as such as for 12, 24, 36,48 or 60 weeks. In some embodiments, a CDP refers to an increase of > 1.0 point from baseline EDSS score in a subject with a baseline EDSS score of < 5.5 points, or an increase of > 0.5 point from baseline EDSS score. Baseline EDSS in a subject with a baseline EDSS score of > 5.5 points. Time to onset of a CDP (e.g., time to onset of CDP12 or CDP24) refers to the period from when the previous EDSS score was established (e.g., a baseline EDSS score from before starting administration. of fenebrutinib or a pharmaceutically acceptable salt thereof) until sustained increase in EDSS score is observed.

[00179] “Composite confirmed disability progression” (cCDP) is a composite measure of disability progression using a combination of EDSS, 9-HPT, and T25FWT. Evaluates the progression of the subject's disability during a particular period as determined by the first occurrence of a progression event. A progression event may include any of the following: a CDP (e.g., increase of > 1.0 point from the baseline EDSS score in a subject with a baseline EDSS score of < 5.5 points, or an increase of > 0.5 points with respect to the baseline EDSS score in a subject with a baseline EDSS score of > 5.5 points); an increase of > 20% from baseline in time to completion of the 9-hole peg test (9-HPT); or an increase of > 20% from baseline in the timed 25-foot walk test (T25FWT); wherein the occurrence of the progression event is confirmed after a specific period has elapsed since the initial appearance. For example, a composite 12-week confirmed disability progression (cCDP12) refers to the occurrence of at least one progression event at an early time point, and the same progression event is confirmed at least 12 weeks later (e.g. when retesting the subject using the same test). A composite 24-week confirmed disability progression (cCDP12) refers to the occurrence of at least one progression event in an early period, and the same progression event is confirmed at least 24 weeks later. Time to onset of a cCDP (e.g., time to onset of cCDP12 or cCDP24) refers to the period from when prior assessment scores were established (e.g., baseline scores from before starting fenebrutinib administration). or a pharmaceutically acceptable salt thereof) until the initial progression event is observed. Without wishing to be limited by theory, compared to assessment criteria based solely on the Expanded Disability Status Scale (EDSS), which emphasizes lower limb function, the cCDP12 requires at least one of the following: 1) an increase in EDSS score of >1.0 point from the baseline (BL) score of <5.5 points, or increase of >0.5 points from the BL score of >5.5 points (confirmed disability progression); 2) a ινΐΛ / a / zuzz / u i uo i □ 20% increase with respect to BL over time to completion of the 9-hole pin test; 3) a 20% increase over BL in the 25-foot timed walk test. Therefore, cCDP12 is a more sensitive assessment of disability, especially in early stages of the disease. Using cCDP12 as the primary outcome may provide a clearer and more complete picture of disability progression or improvement than EDSS alone. II. Treatment methods

[00180] Without being bound by theory, inhibition of BTK results in a decrease in B cell activation and proliferation, which may explain effects on inflammatory pathways related to MS disease activity. Inhibition of BTK also has direct effects on cells of the myeloid lineage. As a result, there is potential for BTK inhibition to affect microglia that is associated with the pathophysiology of MS disease progression independent of relapse.

[00181] Provided herein are methods of treating PPMS in a subject in need thereof, by administering to the subject a daily dose of about 200 mg of fenebrutinib twice daily, or a corresponding amount of a pharmaceutically acceptable salt thereof, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. Further provided is a compound for use in a method of treating PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a twice daily dose. day of about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In further embodiments, a compound is provided herein for use in making a medicament for the treatment of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and in wherein the treatment comprises administering to the subject a twice daily dose of about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, PPMS treatment is evaluated using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combination of these. In some embodiments, PPMS treatment is evaluated based on the time to the onset of confirmed disability progression (e.g., 12-week or 24-week CDP), or based on the time to the onset of confirmed disability progression. compound (e.g., 12-week or 24-week cCDP). For example, in some embodiments, treating a subject with PPMS by administering about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, results in a delay in the worsening of EDSS (e.g. , increase of 0.5, 1.0, 1.5, or more points compared to baseline), a delay in worsening of 9-HPT time (e.g., over 20% compared to baseline), a delay in worsening of T25FWT time (e.g., over 20% compared to baseline), delay to onset of CDP12, delay to onset of CDP24, delay to onset of cCDP12, delay to onset of cCDP24, delay the occurrence of at least one progression event, reduce the risk of having at least one progression event, or reduce disability in a subject with PPMS. In other embodiments, PPMS treatment is evaluated according to MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMs, MSWS12, PGI-S, WPAkMS, 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 comprises delaying the progression of PPMS, where the progression is assessed according to MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMs, MSWS-12, PGI-S , WPAkMS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or NfL levels; or the occurrence of at least one progression event, which can be described by CDP12, cCDP12, CDP24 or cCDP24. In some embodiments, treating PPMS comprises slowing the progression of PPMS. In some embodiments, treating PPMS comprises delaying the occurrence of at least one progression event in the subject. In some embodiments, treating PPMS comprises reducing the risk of the subject experiencing at least one progression event. In some embodiments, treating PPMS comprises delaying progression or delaying the occurrence of at least one progression event by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, less 30% or at least 35% (for example, as assessed using T25FWT time or 9-HPT, or EDSS score, or CDP12, or cCDP12, or CDP24 or cCDP24, etc.).In some embodiments, treating PPMS comprises delaying progression, or delaying the occurrence 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 (for example, a comparative subject), wherein the other subject is not 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 cytolytic antibody directed at CD20). In still other embodiments, treating PPMS comprises reducing the risk of the 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, for example, reducing the risk of having at least one progression event over 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 risk is reduced compared to another subject with PPMS (e.g., a comparative subject) who is not administered fenebrutinib, or a pharmaceutically acceptable salt thereof, and who is optionally administered an antibody. anti-CD20. In some embodiments, the other subject is administered an anti-CD20 antibody (such as a cytolytic antibody directed at CD20). 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 comprises an improvement of at least 5%, at least 10%, at least 15%, at least 20%, at least 25% or at least 30% in a PPMS metric (e.g. in T25FWT time, or 9-HPT time or EDSS score, etc.), compared to the same metric evaluated in the same subject before starting the 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 1 week, or within 0 to 28 days, or within 6 weeks before starting administration of fenebrutinib or a salt thereof pharmaceutically. acceptable. In other embodiments, treating PPMS comprises 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 metric of PPMS (e.g., T25FWT time, or 9-HPT time, or EDSS score, etc.), compared to the same metric evaluated in another subject with PPMS, where the other subject is not administered fenebrutinib or a salt of is pharmaceutically acceptable. 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 (such as a cytolytic antibody directed at CD20).

[00182] A method is further provided for treating (e.g., slowing) the progression of PPMS in a subject in need thereof, by administering to the subject a twice daily dose of about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. Therefore, methods are provided herein for treating (e.g., slowing) the progression of PPMS in a subject in need thereof, by administering to the subject about 200 mg of fenebrutinib twice daily, or a corresponding amount of a salt. of this pharmaceutically acceptable. Further provided is a compound for use in a method of slowing the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a twice daily dose. times of about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In further embodiments, a compound is provided herein for use in making a medicament for use in a method of treating (e.g., slowing) the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject a twice daily dose of about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, PPMS progression is assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the Timed 25-Foot Walk Test (T25FWT), or any combination of these. In some embodiments, PPMS progression is assessed based on the time to the onset of confirmed disability progression (e.g., 12-week or 24-week CDP), or based on the time to the onset of confirmed disability progression. compound (e.g., 12-week or 24-week cCDP). In some embodiments, PPMS progression is slowed 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, progression is slowed ινΐΛ / a / zuzz / u i uo i □ by at least 5%. In some embodiments, progression is slowed by at least 10%. In some embodiments, progression is slowed by at least 15%. In some embodiments, progression is slowed by at least 20%. In some embodiments, progression is slowed by at least 25%. In some embodiments, progression is slowed by at least 30%. In some embodiments, progression is slowed by at least 35%. In some embodiments, progression is slowed as measured by the occurrence of cCDP12 (e.g., by increasing the time to occurrence of cCDP12) or by the risk of cCDP12 (e.g., reducing the risk of experiencing cCDP12 over a period of time). period). In some embodiments, PPMS progression is slowed relative to another subject with PPMS (e.g., a comparator subject), where 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 (such as a cytolytic antibody directed at CD20), and is not administered a BTK inhibitor (such as 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, for example, PPMS progression is slowed by at least 5%, at least 10%, at least 15%, at least 20%, at least 25 %, at least 30% or at least 35%, as assessed over 120 weeks, when compared to another subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof and is optionally administered a targeted cytolytic antibody to CD20.In some embodiments, the other subject is administered an anti-CD20 antibody (such as a cytolytic antibody directed at CD20).

[00183] Still in other embodiments, provided herein is a method of decreasing disability in a subject with PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice per day, or an equivalent amount of a salt of this pharmaceutically acceptable, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt of this. In some embodiments, a compound is provided for use in a method of decreasing disability in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and the method comprises administering to the subject about 200 of mg fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof. In further embodiments, a compound is provided herein for use in making a medicament for use in a method of decreasing disability in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically derived salt thereof. acceptable, and wherein the method comprises administering to the subject a daily dose of about 400 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof. Reducing disability may include reducing the psychological impact of MS; increase the function of the upper limbs; increase walking ability; reduce fatigue; improve employment status; or decrease the overall impression of MS severity; or any combination of these. Lessening the disability may further include lessening one or more symptoms of PPMS or lessening one or more physical effects of PPMS on the subject. The decrease in disability (including, for example, one or more symptoms or physical effects or other aspects as described herein) can be assessed as described herein, such as using MSIS-29, Neuro-QoL of upper extremities, PROMISFatigueMs, MSWS-12, PGI-S, WPAkMS, 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 is used. In some embodiments, decreasing disability comprises a subject being able to complete T25FWT and / or 9-HPT more quickly, or a decrease in EDSS score (e.g., closer to “normal”). In some embodiments, a decrease in disability comprises an improvement in one or more PPMS metrics, as assessed using MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMs, MSWS-12, PGI-S, WPAkMS, 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% in at least one PPMS metric. (e.g., in T25FWT time, or 9-HPT time, or EDSS score), compared to the same metric assessed in the same subject before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, two, three, four, five, or more metrics are improved, where each level of improvement is independent (e.g., one metric improves by at least 10%, another metric 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 1 week, or within 0 to 28 days, or within 6 weeks before starting administration of fenebrutinib or a salt thereof pharmaceutically. acceptable.

[00184] In still other embodiments, a method is provided for delaying the occurrence of at least one progression event in a subject with PPMS, wherein the method comprises administering to the subject a twice daily dose of about 200 mg of fenebrutinib, or a pharmaceutically acceptable salt thereof, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. Further provided is a compound for use in a method of delaying the occurrence of at least one progression event in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. In still other embodiments, a compound is provided for use in the preparation of a medicament for a method of delaying the occurrence of at least one progression event in a subject with PPMS, wherein the compound is fenebrutinib or a salt of is pharmaceutically acceptable, and wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice per day, or an equivalent amount of a pharmaceutically acceptable salt thereof. A progression event may include, for example, an increase from baseline in the time taken to complete 9-HPT, or an increase from baseline in a time taken to complete T25FWT, or an increase from to the baseline value of the score EDSS. In some embodiments, the increase from baseline in the time required to complete the 9-HPT is an increase of at least 20% (e.g., it may be 20%, 25%, 30%, 35%, etc. .). In some embodiments, the increase from baseline in the time required to complete T25FWT is an increase of at least 20% (e.g., may be 20%, 25%, 30%, 35%, etc.) . In still other embodiments, the increase from baseline in the EDSS score is an increase of at least 1.0, wherein the baseline value is less than or equal to 5.5 points; or an increase of at least 0.5 points in a subject with a baseline score of more than 5.5 points. In some embodiments, the progression event is confirmed within a certain period after the initial progression, such as at least 12 weeks or at least 24 weeks. In some embodiments, the baseline value used to determine a progression event is the same metric (e.g., T25FWT, 9-HPT, EDSS, or combinations of these) assessed in the same subject within 1 week, or within 0 to 28 days, or within 6 weeks before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the methods, compounds for use, or use of a compound in the manufacture of a medicament delay the occurrence 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 relative to another subject with PPMS (e.g., a comparator subject), where the other subject is not administered a BTK inhibitor (such as fenebrutinib or a salt of is pharmaceutically acceptable). In some embodiments, the other subject is administered an anti-CD20 antibody (such as a cytolytic antibody directed at CD20), and is not administered a BTK inhibitor (such as 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, for example, the time to the occurrence of at least one progression event increases by at least 5%, at least 10%, at least 15%, at least 15%. less 20%, at least 25%, at least 30%, or at least 35%, as assessed over 120 weeks, when compared to another subject with PPMS who is not given a BTK inhibitor (such as fenebrutinib or a pharmaceutically acceptable salt thereof) and optionally administered an anti-CD20 antibody (such as a cytolytic antibody directed at CD20). In some embodiments, calculating the delay in the occurrence of at least one progression event may comprise, for example, calculating the additional time until the occurrence of a progression event in a subject administered fenebrutinib or a salt of This is pharmaceutically acceptable, compared to a subject who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof (and is optionally administered an anti-CD20 antibody).

[00185] Provided herein is a method of reducing the risk of a subject with PPMS having at least one progression event, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an amount equivalent of a pharmaceutically acceptable salt thereof, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. Further provided is a compound for use in a method of reducing the risk of a subject with PPMS having at least one progression event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof. In still other embodiments, a compound is provided for use in the preparation of a medicament to reduce the risk of a subject with PPMS having at least one progression event, wherein the compound is fenebrutinib or a pharmaceutical salt thereof. acceptable, and wherein about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered to the subject. A progression event may include, for example, an increase from baseline in the time taken to complete 9-HPT, or an increase from baseline in a time taken to complete T25FWT, or an increase from to the baseline value of the EDSS score. In some embodiments, the increase from baseline in the time required to complete 9-HPT is an increase of at least 20% (e.g., it may be 20%, 25%, 30%, etc.). In some embodiments, the increase from baseline in the time required to complete the T25FWT is an increase of at least 20% (e.g., it may be 20%, 25%, 30%, etc.). In still other embodiments, the increase from baseline of the EDSS score is an increase of at least 1.0 (e.g., may be 1.0,1.5, 2.0, etc.) where the baseline value is less than or equal to at 5.5 points; or an increase of at least 0.5 points (for example, it may be 0.5,1.0, 1.5, etc.) in a subject with a baseline score of more than 5.5 points. In some embodiments, the progression event is confirmed within a certain period after the initial progression, such as at least 12 weeks or at least 24 weeks (e.g., as CDP12, cCDP12, CDP24, or cCDP24). In some embodiments, the baseline value used to determine a progression event is the same metric (e.g., T25FWT, 9-HPT, EDSS, or combinations of these) assessed in the same subject within 1 week, or within 0 to 28 days, or within 6 weeks before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the methods, compounds for use, or use of a compound in the manufacture of a medication reduce the risk of the subject with PPMS 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 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 comprises reducing the risk of experiencing cCDP12, or reducing the risk of worsening according to EDSS. In some embodiments, the reduced risk of having at least one progression event is reduced relative to another subject with PPMS, where the other subject is not administered a BTK inhibitor (such as fenebrutinib, or a salt thereof). pharmaceutically acceptable).In some embodiments, the other subject is administered an anti-CD20 ινΐΛ / a / zuzz / u i uo i □ antibody (such as a cytolytic antibody targeting CD20), and is not administered a BTK inhibitor (such as 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, for example, a subject with PPMS administered fenebrutinib or a pharmaceutically acceptable salt thereof has 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, when compared to another PPMS subject not given fenebrutinib or a pharmaceutically acceptable salt thereof and optionally administered a cytolytic antibody directed at CD20. Such a reduced risk of having at least one progression event can be calculated, for example, by calculating the rate of progression events in one or more PPMS subjects administered fenebrutinib or a pharmaceutically acceptable salt thereof (e.g. for 60 weeks or for 120 weeks) and comparing that rate with the rate of progression events in one or more subjects with PPMS who are not administered fenebrutinib or a pharmaceutically acceptable salt thereof and are optionally administered an antibody anti-CD20 (such as a cytolytic antibody directed at CD20).

[00186] Further provided herein are methods of increasing mobility in a subject in need thereof, wherein the subject has PPMS, comprising administering to the subject about 200 mg of fenebrutinib twice per day, or a corresponding amount of a pharmaceutically acceptable salt thereof, for a total daily dose of about 400 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. Therefore, methods are provided herein for increasing mobility in a subject in need thereof, wherein the subject has PPMS, by administering to the subject about 200 mg of fenebrutinib twice a day, or a corresponding amount of a salt of is pharmaceutically acceptable. Increased mobility in a subject may include, for example, increased ability to walk, increased ability to run, increased ability to climb and / or descend stairs, increased ability to stand, improved balance when walking or standing, greater distance than a subject is able to walk, less effort required to walk, less dependence on supports when walking indoors or outdoors (e.g., cane, leaning on furniture, walker, etc.), less amount of concentration required to walk increase in uniformity / softness when walking with any combination of the above. In some embodiments, one, two or more of these mobility aspects are improved, where one or more is not improved. For example, increasing mobility in a subject may involve improved walking ability, while one or more other components of mobility do not improve. Such increased mobility can, for example, be assessed using a subject questionnaire. In some embodiments, increased mobility, or one or more components of increased mobility as described herein, can be evaluated using MSWS-12. In some embodiments, an increase in mobility is assessed in comparison to the mobility (e.g., as assessed using MSWS-12) of the subject prior to beginning administration of fenebrutinib, or a pharmaceutically acceptable salt thereof.

[00187] In some embodiments as provided herein, PPMS progression may be assessed by one or more clinical or laboratory endpoints selected from the group consisting of ινΐΛ / a / zuzz / u i uo i □ in MSIS -29, Upper Extremity Neuro-QoL, PROMIS-FatigueMs, MSWS-12, PGI-S, WPAkMS, PGI-C, EQ-5D5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or levels of NfL. Thus, for example, in some embodiments the progression of PPMS is assessed by one or more of EDSS, T25FWT or 9-HPT. Additionally, in some embodiments PPMS progression is assessed by a sustained increase in one or more PPMS symptoms or signs, such as an increase that is sustained for at least 12 weeks (e.g., confirmed to continue to increase for at least 12 weeks after the initial observed increase) or at least 24 weeks (for example, confirmed to continue increasing at least 24 weeks after the initial observed increase). In some embodiments, PPMS progression is assessed by cCDP or CDP, such as cCDP-12, CDP-12, cCDP24 or CDP24, or any combination thereof. In some embodiments, PPMS progression is assessed by cCDP12. In some embodiments, PPMS progression is assessed using EDSS. In some embodiments, the risk of experiencing cCDP12 is decreased, or the time to occurrence of cCDP12 is increased, in combination with reducing the risk of experiencing CDP12, or in combination with increasing the time to occurrence of CDP12. In some embodiments, the risk of experiencing cCDP12 is decreased, or the time to occurrence of cCDP12 is increased, in combination with reducing the risk of experiencing cCDP24, or in combination with increasing the time to occurrence of cCDP24. Even in other embodiments, the risk of experiencing cCDP12 is decreased, in combination with: reducing the risk of experiencing CDP12 and reducing the risk of experiencing cCDP24. In still other embodiments, the time to appearance of cCDP12 is increased in combination with: increasing the time to appearance of CDP12 and increasing the time to appearance of cCDP24.

[00188] In some embodiments described herein, the response of a subject administered fenebrutinib or a pharmaceutically acceptable salt thereof can be compared to another subject administered an antibody to CD20 (e.g., a anti-CD20 antibody). As used herein, an anti-CD20 antibody may include antibodies that bind to CD20, a cell surface antigen present on mature and pre-B lymphocytes. In some embodiments, the antibody is a humanized monoclonal antibody directed against CD20-expressing B cells. In some embodiments, binding of the anti-CD20 antibody to the cell surface of B cells can result in antibody-dependent cell cytolysis and complement-mediated lysis. In some embodiments, the anti-CD20 antibody is a cytolytic antibody directed at CD20. Examples of such antibodies may include, for example, ocrelizumab. Ocrelizumab is a recombinant humanized glycosylated monoclonal IgG1 antibody that selectively targets and depletes CD20-expressing B cells.

[00189] In some embodiments of the methods, compounds for use or use of a compound as described herein, about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof, is administered two times per day to a subject with PPMS, wherein the subject with PPMS had progressive disease from onset and a progressive stage for at least 12 months before beginning administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject with PPMS has one or more T2 hyperintense lesions in one or more of the brain regions: periventricular, cortical or juxtacortical or infratentorial; two or more T2 hyperintense lesions in the spinal cord; or the presence of specific oligoclonal bands of cerebrospinal fluid. In some embodiments, the subject with PPMS has at least two of: one or more T2 hyperintense lesions in one or more of the brain regions: periventricular, cortical or juxtacortical or infratentorial; two or more T2 hyperintense lesions in the spinal cord; or the presence of specific oligoclonal bands of cerebrospinal fluid. In still other embodiments, the subject with PPMS had progressive disease from onset, and a progressive stage for at least 12 months before beginning administration of fenebrutinib or a pharmaceutically acceptable salt thereof; and has at least two of: one or more T2 hyperintense lesions in one or more of the brain regions: periventricular, cortical, or juxtacortical or infratentorial; two or more T2 hyperintense lesions in the spinal cord; or the presence of specific oligoclonal bands of cerebrospinal fluid. T2 hyperintense lesions can be evaluated, for example, by MRI. The presence of cerebrospinal fluid-specific oligoclonal bands can be assessed, for example, by lumbar puncture. In additional embodiments, the subject with PPMS may have an EDSS score between 3.0 and 6.5 before beginning administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the subject with PPMS is maintained neurologically stable for at least 30 days before beginning administration of fenebrutinib or a pharmaceutically acceptable salt thereof. In some such embodiments, the method, compound for use or use of a compound is to treat PPMS; treat (e.g. slow) the progression of PPMS; reduce disability; delay the onset of at least one progression event; reduce the risk of having at least one progression event; increase mobility; or increase the time to the appearance of cCDP12, in a subject with PPMS who needs it; and comprises administering to the subject in need thereof 200 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof, twice per day.

[00190] In some embodiments of the methods, compounds for use or use of a compound as described herein, about 200 mg of fenebrutinib, or a corresponding amount of a pharmaceutically acceptable salt thereof, is administered two times per day to a subject with PPMS, wherein the subject with PPMS does not have progressive multifocal leukoencephalopathy or has no history of progressive multifocal leukoencephalopathy. In some embodiments, the subject with PPMS has no history of cancer within 10 years prior to beginning administration of fenebrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject with PPMS did not have a hematologic malignancy or solid tumor within 10 years prior to beginning administration of fenebrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject with PPMS is not in an immunocompromised state. An immunocompromised state may include, for example, a CD4 count <250 / uL or ANC < 1.5 x 103 / uL or serum IgG < 4.6 g / L. Even in other embodiments, the subject with PPMS does not have any other neurological disorder. Such other neurological disorders may include, for example, a history of an ischemic cerebrovascular disorder (e.g., stroke, transient ischemic attack, spontaneous intracranial hemorrhage, or traumatic intracranial hemorrhage) or spinal cord ischemia; history or known presence of a spinal cord or CNS tumor (for example, meningioma or glioma); history or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency); history or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, Herpes zoster myelopathy); history of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraplegia, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke syndrome); neuromyelitis optica spectrum disorder; history or known presence of systemic autoimmune disorders potentially causing progressive neurological disease (e.g., lupus, antiphospholipid antibody syndrome, Sjógren's syndrome, Behqet's disease); history or known presence of sarcoidosis; or history of clinically significant and severe brain or spinal cord trauma (e.g., brain concussion, spinal cord compression). In some embodiments, the subject with PPMS has no evidence of cardiovascular (including arrhythmias or QTc prolongation), psychiatric, pulmonary, renal, hepatic (including Gilbert syndrome), endocrine (including uncontrolled diabetes, pancreatitis without clinically significant gallstones or chronic pancreatitis), metabolic or gastrointestinal (Gl). In some embodiments, the subject with PPMS does not have heart disease. In some embodiments, the subject with PPMS does not have congestive heart failure. Congestive heart failure can be evaluated, for example, by using the New York Heart Association criteria. In some embodiments, the subject with PPMS does not meet the class III and class IV criteria for congestive heart failure as described by the New York Heart Association. In still other embodiments, the PPMS subject has no 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 testing, prior coronary artery bypass grafting, or coronary lesions >70% diameter stenosis that was not or cannot be revascularized); clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia); family history of sudden unexplained death; or genetic mutations of cardiac ion channels (for example, congenital long QT syndrome). In some embodiments, the subject with PPMS is not concomitantly administered systemic corticosteroids or immunosuppressants while taking fenebrutinib or a pharmaceutically acceptable salt thereof.In some embodiments, the subject with PPMS was not administered systemic corticosteroids within 4 weeks before beginning administration of fenebrutinib or pharmaceutically acceptable salt thereof. In some embodiments, the subject with PPMS was not administered IV Ig or plasmapheresis within 12 weeks before beginning administration of fenebrutinib, or pharmaceutically acceptable salt thereof. In some embodiments, the subject with PPMS does not have abnormalities in hepatic synthetic function. In still other embodiments, the PPMS subject, while administered fenebrutinib or a pharmaceutically acceptable salt thereof, is not concomitantly administered any of one or more of: a CYP3A4 inhibitor, such as a CYP3A4 inhibitor strong; or a CYP3A4 inducer, such as a strong or moderate CYP3A4 inducer; or a CYP3A4 substrate; or fingolimod, siponimod or ozanimod; or natulizumab; or dimethyl fumarate, interferons, or glatiramer acetate; or an anti-CD20; or mycophenolate mofetil or methotrexate; or teriflunomide; or cladribine, mitoxantrone, daclizumab, alemtuzumab or cyclophosphamide. In still other embodiments, the subject with PPMS, before starting administration of fenebrutinib or a pharmaceutically acceptable salt thereof, is not administered: a strong CYP3A4 inhibitor or a strong or moderate CYP3A4 inducer, within 7 days or 5 drug elimination half-lives (whichever is longer); a CYP3A4 substrate with a narrow therapeutic window within 7 days or drug elimination half-lives (whichever is longer); an anti-CD20 within 2 years; fingolimod, siponimod or ozanimod within 8 weeks; natalizumab within 6 months, if natalzimuab was administered for more than one year; dimethyl fumarate, interferons or glatiramer acetate within 4 weeks; mycophenolate mofetil or methotrexate within 12 weeks; teriflunomide, unless teriflunomide plasma concentrations are < 0.02 mg / L; or cladribine, mitoxantrone, daclizumab, alemtuzumab or cyclophosphamide. Even in other embodiments, the subject with PPMS does not have one or more of: an estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2; ALT or AST > 2 χ ULN; a total bilirubin greater than 1.5 χ ULN; hemoglobin < 9.5 g / dL; a platelet count < 100 * 109 / L; or a clinically significant abnormality in one or more liver synthetic function tests (such as PT, INR, PTT, or albumin). In some embodiments, the subject with PPMS has an estimated glomerular filtration rate (eGFR) > 60 mL / min / 1.73 m2; ALT or AST < 2 χ ULN; a total bilirubin less than 1.5 χ ULN; a hemoglobin >9.5 g / dL; or a platelet count > 100 χ 109 / L. In some such embodiments, the method, compound for use or use of a compound is to treat PPMS; treat (e.g. slow) the progression of PPMS; reduce disability; delay the onset of at least one progression event; reduce the risk of having at least one progression event; increase mobility; or increase the time to the appearance of cCDP12, in a subject with PPMS who needs it; and comprises administering to the subject in need thereof 200 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof, twice per day. III. Pharmaceutical compositions and formulations

[00191] Also provided herein are pharmaceutical compositions and formulations comprising fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in the treatment methods 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. WO 2017 / 148837, which is incorporated herein by reference in its entirety, discloses formulations and dosage forms comprising fenebrutinib and pharmaceutically acceptable salts thereof. In some embodiments, a formulation described in WO 2017 / 148837 is used to administer fenebrutinib to a subject according to one or more of the methods provided herein.

[00192] Fenebrutinib, or a pharmaceutically acceptable salt thereof, may be administered by any suitable means, including oral, parenteral, intrapulmonary and intranasal administration, and, if desired for local treatment, intralesional administration. In some embodiments, oral administration is used.

[00193] Pharmaceutically acceptable salts of fenebrutinib can be used in the methods herein. As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present disclosure contain relatively acidic functionalities, basic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganose, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine , 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, Netylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine , trimethylamine, tripropylamine, tromethamine and the like. When the compounds of the present disclosure contain relatively basic functionality, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphoric acid and the like, as well as salts derived from acids relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, italic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic acids and the like. Also included are salts of amino acids, such as arginate and the like, and salts of organic acids, such as glucuronic or galacturonic acids and the like (see, for example, Berge, S. M., et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66,1-19). The specific compounds determined from the present invention contain basic and acidic functionalities that allow the compounds to be converted to basic or acidic addition salts.

[00194] In some of the embodiments provided herein, an 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, such as one, two, three, four, five or six tablets administered twice a day. 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, such as one, two, three, four, five or six capsules administered twice a day. Such capsules or tablets, in some embodiments, are about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, or about 225 mg each of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof. For example, in some embodiments, about 200 mg is administered twice daily to a subject in need, wherein each 200 mg dose is administered as a capsule comprising about 200 mg of fenebrutinib, or an amount equivalent of a pharmaceutically acceptable salt thereof; or each 200 mg dose is administered as two capsules comprising about 100 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, about 200 mg of fenebrutinib is administered twice per day (e.g., about 400 mg daily total), where each 200 mg is administered as two capsules comprising about 100 mg of fenebrutinib. In other embodiments, about 200 mg is administered twice daily to a subject in need, where each 200 mg dose is administered as a tablet comprising about 200 mg of fenebrutinib, or an equivalent amount of one salt thereof pharmaceutically acceptable; or each 200 mg dose is administered as two tablets comprising about 100 mg of fenebrutinib, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, about 200 mg of fenebrutinib is administered twice per day (e.g., about 400 mg daily total), where each 200 mg is administered as two tablets comprising about 100 mg of fenebrutinib. Thus, in some embodiments, the daily dose of fenebrutinib is about 400 mg daily, such as about 360 mg to about 440 mg daily, or an equivalent amount of a pharmaceutically acceptable salt of fenebrutinib. In some embodiments, 400 mg of fenebrutinib is administered daily.

[00195] In additional embodiments as provided herein, an article of manufacture or a kit is provided comprising fenebrutinib, or a pharmaceutically acceptable salt thereof, and a container. In some embodiments, a package insert comprising instructions for using fenebrutinib, or a pharmaceutically acceptable salt thereof, is also included. Suitable containers for kits include, for example, a bottle, a box, a blister, or combinations of these (for example, a blister in a box). In some embodiments, the container contains the formulation and the label on or associated with the container may indicate instructions for use. The manufacturing article or kit may also include other materials desirable from a commercial and user point of view, including leaflets with instructions for use.

[00196] The descriptive memory is considered sufficient to allow the practice of the invention to a person of the mid-level trade. Various modifications of the invention, in addition to those shown and described herein, will be apparent to persons of mid-level skill from the foregoing description and are within the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety for all purposes. LISTED EMBODIMENTS

[00197] Embodiment 1. A method of treating primary progressive multiple sclerosis (PPMS) in a subject in need thereof, comprising administering to the subject about 200 mg of fenebrutinib twice a day, or an equivalent amount of a salt of is pharmaceutically acceptable.

[00198] Embodiment 2. The method of embodiment 1, further comprising evaluating the progression of disability in the subject, wherein the progression of disability is evaluated using the expanded disability status scale (EDSS), the 9-Hole Pin Test (9-HPT) or the 25-Foot Timed Walk Test (T25FWT), or any combination of these.

[00199] Embodiment 3. The method of embodiment 1 or 2, further comprising evaluating the occurrence of the composite 12-week confirmed disability progression (cCDP12), wherein the occurrence of cCDP12 comprises at least one event progression selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 12 weeks after the initial progression.

[00200] Embodiment 4. The method of any of embodiments 1 to 3, wherein the time until a progression event in the subject increases, wherein the progression event is: an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

[00201] Embodiment 5. The method of any of embodiments 1 to 4, wherein the time to a progression event in the subject increases, wherein the progression event is an increase of at least 20% with compared to the baseline value in the time until completing the 9-HPT.

[00202] Embodiment 6. The method of any of embodiments 1 to 5, wherein the time to a progression event in the subject increases, wherein the progression event is an increase of at least 20% with compared to the baseline value at T25FWT.

[00203] Embodiment 7. The method of any of embodiments 1 to 6, wherein the time to the appearance of CDP12, cCDP12, CDP24 or cCDP24 is increased compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

[00204] Embodiment 8. The method of embodiment 7, wherein the subject with PPMS who is not administered fenebrutinib is administered an anti-CD20 antibody.

[00205] Embodiment 9. The method of any of embodiments 4 to 8, wherein the time to a progression event or the time to occurrence is increased by at least 10%.

[00206] Embodiment 10. A method of 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.

[00207] Embodiment 11. The method of embodiment 10, wherein PPMS progression is assessed using MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMs, MSWS-12, PGI-S, WPAkMS , PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or NfL levels

[00208] Embodiment 12. The method of embodiment 10 or 11, wherein the PPMS progression comprises at least one progression event.

[00209] Embodiment 13. A method of delaying the occurrence of at least one progression event in a subject with PPMS, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof. ινΐΛ / a / zuzz / u i uo i □

[00210] Embodiment 14. A method of reducing the risk of a subject with PPMS having at least one progression event, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00211] Embodiment 15. The method of any of embodiments 12 to 14, wherein the at least one progression event is selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT.

[00212] Embodiment 16. The method of embodiment 15, wherein the progression event is confirmed at least 12 weeks after the initial progression.

[00213] Embodiment 17. The method of any of embodiments 1 to 12, 15 or 16, wherein the progression of PPMS in the subject is slowed by at least 10% compared to another subject with PPMS to which you are not administered fenebrutinib or a pharmaceutically acceptable salt thereof and you are administered an anti-CD20 antibody.

[00214] Embodiment 18. The method of any of embodiments 13, 15 or 16, wherein the occurrence of at least one progression event is delayed by at least 10% compared to another subject with PPMS to which you are not administered fenebrutinib or a pharmaceutically acceptable salt thereof and you are administered an anti-CD20 antibody.

[00215] Embodiment 19. The method of any of embodiments 1 to 16, wherein the risk of the subject having at least one progression event decreases by at least 10% compared to another subject with PPMS at that you are not administered fenebrutinib or a pharmaceutically acceptable salt thereof and you are administered an anti-CD20 antibody.

[00216] Embodiment 20. A method of reducing disability in a subject with PPMS, wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice per day or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00217] Embodiment 21. The method of embodiment 20, wherein the reduction of disability comprises: reduce the psychological impact of MS; increase the function of the upper limbs; increase walking capacity; reduce fatigue; improve employment status; or decrease the overall impression of MS severity; or any combination of these.

[00218] Embodiment 22. The method of any of embodiments 1 to 21, wherein the subject has a reduction in one or more PPMS symptoms after beginning treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[00219] Embodiment 23. The method of any of embodiments 1 to 22, wherein the method further comprises the step of measuring one or more clinical or laboratory endpoints in the subject in order to evaluate efficacy to treat PPMS.

[00220] Embodiment 24. The method of embodiment 23, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of MSIS-29, Upper Extremity Neuro-QoL, PROMIS- FatigueMs, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or NfL levels.

[00221] Embodiment 25. The method of any of embodiments 1 to 24, wherein fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered orally.

[00222] Embodiment 26. The method of any of embodiments 1 to 25, wherein fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered in the form of one or more tablets or capsules.

[00223] Embodiment 27. The method of any of embodiments 1 to 26, wherein fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered in the form of two tablets twice a day, wherein each tablet It comprises about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00224] Embodiment 28. The method of any of embodiments 1 to 27, wherein the free form of fenebrutinib is administered.

[00225] Embodiment 29. 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 wherein the The method comprises administering to the subject about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00226] Embodiment 30. The compound for use of embodiment 29, wherein the method further comprises evaluating the progression of disability in the subject, wherein the progression of disability is evaluated using the expanded disability status scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Timed Walk Test (T25FWT), or any combination of these.

[00227] Embodiment 31. The compound for use of embodiment 29 or 30, wherein the method further comprises evaluating the occurrence of the composite 12-week confirmed disability progression (cCDP12), wherein the occurrence of cCDP12 comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase with ινΐΛ / a / zuzz / u i uo i □ from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT. and wherein the progression event is confirmed at least 12 weeks after the initial progression.

[00228] Embodiment 32. The compound for use of any of embodiments 29 to 31, wherein the time until a progression event increases, wherein the progression event is: an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

[00229] Embodiment 33. The compound for use of any of embodiments 29 to 32, wherein the time to a progression event increases, wherein the progression event is an increase of at least 20% with compared to the baseline value in the time until completing the 9-HPT.

[00230] Embodiment 34. The compound for use of any of embodiments 29 to 33, wherein the time to a progression event increases, wherein the progression event is an increase of at least 20% with compared to the baseline value at T25FWT.

[00231] Embodiment 35. The compound for use of any of embodiments 29 to 34, wherein the time to the appearance of CDP12, cCDP12, CDP24 or cCDP24 is increased compared to a subject with PPMS who is not Fenebrutinib or a pharmaceutically acceptable salt thereof is administered.

[00232] Embodiment 36. The compound for use of embodiment 35, wherein the subject with PPMS who is not administered fenebrutinib is administered an anti-CD20 antibody.

[00233] Embodiment 37. The compound for use of any of embodiments 32 to 36, wherein the time to a progression event or the time to onset increases by at least 10%.

[00234] Embodiment 38. A compound for use in a method of slowing the progression of PPMS in a subject in need thereof, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the compound comprises administering to the subject about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00235] Embodiment 39. The compound for use of embodiment 38, wherein PPMS progression is assessed using MSIS-29, Upper Extremity Neuro-QoL, PROMIS-FatigueMs, MSWS12, PGI-S, WPAkMS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or NfL levels

[00236] Embodiment 40. The compound for use of embodiment 38 or 39, wherein the PPMS progression comprises at least one progression event.

[00237] Embodiment 41. A compound for use in a method of delaying the occurrence of at least one progression event in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein The method comprises administering to the subject about 200 mg of fenebrutinib twice a day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00238] Embodiment 42. A compound for use in a method of reducing the risk of a subject with PPMS having at least one progression event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and in wherein the method comprises administering to the subject about 200 mg of fenebrutinib twice per day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00239] Embodiment 43. The compound for use of any of embodiments 40 to 42, wherein the at least one progression event is selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) increase from baseline of at least 20% over time to completion of 9-HPT; and (c) increase from baseline of at least 20% in T25FWT.

[00240] Embodiment 44. The compound for use of embodiment 43, wherein the progression event is confirmed at least 12 weeks after the initial progression.

[00241] Embodiment 45. The compound for use of any of embodiments 38 to 40, 43 or 44, wherein the progression is slowed by at least 10% compared to another subject with PPMS who is not he is administered fenebrutinib or a pharmaceutically acceptable salt thereof and an anti-CD20 antibody is administered.

[00242] Embodiment 46. The compound for use of any of embodiments 41, 43 or 44, wherein the occurrence of at least one progression event is delayed by at least 10% compared to another subject with PPMS that is not administered fenebrutinib or a pharmaceutically acceptable salt thereof and is administered an anti-CD20 antibody.

[00243] Embodiment 47. The compound for use of any of embodiments 42 to 44, wherein the risk of having at least one progression event decreases by at least 10% compared to another subject with PPMS at that you are not administered fenebrutinib or a pharmaceutically acceptable salt thereof and you are administered an anti-CD20 antibody.

[00244] Embodiment 48. The compound for use of any of embodiments 38 to 47, wherein the progression is slowed, or the onset is delayed or the risk is decreased, compared to a subject with PPMS to which fenebrutinib or a pharmaceutically acceptable salt thereof is not administered.

[00245] Embodiment 49. A compound for use in a method of reducing disability in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the subject around of 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00246] Embodiment 50. The compound for use of embodiment 49, wherein the reduction of disability comprises: reduce the psychological impact of MS; increase the function of the upper limbs; increase walking ability; reduce fatigue; improve employment status; or decrease the overall impression of MS severity; or any combination of these.

[00247] Embodiment 51. The compound for use of any of embodiments 29 to 50, wherein the subject has a reduction in one or more symptoms of PPMS after starting treatment with fenebrutinib or a salt thereof pharmaceutically acceptable.

[00248] Embodiment 52. The compound for use of any of embodiments 29 to 51, wherein the method further comprises the step of measuring one or more clinical or laboratory endpoints in the subject in order to evaluate the effectiveness for treating PPMS.

[00249] Embodiment 53. The compound for use of embodiment 52, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of the MSIS-29, Extremity Neuro-QoL higher, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAkMS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI or NfL levels.

[00250] Embodiment 54. The compound for use of any of embodiments 29 to 53, wherein fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered orally.

[00251] Embodiment 55. The compound for use of any of embodiments 29 to 54, wherein fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered in the form of one or more tablets or capsules.

[00252] Embodiment 56. The compound for use of any of embodiments 29 to 55, wherein fenebrutinib, or the pharmaceutically acceptable salt thereof, is administered in the form of two tablets twice a day, in wherein each tablet comprises about 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

[00253] Embodiment 57. The compound for use of any of embodiments 29 to 56, wherein the free form of fenebrutinib is administered.

[00254] Embodiment 58. A compound for use in the preparation of a medicament for any of the methods of embodiments 1 to 28, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof. EXAMPLES

[00255] The present disclosure will be better understood by reference to the following examples. However, they should not be interpreted as limiting the scope of the invention. It should be noted that the examples and embodiments described herein are illustrative only, and that various modifications or changes based thereon will be apparent to persons in the mid-level trade and should be included in the spirit and scope of the present application and the scope of the attached claims. Example 1: A MULTICENTRIC, RANDOMIZED, DOUBLE-BLIND, DOUBLE-SIMULATION, PARALLEL-GROUP PHASE III STUDY TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED TO OCRELIZUMAB IN ADULT PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS

[00256] This phase III study will analyze the efficacy and safety of fenebrutinib compared to ocrelizumab in adult subjects with PPMS. The specific objectives and corresponding endpoints for the study are indicated below. Study objectives Primary efficacy objective

[00257] The primary efficacy objective for 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 endpoint: • Time to onset of cCDP12, which is the time from baseline to the first occurrence of a progression event according to at least one of the following three criteria, and must be confirmed at a regularly scheduled visit that is at least 12 weeks after initial disability progression: - An increase from baseline in the EDSS score of > 1.0 point in patients with a baseline EDSS score of < 5.5 points or > 0.5 points in patients with a baseline EDSS score of > 5.5 points (confirmed disability progression [CDP]) - > 20% increase from baseline in time to completion of 9-HPT - > 20% increase from baseline at T25FWT Secondary efficacy objective

[00258] The secondary efficacy objective for this study is to evaluate the efficacy of treatment with fenebrutinib compared to ocrelizumab based on the following endpoints. Secondary endpoints do not reflect a statistical hierarchy order. • Time to onset of composite 24-week CDP (cCDP24) • Time to onset of 12-week CDP (CDP12), which is an increase from baseline EDSS score of > 1.0 point in patients with an EDSS score baseline of < 5.5 points or > 0.5 points and in patients with a baseline EDSS score of > 5.5 points • Time to onset of CDP 24 weeks (CDP24) • Percent change in total brain volume from week 24 to week 120 as assessed by scanning MRI • Change from baseline in self-reported physical effects of MS (as measured by Multiple Sclerosis Impact Scale, 29-item physical scale [MSIS-29]) at week 120 • Time to onset of 4-point worsening confirmed at 12 weeks in Symbol Digit Modalities Test (SDMT) score. Exploratory effectiveness objective

[00259] The exploratory efficacy objective for this study is to evaluate the efficacy of fenebrutinib compared to ocrelizumab and may include, but is not limited to, the following endpoints: • Proportion of patients with worsening in SDMT by 4 points • Change from baseline and proportion of patients with significant deterioration from baseline at week 120 for the following patient-reported outcomes (PROs): - Psychological effects of MS (MSIS-29 psychological scale) - Upper Limb Function (Quality of Life in Neurological Disorders [Neuro-QoL-™], Upper Limb Function Form) - Walking (12-item Multiple Sclerosis Walking Scale [MSWS-12]) - Fatigue (Patient-Reported Outcomes Measurement Information System Fatigue Short Form for Multiple Sclerosis [PROMIS®-FatigueMS]) - Work status (Alteration in work activity and productivity [WPAI]:MS v2.0) - MS Global Impression of Severity (Patient Global Impression of Severity [PGI-S]) • Time to occurrence of > 20% increase in T25FWT confirmed at 12 weeks • Time to occurrence of > 20% increase in 9-HPT confirmed at 12 weeks • Time to occurrence of > 20% increase in T25FWT confirmed at 24 weeks • Time to occurrence of > 20% increase in 9-HPT confirmed at 24 weeks • Proportion of patients with a significant deterioration from baseline in patient-reported physical effects of MS (MSIS-29 physical scale) at week 120 • Proportion of patients with a significant deterioration from baseline in patient-reported psychological effects of MS (MSIS-29 Psychological Scale) at Week 120 • Total number of new T1Gd+ lesions relative to baseline as detected by brain MRI scan3 • Total number of new / enlarged T2-weighted lesions as detected by scan MRIa• Total number of new T1 hypointense lesions (black holes) from baseline as detected by MRIa scan• Percent change from screening to week 120 in serum neurofilament light chain (NfL) levels • Proportion of patients without disability progression (cCDP12, cCDP24, CDP12 and CDP24) at week 120 and at clinical cut-off of primary analysisaIn this study, MRI measurements from screening are used as baseline measurements. Security objective

[00260] The safety objective for this study is to evaluate the safety of fenebrutinib compared to ocrelizumab based on the following endpoints: • The nature, frequency, timing and severity of adverse events; serious adverse events; and adverse events leading to withdrawal from study treatment • Change from baseline in target vital signs • Change from baseline in target ECG parameters • Change from baseline in clinical laboratory results after administration of study treatment • Change from baseline on the Columbia Suicidal Ideation Severity Scale (C-SSRS) Pharmacokinetic objectives

[00261] The pharmacokinetic (PK) objective of this study is to characterize the PK profile of fenebrutinib based on the following endpoints: • Plasma concentration of fenebrutinib at specific time points

[00262] Scattered PK samples will be collected from all patients. However, to better characterize the pharmacokinetics of fenebrutinib in MS patients, more intensive PK sampling will be collected in a small subset of patients.

[00263] The exploratory PK objectives for this study are as follows: • To evaluate potential relationships between drug exposure and the efficacy and safety of fenebrutinib based on the following endpoints: - Relationship between plasma concentrations of fenebrutinib and efficacy endpoints - Relationship between fenebrutinib plasma concentrations and safety endpoints • Evaluate potential relationships between selected covariates and fenebrutinib exposure based on the following endpoint: - Relationship between selected covariates and plasma concentrations of fenebrutinib Biomarker targets

[00264] The exploratory biomarker objective for this study is to identify and / or evaluate biomarkers that can predict the response to fenebrutinib (i.e., predictive biomarkers), are indirect markers of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to fenebrutinib, are associated with susceptibility to developing adverse events, or may lead to improved investigation or monitoring of adverse events (i.e., safety biomarkers, including antigen genotyping human leukocyte [HLA]), may provide evidence of fenebrutinib activity (i.e., pharmacodynamic [PD] biomarkers), or may increase knowledge and understanding of disease biology and drug safety, based on the following criteria valuation: • Relationship between baseline blood biomarkers (serum and / or plasma and / or RNA) and efficacy, PK or other biomarker endpoints • Relationship between change from baseline to post-treatment sampling in blood biomarkers (serum and / or plasma and / or RNA) and efficacy, PK or other biomarker endpoints • Relationship between genetics, including but not limited to HLA genotype, and efficacy, PK or other biomarker endpoints Health State Utility Objective

[00265] The exploratory health state utility objective for this study is to evaluate the health state utility scores of patients treated with fenebrutinib based on the following endpoint: • Relationship between EuroQol 5-dimensional, 5-level Questionnaire index score (EQ-5D-5L) and clinical measurements that can support pharmacoeconomic modeling. Detailed study design

[00266] This is a randomized, multicenter, double-blind, double-dummy, parallel-group phase III study to evaluate the efficacy and safety of fenebrutinib on disability progression in adult patients with PPMS. All eligible patients will be randomized 1:1 to daily oral fenebrutinib (or placebo) (200 mg twice daily [BID]) or IV ocrelizumab (or placebo) (600 mg every 24 weeks) in a blinded manner. Voice response or online interactive. Approximately 946 patients will be enrolled and recruited globally. Patients who stop study medication early or discontinue the study will not be replaced.

[00267] This study will consist of the following phases: screening (for up to 4 weeks), double-blind treatment (DBT) phase, DBT safety follow-up (DBT-SFU), optional open-label extension (OLE), and follow-up phase OLE Security System (OLE-SFU).

[00268] The duration of the study will vary for each patient because the primary analysis is event dependent. Study design

[00269] This study will consist of the following: • Screening phase, for approximately 4 weeks • Double-blind treatment (DBT) phase, patients will be randomized in a 1:1 ratio to oral fenebrutinib 200 mg BID or ocrelizumab IV 600 mg. • DBT Safety Follow-up (DBT-SFU), is available for patients who 1) remained on study treatment at the end of the DBT phase and do not wish to participate in OLE or 2) discontinued study treatment but spent less of 24 weeks of follow-up since their last ocrelizumab DBT infusion or less than 8 weeks of follow-up since their last dose of fenebrutinib DBT, whichever applies. Patients will be followed for safety for approximately 48 weeks. • The optional open label extension (OLE) phase, if the primary analysis is positive, will be available to eligible patients. Patients will receive approximately 96 weeks of open-label fenebrutinib; however, the OLE phase can be extended. • The OLE safety follow-up phase (OLE-SFU) is available for patients who discontinue fenebrutinib OLE early or complete the OLE phase. Patients will be monitored in OLE-SFU for approximately 8 weeks.

[00270] The duration of the study will vary for each patient because the primary analysis is event dependent. Patient safety will be monitored using DMC for the initial safety assessment (DMCISA) and at regular intervals throughout the DBT phase. Screening phase

[00271] The screening phase will be approximately 4 weeks. Patients who are ineligible at screening may qualify for a rescreening opportunity (a total of two screenings per patient). Screening procedures will include a medical history collection, physical examination, complete neurological examination, EDSS score, 9-HPT, T25FWT, ECG, MRI scan, and blood and urine samples. Double-blind treatment phase

[00272] The duration of the DBT phase partially depends on the events. The primary analysis will be performed when around 486 cCDP12 events have occurred and when all patients have participated in the DBT phase for at least 120 weeks. The DBT phase is considered complete when the results of the primary analysis are released and the study is released to the sites. If the projected number of cCDP events (486) has not been reached by the time the last patient completes week 120 in the DBT phase due to slower than anticipated rates of disability progression, the DBT phase will be extended until the necessary number occur. of cCDP12 events, to maintain statistical power to detect a difference in treatment. The DBT phase may extend beyond 120 weeks for the initial group of patients participating in the study, based on the final length of the study recruitment period.

[00273] Patients who discontinue study treatment for any reason during the DBT phase will remain in the DBT phase but will not receive study treatment. These patients will continue to attend DBT visits as scheduled but will have abbreviated efficacy and safety assessments.

[00274] Patients who discontinue study treatment during the DBT phase will be permitted to initiate another disease-modifying treatment (DMT), at the discretion of the patient and investigator, after waiting at least 24 weeks since the last infusion of ocrelizumab / placebo DBT or at least 8 weeks after the last DBT administration of fenebrutinib / placebo, whichever is longer.

[00275] Unscheduled visits may be performed for evaluation of potential disease progression, new neurological symptoms, or safety events. Patients with new neurological symptoms uoi or suggesting MS relapse or worsening of MS will undergo EDSS, 9-HPT and T25FWT by the examining investigator for 7 days from the onset of new neurological symptoms. Double-blind treatment phase safety monitoring

[00276] After completing the DBT phase, patients will enter a DBT-SFU for approximately 48 weeks if patients 1) remained on study treatment at the end of the DBT phase and do not wish to participate in OLE or 2) discontinued the study. DBT study treatment but less than 24 weeks of follow-up since their last ocrelizumab DBT infusion or less than 8 weeks of follow-up since their last dose of fenebrutinib DBT, whichever applies. Patients will be followed for safety for approximately 48 weeks. Patients may begin another DMT at the investigator's and patient's discretion after at least 24 weeks from the last ocrelizumab DBT infusion or at least 8 weeks from the last fenebrutinib DBT administration, as appropriate. Optional open extension

[00277] At the end of the DBT phase (dissemination of DBT results and disclosure to sites), if the primary analysis and risk-benefit assessment of the use of fenebrutinib treatment are positive, an optional OLE phase is planned for the patients. eligible patients who complete the DBT phase and who, according to the investigator's criteria, could benefit from treatment with fenebrutinib.

[00278] Additional unscheduled visits may be performed for evaluation of potential disease progression, new neurological symptoms, or safety events. Patients with new neurological symptoms suggesting MS relapse or worsening of MS will undergo EDSS, 9-HPT and T25FWT by the examining investigator (for 7 days from the onset of new neurological symptoms). Tracking and open outreach

[00279] Patients who discontinue fenebrutinib OLE early or complete the OLE phase will enter OLE-SFU. Patients will be followed for safety for approximately 8 weeks. During the OLE-SFU only security assessments will be collected. Laboratory and safety evaluations for the OLE-SFU phase will be performed at clinical visits every approximately 4 weeks. Patient population

[00280] Approximately 946 patients with PPMS will participate in this study. Enrollment limits can be added to ensure that the distribution of patients according to stratification factors is balanced between region, screening EDSS score, and the presence or absence of T1Gd+ at screening. Inclusion criteria

[00281] Patients must meet the following criteria to enter the study: • Signed informed consent form • 18-65 years inclusive at the time of signing the informed consent form • Ability to comply with the study protocol • A diagnosis of PPMS according to the revised 2017 McDonald Criteria (Thompson et al. 2018) : o Progressive disease with respect to the beginning. Superimposed relapses may occur in PPMS; therefore, it is necessary for the investigator to provide clinical evidence to the sponsor to confirm the diagnosis of PPMS. o One year of disability progression (determined retrospectively or prospectively) independent of clinical relapse provided as a synthesis of clinical evidence by the investigator to the sponsor is necessary to confirm a progressive stage for at least 12 months before randomization. Additionally, two of the following criteria: o Documented evidence of one or more T2 hyperintense lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial (established by historical MRI scan) o Documented evidence of two or more T2 hyperintense lesions in the spinal cord (established by historical MRI scan) or Documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands (established by historical lumbar puncture) • EDSS score of 3.0 to 6.5 inclusive at screening • For patients currently receiving proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs): treatment at a stable dose during the screening period before the start of study treatment and plans to remain on a stable dose during study treatment • Patients should not start PPI or H2RA within 2 weeks prior to randomization. • For patients requiring symptomatic treatment for MS (e.g., fampridine, cannabis) and / or physical therapy: treatment on a stable dose / regimen during the screening period prior to initiation of study drug and plans to remain on a stable dose during study treatment • Patients should not initiate symptomatic treatment for MS or physical therapy within 4 weeks prior to randomization. • Neurologically stable for at least 30 days prior to randomization and baseline assessments • Ability to complete 9-HPT for each hand in < 240 seconds • Ability to perform T25FWT • For women of reproductive potential: agreement to remain abstinent (refrain from intercourse heterosexuals) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 6 or 12 months (as appropriate according to the local package insert for ocrelizumab) after the final dose of study medication . Women should refrain from donating eggs during the same period. Hormonal contraceptive methods must be supplemented with a barrier method. • For men: agreement to remain abstinent (refrain from heterosexual relations) or use a condom and agree to refrain from donating sperm Exclusion criteria

[00282] Patients who meet any of the following criteria will be excluded from study entry: • Any suspected or known active infection at screening or baseline, or any serious episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks before and during screening or treatment with oral antimicrobials within 2 weeks before and during screening • History of suspected or confirmed progressive multifocal leukoencephalopathy • History of cancer, including hematologic malignancies and solid tumors, within 10 years prior to screening. Squamous or basal cell carcinoma of the skin that was removed and considered cured and carcinoma in situ of the cervix treated with apparent success by curative treatment > 1 year before screening are not considered exclusive. • Immunocompromised status, defined as one or more of the following: CD4 count < 250 / pL or ANC < 1.5 x 103 / pL or serum IgG < 4.6 g / L • Known presence of other neurological disorders, including but not limited to: - History of ischemic cerebrovascular disorders (for example, stroke, transient ischemic attack, spontaneous intracranial hemorrhage, or traumatic intracranial hemorrhage) or spinal cord ischemia - History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma) - History or known presence of potential metabolic causes of myelopathy (for example, untreated vitamin B12 deficiency) - History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, Herpes zoster myelopathy) - History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraplegia, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke syndrome) - Neuromyelitis optica spectrum disorder - History or known presence of systemic autoimmune disorders that could potentially cause progressive neurological disease (e.g., lupus, antiphospholipid antibody syndrome, Sjógren's syndrome, Behget's disease) - History or known presence of sarcoidosis - History of clinically significant and severe brain or spinal cord trauma (e.g., brain contusion, spinal cord compression) • Evidence of cardiovascular (including arrhythmias or QTc prolongation), psychiatric, pulmonary, renal, hepatic, endocrine ( including uncontrolled diabetes, pancreatitis without gallstones, or chronic pancreatitis), metabolic or clinically significant gastrointestinal (GI) that, in the opinion of the investigator, may preclude patient participation • Patients who meet class III and class IV criteria from the New York Heart Association for congestive heart failure • Screening 12-lead ECG demonstrating clinically relevant abnormalities that may affect patient safety or interpretation of study results that include QT interval corrected by Fridericia formula > 440 ms demonstrated by at least two ECGs > 30 minutes apart • Current treatment with medications known to prolong the QT interval at doses that have a clinically significant effect on QT, as determined by the investigator • History of ventricular arrhythmias or risk factors for ventricular arrhythmias, such as syndrome long QT and other genetic risk factors (eg, Brugada syndrome); structural heart disease; coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing, prior coronary artery bypass grafting, or coronary lesions >70% diameter stenosis that was not or cannot be revascularized); clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia); family history of sudden unexplained death; or genetic mutations of cardiac ion channels (for example, congenital long QT syndrome) • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study • History of alcohol or illicit drug abuse within 12 months prior to screening • Woman who is pregnant or breastfeeding, or trying to become pregnant during the study or within 6 or 12 months (as appropriate according to the local package insert for ocrelizumab) after the final dose of study drug All women of reproductive potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed locally at specified subsequent visits. If a urine pregnancy test is positive, it should be confirmed by a serum pregnancy test (performed locally). • Positive screening tests for active, latent, or inadequately treated hepatitis B (as demonstrated by any of the following): - Positive result with respect to hepatitis B surface antigen - Positive result for hepatitis B core antibody [total HBcAb] and detectable hepatitis B virus DNA • Positive screening tests for hepatitis C (positive for hepatitis C antibodies). • Evidence of active, latent, or inadequately treated tuberculosis (TB) infection as defined by the following: - Positive QuantiFERON TB-Gold® (QFT) test is required at screening or within 3 months prior to screening. If QFT is not available, a negative Mantoux purified protein derivative skin test, as defined by the Centers for Disease Control and Prevention guidelines, may be performed at the screening visit or within 3 months prior to screening and with local reading. - Patients with a history of Bacille Calmette-Guerin vaccination should be screened using the QFT test only. - An undetermined QFT test must be repeated. - A positive QFT test or two consecutive indeterminate QFT results should be considered a positive diagnostic TB test. - An indeterminate QFT test followed by a negative QFT test should be considered a negative diagnostic TB test. • Abnormalities in liver synthetic function tests (e.g., PT, INR, PTT, albumin) that the investigator considers clinically significant • History of hospitalizations or transfusions for Gl bleeding • Known bleeding diathesis • Any condition that would possibly affect oral drug absorption • History of currently active primary or secondary (non-drug related) immunodeficiency, including known history of HIV infection or IgG < 500 mg / dL • Contraindications to mandatory premedications (i.e., corticosteroids and antihistamines) for related reactions with infusion (IRR), including: - Psychosis not controlled for corticosteroids - Angle closure glaucoma for antihistamines • Inability to complete an MRI scan (contraindications for MRI scan, including but not limited to pacemakers, cochlear implants, intracranial vascular clips, surgery within 6 weeks prior to study entry, coronary stent implanted within 8 weeks prior to the time of the desired MRI scan) or contraindication to gadolinium administration • Poor peripheral venous access • Any previous treatment with bone marrow transplant and hematopoietic stem cell transplant • Any previous history of transplant or treatment against rejection • Treatment with systemic corticosteroids within 4 weeks before screening The screening period may be extended for patients who used systemic corticosteroids for MS before screening. For a patient to be eligible, no systemic corticosteroids should be administered between screening and baseline. • Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization • Sensitivity or intolerance to any ingredient (including excipients) of fenebrutinib or ocrelizumab • Received live or live attenuated vaccine within 6 weeks prior to randomization. Influenza vaccination is permitted if the inactivated vaccine formulation is administered. • Requirement of systemic anticoagulant (oral or injectable) or antiplatelet agent other than non-steroidal anti-inflammatory drugs, aspirin and other salicylates (aspirin allowed up to 162 mg once daily) • Prior treatment with fenebrutinib or another Bruton's tyrosine kinase inhibitor for any indication • Treatment with any investigational agent (including high-dose biotin) within 24 weeks prior to screening (visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency) • Need for any prohibited concomitant medications • Use of treatments that act on upstream B cells (including alemtuzumab). Patients on historical anti-CD20 therapy who have CD19+ B cell levels within a normal range at screening and baseline as determined by screening and baseline results from the central laboratory may be eligible. study. • Previous use of fingolimod or another sphingosine-1 -phosphate receptor modulator within 3 months prior to randomization9• Previous use of cladribine within 12 months prior to randomization3• Previous use of natalizumab for more than 1 year and within 6 months prior to randomization9• Previous treatment with mycophenolate mofetil, methotrexate, mitoxantrone, dimethyl fumarate, glatiramer acetate, interferons, teriflunomide, or laquinimod within 3 months prior to randomization3 Patients previously treated with teriflunomide will require the appropriate elimination protocol (according to the local package insert). • Any prior treatment with daclizumab, alemtuzumab, or cyclophosphamide • Previous treatment with any other immunomodulatory or immunosuppressive medication not listed above without adequate rest as described in the applicable local package insert. If washout requirements are not described in the applicable local package insert, the washout period should exceed 5 times the half-life of the medication. The PD effects of previous medication should also be considered when determining the time required for rest.3• Have one or more of the following laboratory results: - Estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2 (can be repeated if eGFR 45-59 mL / min / 1.73 m2) - ALT or AST > 2 x ULN (can be repeated if 2-3 x ULN) - Total bilirubin of more than 1.5 x ULN (can be repeated if 1.6-3 x ULN), with the exception of patients with Gilbert's disease - Hemoglobin < 9.5 g / dL (can be repeated if 9-9.4 g / dL) - Platelet count < 100 x 109 / L (can be repeated if 80-100 x 109 / L) - Abnormalities in liver synthetic function tests (e.g., PT, INR, PTT, albumin) that are considered clinically significant by the investigator. aPatients screened for this study should not be withdrawn from other treatments for the sole purpose of meeting trial eligibility. . Patients who discontinue their current treatment for non-medical reasons should be specifically informed about their treatment options before deciding to enter the study. Eligibility criteria for the open extension phase

[00283] Patients who meet the following criteria can participate in the OLE phase: • Completed the DBT phase of the study (remaining on study treatment; no administration of another DMT) and who, in the opinion of the investigator, may benefit from treatment with fenebrutinib • Are able and willing to provide written informed consent for participate in the OLE phase and to comply with the study protocol • For women of reproductive potential: agreement to remain abstinent (refrain from heterosexual relations) or use contraceptive methods with a failure rate of < 1% per year during the study period treatment and for at least 28 days after the final dose of fenebrutinib. Women should refrain from donating eggs during the same period. • For men: agreement to remain abstinent (refrain from heterosexual relations) or use a condom and agree to refrain from donating sperm. Completion of the study

[00284] The completion of this study is defined as the date on which the last patient visit (LPLV) occurs in the OLE phase or the LPLV in the OLE-SFU phase, whichever occurs later. Study duration

[00285] The duration of the DBT phase will be approximately 225 weeks or approximately 4.7 years (assuming the last patient is randomized after 122 weeks of enrollment + 120 weeks of the DBT phase for the last patient entered into the study). The maximum duration of the study, from screening of the first patient 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 the DBT phase + 24 weeks of rest + 96 weeks of treatment with fenebrutinib OLE + 8 weeks of OLE-SFU for the last patient entered into the study).

[00286] Additionally, the sponsor may decide to end the study at any time or extend the duration of the OLE. Research medicinal products Fenebrutinib or placebo

[00287] Patients will take two 100 mg tablets orally BID for a total dose of 400 mg of fenebrutinib (or placebo) once daily. Patients will self-administer two 100 mg tablets in the morning and two 100 mg tablets in the evening orally. Fenebrutinib (or placebo) can be taken by mouth with or without food. Administration of the study drug should be spaced with the use of antacid (i.e., the study drug should be taken 2 hours before or 2 hours after antacid administration). Patients will be instructed that a missed dose should not be taken with the next scheduled dose.

[00288] For patients participating in the intensive PK sampling subgroup, the daytime dose of fenebrutinib (or placebo) on days 1 and 15 will be administered at the daytime clinic visit (mandatory) while the patient is fasting. Patients will be instructed that a missed dose should not be taken with the next scheduled dose. Ocrelizumab or placebo

[00289] Patients will be administered IV infusions of 600 mg of ocrelizumab (or placebo) every 24 weeks. The first dose of ocrelizumab (or placebo) will be administered as two 300 mg IV infusions given 14 days apart. For subsequent doses, ocrelizumab (or placebo) will be administered as a single 600 mg IV infusion every 24 weeks. A minimum interval of 22 weeks should be maintained between each single infusion. Each 300 mg dose of ocrelizumab (or placebo) should be administered as a slow IV infusion over about 2.5 hours. Each 600 mg dose of ocrelizumab should be administered as a slow IV infusion over about 3.5 hours.

[00290] All patients should receive mandatory prophylactic treatment with 100 mg of methylprednisolone administered by slow IV infusion, which should be completed approximately 30 minutes before the start of each ocrelizumab (or placebo) infusion. The use of an equivalent dose of an alternative steroid should be used as premedication before the infusion in case the use of methylprednisolone is contraindicated for the patient. Additionally, a mandatory IV or oral antihistamine drug (such as 50 mg of diphenhydramine or an equivalent dose of an alternative) should be administered approximately 30-60 minutes before the start of each ocrelizumab (or placebo) infusion. An analgesic / antipyretic, such as acetaminophen / paracetamol (1 g), may also be considered. Statistical methods Primary analysis

[00291] The primary efficacy endpoint for this trial is time to appearance of cCDP12, defined as the time from baseline to the first cCDP12. The independent analysis investigator at each study site will evaluate cCDP components (EDSS, 9-HPT, and T25FWT) for all patients at the site at screening, baseline, regularly scheduled visits during the DBT phase, at visits unscheduled and at the treatment interruption visit. The independent analysis investigator is not the physician responsible for the patient's care (i.e., the treating investigator).

[00292] The time to the appearance of cCDP12 in the fenebrutinib group and the ocrelizumab group will be compared and evaluated using a stratified log-rank test with null and alternative hypotheses as follows: Ho: There is no difference in time to appearance of cCDP12 between the fenebrutinib and ocrelizumab groups. Hi: There is a difference in the time to the appearance of cCDP12 between the fenebrutinib and ocrelizumab groups.

[00293] The proportion of patients with cCDP12 over time will be estimated using KaplanMeier methodology and the total hazard ratio will be estimated using the stratified Cox proportional hazards model.

[00294] The specific composite component that generated the initial composite disability progression event is necessary for confirmation of cCDP. All assessments between the baseline event and the confirmatory visit need to match the definition of a composite disability progression event to be confirmed. Assessments occurring within 30 days of a protocol-defined relapse will not be used for confirmation of initial disease progression. Patients who prematurely discontinue study drug will be asked to continue with the assessments specified for the study, and an attempt will be made to follow up on their primary and secondary assessments at the next scheduled visit. All baseline disability progression events with corresponding confirmatory visits at the next scheduled visit will be considered for statistical analysis regardless of whether the patient discontinued study drug or the confirmatory visit occurred during the DBT phase. Determination of sample size

[00295] The objective of this study is the estimation and analysis of hypotheses regarding the effect of fenebrutinib on the time from baseline to cCDP12 relative to ocrelizumab. P values ​​and point and interval estimates of the underlying true hazard ratio will be obtained.

[00296] The sample size of this trial is based on the evaluation of the null hypothesis of no difference between the control and experimental groups. Approximately 946 patients will be enrolled in the study with an expected enrollment of more than 122 weeks. The sample size of this study depends on the primary efficacy analysis of cCDP12 and the following assumptions: • A two-group test of equal time to cCDP12 • Two-sided type I error = 0.05 • Time to cCDP12 after an exponential distribution in each group • 50% of patients in the control group have cCDP12 events that occur for week 120 • A final analysis is based on approximately 486 cCDP12 events • Approximately 89% power when actual risk reduction = 25% (i.e., hazard ratio = 0.75) • 20% dropout per group by week 120 Example 2: A MULTICENTRIC, RANDOMIZED, DOUBLE-BLIND, DOUBLE-SIMULATION, PARALLEL-GROUP PHASE III STUDY TO EVALUATE THE EFFICACY AND SAFETY OF FENEBRUTINIB COMPARED TO OCRELIZUMAB IN ADULT PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS

[00297] This phase III study will analyze the efficacy and safety of fenebrutinib compared to ocrelizumab in adult subjects with PPMS. The specific objectives, corresponding endpoints, inclusion criteria, exclusion criteria and other aspects of this study are as described in Example 1 above, with the following additions and / or changes: • Primary efficacy objective: Assess time to onset of cCDP12: All assessments between the baseline event and confirmation visit need to match the definition of a composite disability progression event to be confirmed. Assessments occurring within 90 days of a protocol-defined relapse will not be used for confirmation of initial disease progression. • Secondary efficacy objectives: - Percent change in total brain volume from week 24 as assessed by MRI scan - Change from baseline in self-reported physical effects of MS (as measured by Multiple Sclerosis Impact Scale, 29-Item Physical Scale [MSIS-29]) • An exploratory endpoint is added: change with from baseline and proportion of patients with significant deterioration from baseline at week 120, global impression of change in MS (patient global impression of change) • The safety endpoint, change from baseline in Columbia Scale for Assessing the Seriousness of Suicidal Ideation is changed to: Proportion of patients with suicidal behavior or ideation, as assessed by Columbia Scale for Assessing the Seriousness of Suicidal Ideation ινΐΛ / a / zuzz / u i uo i □ • Randomization will be stratified according to the following criteria: - Global region (US vs. non-US) - EDSS score (< 5.0 vs > 5.0) - T1Gd+ MRI at screening (presence or absence) • Inclusion criteria: - Patients must be able and willing to provide a signed informed consent form to participate. - The disability progression questionnaire prior to baseline will be used to confirm one year of disability progression independent of clinical relapse • Exclusion criteria: -Patients with a previous history of severe IRR (common terminology criteria for grade > 4 adverse events) and / or any hypersensitivity reaction to ocrelizumab - Gilbert syndrome is included in clinically significant liver disease that may, in the opinion of the investigator, prevent patient participation - Men who intend to father a child during the study or within 6 or 12 months (as appropriate according to the local package insert for ocrelizumab) after the final dose of study drug • Exclusion criteria regarding concomitant and / or previously administered medications is updated to include: -Treatment with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, within 7 days or 5 drug elimination half-lives (whichever is longer) before randomization -Treatment with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug elimination half-lives (whichever is longer) before randomization -Prior use of anti-CD20, including ocrelizumab, within 6 months prior to randomization, and where treatment discontinuation was not due to safety reasons or lack of efficacy - Previous use of fingolimod, siponimod, or ozanimod within 8 weeks prior to randomization -Previous use of natalizumab for more than 1 year and within 6 months prior to randomization -Previous treatment with dimethyl fumarate, interferons, and glatiramer acetate within 4 weeks prior to randomization ινΐΛ / a / zuzz / u i uo i □ -Previous treatment with mycophenolate mofetil or methotrexate 12 weeks prior to randomization -Prior teriflunomide treatment, unless >1= 24 months before screening or if teriflunomide plasma concentrations are < 0.02 mg / L at screening -Any prior treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide • Pregnancy testing: Prior to week 12, pregnancy testing will be performed at each scheduled clinic visit. After week 12, women of reproductive potential will be required to perform monthly home urine pregnancy tests in addition to the urine pregnancy tests performed at each scheduled clinic visit. Urine pregnancy test kits will be provided to female patients at each scheduled clinic visit. If a patient becomes pregnant during the study, the patient will be instructed to immediately discontinue the study drug, inform the investigator, and report for an unscheduled visit within 5 days of discovering the pregnancy. A positive result from a home urine pregnancy test should be confirmed by a serum pregnancy test, preferably by the central laboratory. Home pregnancy testing is not necessary beyond 28 days after permanently stopping study treatment. • If pregnancy is detected, it should be confirmed by serum pregnancy test. If pregnancy is confirmed, the patient must permanently discontinue the study drug. • In the double-blind treatment (DBT) phase, patients will be randomized in a 1:1 ratio to oral fenebrutinib 200 mg BID (or placebo) or ocrelizumab IV 600 mg (or placebo). • Semi-structured telephone interviews will be conducted during the DBT phase every 6 weeks (± 3 days) between study visits from week 24 onwards. • Semi-structured telephone interviews will be conducted in the OLE phase every 6 weeks (± 3 days) between study visits from week 24 onwards. Prohibited treatments

[00298] Medications in the categories below should be prohibited for 7 days or 5 half-lives, whichever is longer, prior to the first dose of study drug until the final dose of study drug: • Strong CYP3A4 inhibitors • Strong or moderate CYP3A inducers

[00299] The following medications should be prohibited during study treatment: • CYP3A4 substrates with a narrow therapeutic window Table 1 summarizes a list of prohibited medications. The list is not exhaustive: Class Examples of drugs in this class Strong CYP3A4 inhibitors Boceprevir, cobicistat, clarithromycin, danoprevir / ritonavir, elvitegravir / ritonavir, indinavir / ritonavir, itraconazole, idelalisib, ketoconazole, lopinavir / ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir , telithromycin and voriconazole Strong CYP3A inducers Apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin and hyperforin (St. John's wort) Moderate CYP3A inducers Bosentan, dexamethasone, efavirenz, etravirine, phenobarbital, pidone, phenobarbital and rifabutin CYP3A4 substrate with a narrow therapeutic window Alfentanil, astemizole, cyclosporine, cisapride, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, terfenadine and tacrolimus Other prohibited treatments

[00300] The use of the following concomitant treatments is prohibited as described below for patients in the DBT phase who remain on study treatment, in the OLE phase, and in the OLE-SFU phase: • Investigational treatment (other than study treatment indicated per protocol) • Any treatment that acts on B cells (for example, rituximab, alemtuzumab, atacicept, belimumab, ofatumumab or commercial ocrelizumab) • BTK inhibitors (other than fenebrutinib) • Any other DMT for MS (including, but not limited to, high-dose biotin, cladribine, mitoxantrone, interferons, dimethyl fumarate and other fumarates, and fingolimod and other sphingosine-1-phosphate receptor modulators) • Systemic anticoagulant agent (oral or injectable) ) or antiplatelet therapy other than nonsteroidal anti-inflammatory drugs, aspirin, and other salicylates (aspirin allowed up to 162 mg once daily) • Use of separate doses of acid-lowering agents (e.g., PPI, H2RA) at visits requiring PK sampling is prohibited.

[00301] The use of the following concomitant treatment is prohibited as described below during the DBT phase for patients discontinuing DBT and DBT-SFU treatment: • Investigational treatment (other than study treatment indicated by protocol)

[00302] Caution is recommended when administering DMT after the use of fenebrutinib. There are insufficient data available regarding the risk associated with switching from fenebrutinib to other products. Table 2 summarizes a list of medications that can be administered concomitantly, but such administration may include some precautions. The list is not exhaustive: Class Recommendation Examples of drugs in this class Antacids Take fenebrutinib 2 hours before or 2 hours after antacid • Bismuth subsalicylate, calcium carbonate, aluminum-magnesium hydroxide (e.g., Maalox®, Pepto-Bismol®, Rolaids®) Substrates of breast cancer resistance protein (BCRP) Use with caution and monitoring for adverse events related to BCRP substrates according to the product package insert • Antihypertensive (prazosin) • Anti-inflammatory (sulfasalazine) • Lipid-lowering (rosuvastatin [maximum dose recommended: 10 mg / day], atorvastatin [maximum recommended dose: 20 mg / day]) • Muscle relaxants (dantrolene) • Steroids (estrone-3-sulfate) Sensitive CYP3A substrates Use with caution and monitoring for substrate-related adverse events of CYP3A according to the product package insert • Antiemetic / prokinetic (aprepitant) • Antihistamine (astemizole) • Antihypertensive / cardiac (dronedarone, eplerenone, felodipine, nisoldipine, ticagrelor, vardenafil) • Benzodiazepines (alprazolam, diazepam, midazolam) • Reducer lipids (simvastatin [maximum recommended dose: 10mg / day], lovastatin [maximum recommended dose: 20mg / day]) • Antimigraine (eletriptan, ergotamine) • Steroids (budesonide, fluticasone) • Other (buspirone, conivaptan, darifenacin, dasatinib, lurasidone , quetiapine, sildenafil, tolvaptan, triazolam) Relapse evaluation

[00303] For this study, a relapse is the appearance of new or worsening neurological symptoms attributed to MS and immediately preceded by an improving neurological state with relative stability of at least 90 days. Symptoms must persist for > 24 hours and must not be attributed to clinical confounding factors (e.g., fever, infection, injury, adverse reactions to concomitant medications). New or worsening neurological symptoms must be accompanied by objective neurological worsening consistent with an increase in at least one of the following: • Half stage (0.5 points) in EDSS • Two points in one of the selected FSS listed below • One point in two or more of the selected FSS listed below

[00304] The change must affect the following selected FSS: pyramidal, ambulation, cerebellar, brainstem, sensory, or visual. Episodic spasms, sexual dysfunction, fatigue, mood changes, or urinary and / or bowel incontinence will not be enough to establish a relapse. Note that it is not necessary to rate the following items: sexual dysfunction and fatigue. Example 3: Comparison of in vitro properties of BTK inhibitors

[00305] The in vitro properties of the three BTK inhibitors fenebrutinib, evobrutinib and tolebrutinib are compiled in Table 3. Evobrutinib and tolebrutinib are covalent inhibitors, while fenebrutinib is a non-covalent inhibitor. The kinase selectivities of fenebrutinib, evobrutinib, tolebrutinib, and the covalent BTK inhibitor ibrutinib are also shown in Figure 1A-1B.

[00306] The BTK inhibitor potency (IC50) and kinase selectivity of fenebrutinib (FEN), evobrutinib (EVO), and tolebrutinib (TOL) were evaluated in-house or in a commercial panel of over 200 human kinases. FEN, TOL and EVO were screened at 1 μΜ, and EVO was also screened at 10 μΜ since it has weaker BTK IC50 than FEN and TOL. IC50 values ​​were determined for all kinases inhibited by at least 50% in the initial screening at 1 or 10 μΜ. In order to demonstrate that the selectivity values ​​determined using IC50 values ​​are relevant for the covalent inhibitors EVO and TOL, their covalent reactivity, or k-maM inactivation efficiency, was measured in biochemical assays by monitoring real-time competition for the inhibitors. covalently with a fluorescent active site ligand against BTK and BMX. FEN was also evaluated in human blood for its ability to block the activation of B lymphocytes (CD69) and basophils (CD63). The release rate of FEN from the BTK«FEN complex was quantified in a biochemical preincubation and dilution experiment, where the BTK activity was recovered with a rate constant H and residence time 1 / koff.

[00307] FEN potently inhibits BTK (ICso=2.3 nM); TOL inhibits BTK with ICso=1 -5 nM, while EVO is much less potent (ICso=32 nM). In whole blood, FEN potently blocks the activation of B lymphocytes (CD69 ICso=8 nM) and basophils (CD63 ICso=31 nM). In the kinase panel, FEN (1 μΜ) inhibits by >50% only 3 / 286 off-target kinases, while TOL (1 μΜ) inhibits 19 / 218 off-target kinases. EVO inhibits 3 / 221 off-target kinases at 1 μΜ, but at 10 μΜ it inhibits 18 / 218 kinases. Based on kinase IC50 values, FEN is >130-fold selective against all 286 kinases tested, while EVO is <75-fold selective against Bmx (0.5x), TEC (2x), ErbB4 (10x), Blk ( 23x) and Flt3 (71x). TOL is <10-fold selective against BMX, BLK, ERBB4, TXK, and LCK, and inhibits eleven additional kinases with <100-fold selectivity (Src, Fgr, TEC, RIPK2, BRK, CSK, YES, ERBB2, EGFR, HCK, and SRM). The difference in kinase selectivity between the compounds tested is illustrated in greater detail in Figure 1 A-1 B. Additionally, the covalent kinetic selectivity of EVO and TOL, as assessed by the ratio of kmüIKi for BMX versus to BTK (EVO=0.5, TOL=1), was almost equal to the IC50 selectivity for these inhibitors against these kinases (EVO=0.5, TOL=2). Finally, in a preincubation-dilution assay, the BTK»FEN complex demonstrated high stability; FEN dissociates slowly from BTK and has a residence time of 18.3 hours bound to BTK. Table 3 summarizes the in vitro properties of fenebrutinib, evobrutinib and tolebrutinib. Parameter Fenebrutinib Evobrutinib Tolebrutinib Kinase selectivity qty. off-target kinases >50% INH / qty. total kinases evaluated at 1 μΜ 2 / 286a 3 / 221a 19 / 218d BTK IC50, nM (selectivity factor) 2.3 (1)a 31.7 (1)a 1.5 (1) d Src IC50, nM (selectivity factor) 302 (131)a - 54 (36)d BMXIC50, nM (selectivity factor) 351 (153)a 15 (0.5)d 2.5 (2)d Fgr IC50, nM (selectivity factor) 387 (168)a 2,330 (74) )d 33 (22)d BLK IC50, nM (selectivity factor) - 727 (23)d 3.0 (2) d ERBB4 IC50, nM (selectivity factor) - 326 (10)d 6.1 (4) d FLT3IC50, nM (selectivity factor) - 2,250 (71 )d - TEC IC50, nM (selectivity factor) - 64.1 (2)d 18 (12)d TXK IC50, nM (selectivity factor) - 254 (8)d 3.9 (3 )d CK1 e1 IC50, nM (selectivity factor) - 1,450 (46)d - CDK8 / cycC IC50, nM (selectivity factor) - 3,500(110)d - LCKIC50, nM (selectivity factor) - 3,800 (120) d 7.5 (5)d MLK2 IC50, nM (selectivity factor) - 3,980 (126)d - MKNK2 IC50, nM (selectivity factor) - 4,130 (130)d - FGFR1 IC50, nM (selectivity factor) - 4,150 ( 131)d - RIPK2 IC50, nM (selectivity factor) - 4.330 (137)d 125 (83)d ITKIC50, nM (selectivity factor) - 4.640 (146)d - BRKIC50, nM (selectivity factor) - 6.020 ( 190)d 44 (29)d CSK IC5o, nM (selectivity factor) - 7.820 (247)d 87 (58)d RET IC50, nM (selectivity factor) - 8.630 (272)d - YES IC50, nM (selectivity factor) - - 16 (11 )d ERBB2 IC50, nM (selectivity factor) - - 25 (17)d EGFR IC50, nM (selectivity factor) - - 60 (40)d HCK IC50, nM (selectivity factor) - - 91 (61)d SRM IC50, nM (selectivity factor) - - 116 (77)d LYN IC50, nM (selectivity factor) - - 194 (129)d FRK IC50, nM (selectivity factor) - - 231 (154)d TNK2 IC50 , nM (selectivity factor) - - 847 (565)d Covalent reaction BTK K¡, nM NA 290d 8.7d BTK Ainact, S'1 NA 0.0052d 0.00063d BTK Ainact / Ki, M'1 S'1 NA 18,000d 58,100d Covalent reaction BMX K¡, nM NA 84d 42 d BMX k¡nact, S'1 NA 0.0032d 0.0029d BMX kinact / Ki, M-1 S-1 NA 38,100d 60,800d Kinetic selectivity Covalent (BTK kinact / Ki ) / (BMX Ainact / K¡) NA 0.5d 1.0d Kinetics and residence time BTK residence time, h (jump dilution versus 50 μ M ATP) 18.3a NA NA BTK K. nM 7.1d NA NA BTK K*, nM 0.17d NA NA BTK residence time, h (competitive binding) 6.6d NA NA ω or < Human blood IC50 for CD69, nM 8.4a 84b 10c ινΐΛ / a / zuzz / u i uo i □ IC50 of human blood for CD63, nM 30.7a 1,660b 166c a - Crawford, et al., J Med Chem 2018, 61: 2227-2245 b - Haselmeyer, J Immunol 2019, 202: 2888-2906 c - Francesco, ECTRIMS 2017 poster (PRN), available at <https: / / onlinelibrary .ectr¡mscongress.eu / ectrims / 2017 / ACTRIMSECTRIMS2017 / 200644 / m¡chelle.r.francesco.prn2246.a.potent.and.selective.blood.bra¡n.barrier.html> d - Not published NA = Not applicable

[00308] Unpublished data on kinase selectivity were generally obtained according to the procedures of Crawford, ef al., J Med Chem 2018, 61: 2227-2245 (SI pp S31-S32). Unpublished data on covalent reaction (k¡nact / K¡) were generally obtained according to the procedures of Schnute, et al., ACS Med Chem Lett 2018, 10: 80-85 (SI pp S29-S31), using N-terminal His-tagged full-length recombinant human BTK. BTK residence time data were obtained according to the procedures of Crawford, ef al., J Med Chem 2018, 61: 2227-2245 (SI pp S43) . Unpublished data on competitive binding kinetics were generally obtained according to the procedures of Schnute, ef al., ACS Med Chem LettZMS, 10: 80-85 (SI pp S29-S31), using labeled full-length recombinant human BTK with N-terminal His. The impact of ibrutinib, another covalent BTK inhibitor, on the activation of B lymphocytes and basophils in human blood was also evaluated (CD63 IC50 nM = 171; CD69IC50 nM = 12; Crawford, et al., J Med Chem 2018, 61:2227-2245).

Claims

1. Use of approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof, for the production of a drug to treat primary progressive multiple sclerosis (PPMS) in a subject in need.

2. Use according to claim 1, further comprising assessing the progression of disability in the subject, wherein the progression of disability is assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Timed Walk Test (T25FWT), or any combination thereof.

3. Use according to claim 1 or 2, further comprising assessing the occurrence of the composite 12-week confirmed disability progression (cCDP12), wherein the occurrence of cCDP12 comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) an increase from baseline of at least 20% over time until completion of 9-HPT; and (c) an increase from baseline of at least 20% in the T25FWT, and wherein the progression event is confirmed at least 12 weeks after the initial progression.

4. Use according to any of claims 1 to 3, wherein the time to a progression event in the subject increases, wherein the progression event is: an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

5. Use according to any of claims 1 to 4, wherein the time to a progression event in the subject increases, wherein the progression event is an increase of at least 20% from the baseline value at the time to completion of 9-HPT.

6. Use according to any of claims 1 to 5, wherein the time to a progression event in the subject increases, wherein the progression event is an increase of at least 20% with respect to the baseline value in T25FWT.

7. Use according to any of claims 1 to 6, wherein the time to the appearance of CDP12, cCDP12, CDP24 or cCDP24 is increased compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

8. Use according to claim 7, wherein an anti-CD20 antibody is adapted for administration to the PPMS subject who is not being administered fenebrutinib.

9. Use in accordance with any of claims 4 to 8, wherein the time to a progression event or the time to onset is increased by at least 10%.

10. Use of approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof for the production of a drug to slow the progression of PPMS in a subject who needs it.

11. Use according to claim 10, wherein PPMS progression is assessed using MSIS29, upper limb Neuro-QoL, PROMIS-FatigueMs, MSWS-12, PGI-S, WPAkMS, PGI-C, EQ-5D-5L, CSSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels 12. Use according to claim 10 or 11, wherein the PPMS progression comprises at least one progression event.

13. Use of approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof for the production of a drug to delay the onset of at least one progression event in a subject with PPMS.

14. Use of about 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof for the production of a drug to reduce the risk of a subject with PPMS having at least one progression event.

15. Use according to any of claims 12 to 14, wherein the at least one progression event is selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) an increase from baseline of at least 20% in the time to completion of the 9-HPT; and (c) an increase from baseline of at least 20% in the T25FWT.

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

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

18. Use according to any of claims 13, 15 or 16, wherein the occurrence of at least one progression event is delayed by at least 10% compared to another subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof and is administered an anti-CD20 antibody.

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

20. Use of approximately 200 mg of fenebrutinib twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof for the production of a drug to reduce disability in a subject with PPMS.

21. Use according to claim 20, wherein the reduction of disability comprises: reducing the psychological impact of MS; increasing upper limb function; increasing walking ability; decreasing fatigue; improving work status; or decreasing the overall impression of severity of MS; or any combination thereof.

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

23. Use according to any of claims 1 to 22, wherein the method further comprises the step of measuring one or more clinical or laboratory assessment criteria in the subject in order to evaluate efficacy for treating PPMS.

24. Use according to claim 23, wherein one or more clinical or laboratory assessment criteria are selected from the group consisting of MSIS-29, Upper Extremity Neuro-QoL, PROMISFatigueMs, MSWS-12, PGI-S, WPAI:MS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels 25. Use according to any of claims 1 to 24, wherein fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted for oral administration.

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

27. Use according to any of claims 1 to 26, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered in the form of two tablets twice daily, wherein each tablet comprises approximately 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

28. Use in accordance with any of claims 1 to 27, wherein the free form of fenebrutinib is adapted for administration.

29. A compound for use in treating primary progressive multiple sclerosis (PPMS) in a subject in need, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the compound is adapted to be administered to the subject at approximately 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 progression of disability in the subject is further assessed using the Expanded Disability Status Scale (EDSS), the 9-Hole Peg Test (9-HPT), or the 25-Foot Timed Walk Test (T25FWT), or any combination thereof.

31. The compound for use according to claim 29 or 30, wherein the occurrence of composite confirmed disability progression (cCDP12) is further evaluated, wherein the occurrence of cCDP12 comprises at least one progression event selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) an increase from baseline of at least 20% over time until completion of 9-HPT; and (c) an increase from baseline of at least 20% in T25FWT, and wherein the progression event is confirmed at least 12 weeks after the initial progression.

32. The compound for use according to any of claims 29 to 31, wherein the time to a progression event increases, wherein the progression event is: an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points.

33. The compound for use according to any of claims 29 to 32, wherein the time to a progression event increases, wherein the progression event is an increase of at least 20% from the baseline value at the time to completion of 9-HPT.

34. The compound for use according to any of claims 29 to 33, wherein the time to a progression event increases, wherein the progression event is an increase of at least 20% from the baseline value at T25FWT.

35. The compound for use according to any of claims 29 to 34, wherein the time to the appearance of CDP12, cCDP12, CDP24 or cCDP24 is increased compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

36. The compound for use according to claim 35, wherein an anti-CD20 antibody is adapted for administration to the PPMS-nonadministered subject.

37. The compound for use according to any of claims 32 to 36, wherein the time to a progression event or the time to onset is increased by at least 10%.

38. A compound for use in slowing the progression of PPMS in a subject in need, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the compound is adapted to be administered to the subject at approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

39. The compound for use according to claim 38, wherein PPMS progression is assessed using MSIS-29, upper limb Neuro-QoL, PROMIS-FatigueMS, MSWS-12, PGI-S, WPAkMS, PGI-C, EQ-5D-5L, C-SSRS, 9-HPT, T25FWT, EDSS, SDMT, MRI, or NfL levels 40. The compound for use according to claim 38 or 39, wherein the PPMS progression comprises at least one progression event.

41. A compound for use in delaying the onset of at least one progression event in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the compound is adapted to be administered to the subject at approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

42. A compound for use in reducing the risk of a subject with PPMS having at least one progression event, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the compound is adapted to be administered to the subject at approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

43. The compound for use according to any one of claims 40 to 42, wherein the at least one progression event is selected from the group consisting of: (a) an increase from baseline in the EDSS score of at least 1.0 point in a subject with a baseline EDSS score of less than or equal to 5.5 points; or an increase from baseline in the EDSS score of at least 0.5 points in a subject with a baseline EDSS score of more than 5.5 points; (b) an increase from baseline of at least 20% in the time to completion of 9-HPT; and (c) an increase from baseline of at least 20% in T25FWT.

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

45. The compound for use according to any of claims 38 to 40, 43 or 44, wherein progression is slowed by at least 10% compared to another subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof and is administered an anti-CD20 antibody.

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

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

48. The compound for use according to any of claims 38 to 47, wherein progression is slowed, or onset is delayed, or risk is reduced, compared to a subject with PPMS who is not administered fenebrutinib or a pharmaceutically acceptable salt thereof.

49. A compound for use in reducing disability in a subject with PPMS, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the compound is adapted to be administered to the subject at approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

50. The compound for use according to claim 49, wherein the reduction of disability comprises: reducing the psychological impact of MS; increasing upper limb function; increasing walking ability; decreasing fatigue; improving work status; or decreasing the overall impression of severity of MS; or any combination thereof.

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

52. The compound for use according to any of claims 29 to 51, wherein one or more clinical or laboratory assessment criteria in the subject are additionally measured in order to evaluate efficacy for treating PPMS.

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

54. The compound for use according to any of claims 29 to 53, wherein fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted for oral administration.

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

56. The compound for use according to any of claims 29 to 55, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted for administration in the form of two tablets twice daily, wherein each tablet comprises approximately 100 mg of fenebrutinib or an equivalent amount of a pharmaceutically acceptable salt thereof.

57. The compound for use according to any of claims 29 to 56, wherein the free form of fenebrutinib is adapted for administration.

58. The use according to any of claims 1 to 28, or the compound for use according to any of claims 29 to 57, wherein the subject with PPMS had a progressive disease from onset, and was in a progressive stage for at least 12 months prior to commencement of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

59. Use according to any of claims 1 to 28 or 58, or the compound for use according to any of claims 29 to 58, wherein prior to commencement of administration of fenebrutinib or a pharmaceutically acceptable salt thereof, the subject has at least two of: (a) one or more characteristic T2 hyperintense lesions of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical or infratentorial; (b) two or more T2 hyperintense lesions in the spinal cord; and (c) the presence of specific cerebrospinal fluid oligoclonal bands.

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

61. Use according to any of claims 1 to 28 or 58 to 60, or the compound for use according to any of claims 29 to 60, wherein the subject with PPMS does not have one or more of: estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2; ALToAST > 2 x ULN; total bilirubin > 1.5 x ULN; hemoglobin < 9.5 g / dL; platelet count < 100 x 109 / L; or abnormalities in one or more of the liver synthetic function tests PT, INR, PTT, or albumin.

62. The use according to any of claims 1 to 28 or 58 to 61, or the compound for use according to any of claims 29 to 61, wherein the subject is not concomitantly administered a strong CYP3A4 inhibitor while being administered approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

63. The use according to any of claims 1 to 28 or 58 to 62, or the compound for use according to any of claims 29 to 62, wherein the subject is not concomitantly administered a strong CYP3A4 inducer while being administered approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

64. Use according to any of claims 1 to 28 or 58 to 63, or the compound for use according to any of claims 29 to 63, wherein the subject is not concomitantly administered a moderate CYP3A4 inducer while being administered approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

65. The use according to any of claims 1 to 28 or 58 to 64, or the compound for use according to any of claims 29 to 64, wherein the subject is not concomitantly administered a CYP3A4 substrate with a narrow therapeutic window while being administered approximately 200 mg of fenebrutinib twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

66. A compound for use in the preparation of a medicament according to any of claims 1 to 28 or 58 to 65, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof.