Methods for treating rheumatoid arthritis, chronic spontaneous urticaria, and systemic lupus erythematosus using inhibitors of Bruton's tyrosine kinase

Abstract

Methods for treating rheumatoid arthritis, chronic spontaneous urticaria, and systemic lupus erythematosus are provided. [Solution] Provided is a method for treating a human patient with moderate to severe active rheumatoid arthritis, wherein the patient has not shown an adequate response to prior treatment with one or more conventional non-biologic DMARDs, the method comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 to about 400 mg per day.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 795,477, filed January 22, 2019, and U.S. Provisional Application No. 62 / 913,270, filed October 10, 2019, the contents of which are incorporated by reference in their entireties. [Technical Field]

[0002] The present disclosure relates to methods of treating rheumatoid arthritis, chronic spontaneous urticaria, and systemic lupus erythematosus using inhibitors of Bruton's tyrosine kinase (BTK). [Background technology]

[0003] Bruton tyrosine kinase (BTK): Discovering the genetic basis of primary immunodeficiencies has provided a source of novel therapeutic targets for immunomodulatory therapy. In humans, mutations in the Bruton tyrosine kinase (BTK) gene, located on the X chromosome, can lead to the development of immunodeficiency states characterized by a significant lack of circulating B cells (Bruton OC. Pediatrics 1952,9:722-8; Conley ME, et al., Immunol Rev 2005,203:216-34). These mutations can also result in very low immunoglobulin levels due to defects in B cell differentiation at the pro- to pre-B cell stage, which prevent assembly of the B cell receptor (BCR) complex 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 immunodeficiency, X-linked agammaglobulinemia (XLA), which predisposes them to recurrent infections beginning shortly after birth. Patients with XLA can live relatively normal lives with standard treatment of intravenous (IV) immunoglobulin, suggesting that BTK can be safely inhibited, particularly in people with established immune systems. IV immunoglobulin replacement therapy has reduced infection rates and hospitalization rates in XLA patients and significantly improved the long-term prognosis of these patients.

[0004] BTK is essential for B cell differentiation and activity 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 occur on tyrosine Y223 in a BTK-specific manner. Upon activation, BTK mediates PLCγ2-dependent and Ca2+-dependent cellular upregulation. 2+BTK induces FcεRI signaling, which leads to activation of NF-κB and NFAT-dependent pathways, resulting in cell activation and differentiation (Niir H, Clark EA. Nat Rev Immunol 2002, 2:945-56). Furthermore, BTK is important in FcεRI signaling in both basophils and mast cells, a cell type important in the pathogenesis of CSU. BTK-deficient mice have impaired FcεRI signaling, leading to reduced histamine and proinflammatory cytokine release (Iyer AS, et al., J Bio Chem 2011, 286:9503-13. doi:10.1074 / jbc.M110.1656131).

[0005] Rheumatoid arthritis (RA): RA is an autoimmune disorder characterized by progressive synovitis, systemic inflammation, and the production of characteristic autoantibodies that can lead to progressive joint damage, arthropathy, and impaired joint-dependent movement, potentially resulting in a significant decrease in quality of life, unemployment, and premature death. Hypotheses about the pathogenesis of RA have focused on autoantibody production, immune complex formation in synovial membrane, proinflammatory cytokine production, especially interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and the role of B cells and myeloid cells in inflamed synovial membrane (see, for example, Martin F, Chan AC. Immunity 2004,20:517-27; Looney RJ. Drugs 2006,66:625-39; Shlomchik MJ. Immunity 2008,28:18-28; Goronzy J, Weyand C., Arthritis Res. Ther. 2009,11:249). Although there are many drugs available for the treatment of RA, there is still an unmet need for safer treatments with improved efficacy, especially in the signs and symptoms of the disease that lead to complete remission.

[0006] Targeted B cell treatments have become a focus of development as immunomodulatory agents in autoimmune disorders. BTK is a key kinase in the signaling cascade following B cell-antigen receptor activation in B cells, Fc receptor binding of immune complexes in myeloid cells, and several Toll-like receptor signaling events in B cells, myeloid cells, and dendritic cells (Satterthwaite AB, Witte ON, Immunol. Rev. 2000, 175:120-7; Sochorova et al., Blood 2007, 109; 2553-6). Autoimmune disorders characterized by prominent B cell and immune complex-mediated activity, such as RA and systemic lupus erythematosus, may benefit from targeted antagonism of BTK signaling.

[0007] Chronic spontaneous urticaria (CSU): CSU, also known as chronic idiopathic urticaria (CIU), is defined by the presence of blisters (hives), angioedema, or both for at least 6 weeks without an apparent cause (Greaves M., Curr Opin Allergy Clin Immunol 2003, 3:363-8). Previously estimated prevalence of CSU was approximately 0.1%, with this persisting in 20% of patients 20 years after diagnosis (Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000, 105:664-72; Saini SS. Chronic spontaneuos urticaria: etiology and pathogenesis. Immunol Allergy Clin North. Am 2014, 34:33-52. doi:10.1016 / j.iac.2013.09.012). More recent evidence indicates a point prevalence of the disease of approximately 1% (Maurer M, et al., Arch Dermatol 2006, 142:1337-42). Affected patients experience frequent pruritic urticaria with associated episodes of erythema and / or angioedema. CSU has been reported to be associated with angioedema in approximately 50% of cases (McGirt LY, et al., Allergy 2011, 66:317-30). The typical description of urticaria is wheals and erythema with pale, raised lesions and surrounding erythema, ranging in size from a few millimeters to several centimeters, usually occurring in groups, often coalescing to form larger, confluent lesions.

[0008] The etiology of CSU is unclear. Several theories exist, including those suggesting an infectious origin and those related to an autoimmune origin (Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 2002, 346:175-9). Some studies have found that approximately 30% to 60% of CSU patients have an autoimmune component, as evidenced by the presence of a positive autologous serum skin test (Zweiman B, et al., Immunopharmacology 1998, 39:225-34). Another hypothesis regarding the etiology of CSU is that it is due to specific IgE antibodies targeting endogenous antigens. A study of over 450 CSU patients showed that over 50% of CSU patients had IgE antibodies against thyroid peroxidase (Altrichter S, et al., PLoS ONE 2011, 6:e14794).

[0009] Another common pathway in CSU is the abnormal activation of mast cells and basophils in the skin. Patients with CSU may exhibit increased mast cell numbers in both affected and unaffected skin (Kay AB, et al., Br J Dermatol 2014, 171:505-11. doi:10.1111 / bjd.12991). Mast cells from CSU patients are more sensitive, have a lower threshold for activation, and respond more strongly by releasing more histamine and other inflammatory mediators. Similarly, increased numbers of basophils have been observed in both affected and unaffected skin of patients with CSU (Ying S, et al., J Allergy Clin Immunol 2002, 109:694-700).

[0010] Approximately half of patients with CSU achieve symptomatic control with approved doses of H1 antihistamine therapy. In some cases, the antihistamine dose is increased (up to four times the approved dose per topical treatment guidelines) and additional therapies such as leukotriene receptor antagonists (LTRAs) are used, although increased doses of antihistamines and LTRAs are not approved for the treatment of CSU. Treatment success with these agents is variable and can be associated with severe adverse effects. Patients may remain symptomatic despite ongoing H1 antihistamine treatment (up to four times the approved dose according to topical treatment guidelines; Powell RJ, et al. Clin Exp Allergy 2015, 45:547-65. doi:10.1111 / cea.12494). Treatments such as immunosuppressants (e.g., cyclosporine, corticosteroids, intravenous immunoglobulin G, and methotrexate) and plasmapheresis have been used in this patient population (Kozel MA, Sabroe RA. Chronic urticaria, etiology, management, and current and future treatment options. Drugs 2004, 64:2515-36). Treatment success with these agents is variable and can be associated with severe adverse effects. More recently, omalizumab was approved for the treatment of refractory chronic urticaria / cirrhosis. CSU can be a debilitating condition due to the lack of clinical response and the inability to predict the disease course, both of which can have a significant negative impact on the patient's quality of life.

[0011] Systemic lupus erythematosus (SLE): SLE is an autoimmune rheumatic disease that primarily affects women of childbearing age. It is characterized by multisystem involvement and immunological abnormalities, with much of the tissue damage thought to occur via the formation of autoantibodies and deposition of immune complexes. The disease is heterogeneous in its clinical manifestations, course, and prognosis. However, most patients present with joint lesions, skin rash, oral ulcers, Raynaud's phenomenon, and / or severe fatigue. Inflammation of pericardial and pleural tissues may also be present. The most severe manifestations include central nervous system and renal involvement, which correlate with poor outcomes, including temporary or permanent disability or death. The disease usually follows a relapsing-remitting course, with periods of intermittent disease activity (skin redness) interspersed with periods of relative quiescence.

[0012] The number of drugs for the successful treatment of SLE, as measured by long-term remission, is limited, and only one new drug for the treatment of SLE has been approved in over 50 years (Burness CB, McCormack PL, Drugs 2011, 71:2435-44). Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) provide partial symptomatic relief. Antimalarial drugs are generally well tolerated by patients with SLE and appear to have beneficial effects in preventing lupus flares, increasing long-term survival, and possibly ameliorating certain types of organ damage (Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, et al., Arthritis Res. Ther. 2009, 11:R109). However, these drugs are generally considered insufficiently effective against moderate to severe manifestations of SLE.

[0013] As a measure of unmet need, the risk of death remains high for patients with lupus. Based on a contemporary multicenter international cohort of 9,500 patients with lupus, the standardized mortality rate was 2.4, with renal disease accounting for a particularly high mortality rate (Fors Nieves CE, Izmirly PM., Curr. Rheumatol. Rep. 2016, 18:21). The development of new treatments for SLE patients with high efficacy and low toxicity remains an important and necessary area of ​​research.

[0014] All references cited herein, including patent applications and patent publications, are hereby incorporated by reference in their entirety as if each individual reference was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0015] Provided herein are methods and uses of the BTK inhibitor, fenebrutinib, or a pharmaceutically acceptable salt thereof, for treating rheumatoid arthritis, chronic spontaneous urticaria, and systemic lupus erythematosus. Specifically, the methods and uses provided herein include administering fenebrutinib to patients with: (i) moderately to severely active RA that has responded inadequately to previous treatment; (ii) symptomatic CSU despite prior H1 antihistamine treatment; or (iii) moderately to severely active SLE that has responded inadequately to previous treatment.

[0016] Fenebrutinib has the formula: TIFF2026041743000001.tif36170, a compound of Names as follows: GDC-0853: (6 2 S)-2 3 -(hydroxymethyl)-1 7 ,1 7 ,3 1 ,6 2 -tetramethyl-1 3 ,1 4 ,1 7,1 8 -Tetrahydro-4-aza-1(2)-cyclopenta[4,5]pyrrolo[1,2-a]pyrazina-6(1,4)-piperazina-2(2,4),3(3,5),5(2,5)-tripyridina-7(3)-oxetanaheptaphane-1 1 (1 6 H),3 6 (3 1 H)-dione; and Also known as (S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one. The R enantiomer is: (R)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.

[0017] Fenebrutinib is a highly selective, orally administered, reversible inhibitor of BTK. U.S. Patent No. 8,716,274, incorporated herein by reference in its entirety, discloses a class of heteroarylpyridine and aza-pyridone compounds useful for inhibiting Btk, including fenebrutinib. International Publication No. WO 2017 / 148837, incorporated herein by reference in its entirety, discloses solid forms and formulations of fenebrutinib and its pharmaceutically acceptable salts.

[0018] In a first embodiment (Embodiment 1, "E1"), provided herein is a method of treating a human patient with moderate to severe active rheumatoid arthritis, wherein the patient has had an inadequate response to prior treatment with one or more conventional non-biologic DMARDs, comprising administering fenebrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 150 mg to about 400 mg daily.

[0019] E2: The method of E1, wherein the dose of fenebrutinib is about 200 mg administered twice daily.

[0020] E2a: The method of E1, wherein the daily dose of fenebrutinib is about 400 mg, administered as about 200 mg twice daily.

[0021] E3: The method of E1, wherein the dose of fenebrutinib is about 200 mg administered once daily.

[0022] E4: The method of E1, wherein the dose of fenebrutinib is about 100 mg administered twice daily.

[0023] E4a: The method of E1, wherein the daily dose of fenebrutinib is about 200 mg, administered as about 100 mg twice daily.

[0024] E5: The method of E1, wherein the dose of fenebrutinib is about 150 mg administered once daily.

[0025] E6: The method according to E1, wherein the dose of fenebrutinib is about 150 mg to about 300 mg per day.

[0026] E7: The method according to E1, wherein the dose of fenebrutinib is about 200 mg to about 300 mg per day.

[0027] E9: The method according to E1, wherein the dose of fenebrutinib is about 200 mg to about 400 mg per day.

[0028] E10: The method according to E1, wherein the dose of fenebrutinib is about 150 mg to about 200 mg per day.

[0029] E11: The method according to any one of E1 and E6 to E10, wherein the daily dose is administered once a day or twice a day.

[0030] E12: The method of E11, wherein when administered twice daily, each dose contains the same amount of fenebrutinib.

[0031] E13: The method of any one of E1 to E12, wherein the conventional non-biologic DMARD in the previous treatment is methotrexate.

[0032] E14: The method of any one of E1 to E13, wherein said fenebrutinib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

[0033] E15: The method of E14, wherein the additional therapeutic agent is methotrexate.

[0034] E16: The method of E14, wherein said additional therapeutic agent is a Janus kinase inhibitor.

[0035] E17: The method of E16, wherein said Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, pefitinib, and upadacitinib, and pharmaceutically acceptable salts thereof.

[0036] E18: The method of E16, wherein the Janus kinase inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.

[0037] E19: The method of any one of E16 to E18, wherein both therapeutic agents are orally administered in a single tablet or capsule.

[0038] E20: The method according to any one of E16 to E19, wherein methotrexate is also administered.

[0039] E21: The method of any one of E1-E20, wherein patients who have an inadequate response to prior treatment with one or more conventional non-biologic DMARDs are identified by RA disease activity according to the following joint counts and laboratory markers of inflammation: ≥6 tender / painful joints on movement (68 joint count) and ≥6 swollen joints (66 joint count).

[0040] E22: The method of any one of E1-E20, wherein patients exhibiting an inadequate response to prior treatment with one or more conventional non-biologic DMARDs are identified by an hsCRP of 0.400 mg / dL or greater.

[0041] E23: The method of any one of E1-E20, wherein the patient exhibiting an inadequate response to prior treatment with one or more conventional non-biologic DMARDs is identified as testing positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both.

[0042] E24: The method of any one of E1 to E20, wherein patients who have an inadequate response to prior treatment with one or more conventional non-biologic DMARDs are identified by: ·Having a diagnosis of adult-onset RA as defined by the 2010 ACR / European League Against Rheumatism Classification Criteria for RA; RA disease activity by joint count and laboratory markers of inflammation: ≥6 tender / painful joints on exercise (68 joint count) and ≥6 swollen joints (66 joint count); · hsCRP ≥ 0.400 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and -Received one or more conventional non-biologic DMARDs at a stable dose for at least 12 weeks prior to treatment with fenebrutinib.

[0043] E25: The method according to any one of E21 to E24, wherein said conventional non-biologic DMARD is methotrexate.

[0044] E26: A method of treating a human patient with moderate to severe active rheumatoid arthritis, wherein the patient has had an inadequate response to or intolerance to prior treatment with one or more biologic rheumatoid arthritis drugs, the method comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 to about 400 mg daily.

[0045] E27: The method of E26, wherein the dose of fenebrutinib is about 200 mg administered twice daily.

[0046] E27a: The method of E26, wherein the daily dose of fenebrutinib is about 400 mg administered twice daily as about 200 mg.

[0047] E28: The method of E26, wherein the dose of fenebrutinib is about 300 mg and is administered once daily.

[0048] E29: The method of E26, wherein the dose of fenebrutinib is about 100 mg administered twice daily.

[0049] E29a: The method of E26, wherein the daily dose of fenebrutinib is about 200 mg, administered as about 100 mg twice daily.

[0050] E30: The method of E26, wherein the dose of fenebrutinib is about 200 mg and is administered once a day.

[0051] E31: The method of E26, wherein the dose of fenebrutinib is about 150 mg administered twice daily.

[0052] E31a: The method of E26, wherein the daily dose of fenebrutinib is about 300 mg administered twice daily as about 150 mg.

[0053] E32: The method of E26, wherein the dose of fenebrutinib is about 150 mg and is administered once a day.

[0054] E33: The method of any one of E26 to E32, wherein said biological rheumatoid arthritis drug is selected from the group consisting of a TNF-alpha inhibitor, abatacept, tocilizumab, sarilumab, sirumab, anakinra, and any biosimilar equivalents thereof.

[0055] E34: The method of E33, wherein said biological rheumatoid arthritis drug is a TNF-alpha inhibitor.

[0056] E35: The method of E34, wherein said TNF-alpha inhibitor is selected from the group consisting of adalimumab, infliximab, etanercept, golimumab, certolizumab, or biosimilar equivalents thereof.

[0057] E36: The method of E35, wherein said TNF-alpha inhibitor is adalimumab.

[0058] E37: The method of any one of E26 to E36, wherein said fenebrutinib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

[0059] E38: The method of E37, wherein the additional therapeutic agent is methotrexate.

[0060] E39: The method of E37, wherein said additional therapeutic agent is a Janus kinase inhibitor.

[0061] E40: The method of E39, wherein the Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, pefitinib and upadacitinib, and pharmaceutically acceptable salts thereof.

[0062] E41: The method according to E40, wherein the Janus kinase inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.

[0063] E42: The method of any one of E39 to E41, wherein both therapeutic agents are administered orally in a single tablet or capsule.

[0064] E43: The method according to any one of E39 to E42, wherein methotrexate is also administered.

[0065] E44: The method of any one of E26 to E43, wherein the patient showing an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs is identified by insufficient efficacy or loss of efficacy at doses and durations considered acceptable for adequately assessing clinical response to prior treatment with at least one or no more than two biologic rheumatoid arthritis drugs according to the clinical practice of each institution.

[0066] E45: The method of any one of E26-E43, wherein patients who have an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs are identified by: Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0067] E46: The method of any one of E26 to E43, wherein patients who have an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs are identified by: · hsCRP ≥ 0.650 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0068] E47: The method of any one of E26-E43, wherein patients who have an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs are identified by: RA disease activity by joint count and laboratory markers of inflammation: ≥6 tender / painful joints on exercise (68 joint count) and ≥6 swollen joints (66 joint count); · hsCRP ≥ 0.650 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0069] E48: The method of any one of E26-E43, wherein patients who have an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs are identified by: ·Having a diagnosis of adult-onset RA as defined by the 2010 ACR / European League Against Rheumatism Classification Criteria for RA; RA disease activity by joint count and laboratory markers of inflammation: ≥6 tender / painful joints on exercise (68 joint count) and ≥6 swollen joints (66 joint count); · hsCRP ≥ 0.650 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0070] E49: The method of any one of E1-E48, wherein the patient exhibits relief of one or more symptoms of rheumatoid arthritis after treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0071] E50: The method of E49, wherein the reduction in the patient's symptoms is measured by at least a 50% reduction in the patient's American College of Rheumatology score (ACR50).

[0072] E51: The method of E49, wherein the reduction in the patient's symptoms is measured by a 70% reduction in the patient's American College of Rheumatology score (ACR70).

[0073] E52: The method of E49, wherein the reduction in the patient's symptoms is measured by a 20% reduction in the patient's American College of Rheumatology score (ACR20).

[0074] E53: The method of E49, wherein the reduction in the patient's symptoms is a reduction in the patient's HAQ-DI score.

[0075] E54: The method according to E49, wherein the reduction in the patient's symptoms is a reduction in the patient's DAS28 score.

[0076] E55: The method according to E49, wherein the alleviation of the patient's symptoms is a decrease in the patient's DAS28-3-CRP score.

[0077] E56: The method of E49, wherein the reduction in the patient's symptoms is a decrease in the patient's CRP relative to baseline.

[0078] E57: The method of E49, wherein the alleviation of the patient's symptoms is a decrease in the patient's ESR relative to baseline.

[0079] E58: The method according to E49, wherein the reduction in the patient's symptoms is a reduction in the patient's SF-36 score.

[0080] E59: The method of E49, wherein the reduction in the patient's symptoms is a decrease in the patient's FACIT-Fatigue score.

[0081] E60: The method according to E49, wherein the alleviation of the patient's symptoms is a reduction in two or more of the measures listed in E50 to E59.

[0082] E61: The method according to any one of E50 to E52, wherein the relief of the patient's symptoms is also assessed by a decrease in one or more of the measures set out in E54 to E59.

[0083] E62: The method of any one of E49-E61, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at the second week of treatment.

[0084] E63: The method of any one of E49-E61, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at week 4 of treatment.

[0085] E64: The method of any one of E49-E61, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at 8 weeks of treatment.

[0086] E65: The method of any one of E49-E61, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at 12 weeks of treatment.

[0087] E66: The method of any one of E1 to E65, further comprising measuring one or more clinical or laboratory endpoints for the patient to assess the effectiveness of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0088] E67: The method of E66, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of: patient: ACR50 score, ACR70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-Fatigue score, CRP relative to baseline, and ESR relative to baseline.

[0089] E67a: The method of E56 or E67, wherein the CRP baseline is the level of CRP in a sample from the patient before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0090] E67b: The method of E57, E67 or E67a, wherein the ESR baseline is the level of ESR in a sample from the patient before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0091] E68: The method of E66 or E67, wherein the clinical or laboratory endpoint is measured after 2 weeks of treatment.

[0092] E69: The method of E66 or E67, wherein the clinical or laboratory endpoint is measured after 4 weeks of treatment.

[0093] E70: The method of E66 or E67, wherein the clinical or laboratory endpoint is measured after 8 weeks of treatment.

[0094] E71: The method of E66 or E67, wherein the clinical or laboratory endpoint is measured after 12 weeks of treatment.

[0095] E72: The method of any one of E1 to E71, wherein the patient to be treated is positive for autoantibodies.

[0096] E73: A method according to any one of E1 to E71, comprising a first step of identifying in a patient's blood sample (i) the presence of autoantibodies, and (ii) an elevated ESR level compared to baseline prior to administering fenebrutinib or a pharmaceutically acceptable salt thereof to a patient who has tested positive for said autoantibodies and an elevated ESR.

[0097] E74: A method according to any one of E1 to E71, comprising a first step of identifying in a patient's blood sample (i) the presence of autoantibodies, and (ii) elevated CRP levels compared to baseline in the patient's blood sample prior to administration of fenebrutinib or a pharmaceutically acceptable salt thereof to a patient who has tested positive for said autoantibodies and elevated CRP.

[0098] E75: A method according to any one of E1 to E71, comprising a first step of identifying in a patient's blood sample (i) the presence of autoantibodies, (ii) an elevated level of CRP compared to baseline, and (iii) an elevated level of ESR compared to baseline prior to administering fenebrutinib or a pharmaceutically acceptable salt thereof to a patient who has tested positive for said autoantibodies and elevated CRP.

[0099] E75a: The method of any one of E74 to E75, wherein the CRP baseline is the level of CRP in a blood sample from a healthy subject without rheumatoid arthritis.

[0100] E75b: The method of any one of E73, E75, or E75a, wherein the ESR baseline is the level of ESR in a blood sample from a healthy subject without rheumatoid arthritis.

[0101] E76: The method according to any one of E72 to E75, wherein the autoantibody is selected from the group consisting of rheumatoid factor antibodies and anti-citrullinated peptide antibodies (ACPA).

[0102] E77: The method according to any one of E72 to E76, wherein the autoantibody comprises an IgM antibody.

[0103] E78: The method of any one of E1 to E71, comprising first confirming that the patient is seropositive prior to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0104] E79: A method for treating moderately to severely active rheumatoid arthritis in a human patient by administering fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the patient exhibits abnormalities in one or more biomarkers of liver function after administration of fenebrutinib, the method comprising: (a) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose lower than about 150 mg / day to about 400 mg / day for a fixed period of time; and subsequently (b) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg / day to about 400 mg / day.

[0105] E80: The method according to E79, wherein the dosage in step (a) is about 200 mg / day or less.

[0106] E81: The method of E79, wherein the dosage in step (a) is about 150 mg / day or less.

[0107] E82: The method according to any one of E79 to E81, wherein the dose in step (b) is the same as the dose in step (a).

[0108] E83: The method according to any one of E79 to E81, wherein the dose in step (b) is lower than the dose in step (a).

[0109] E84: The method according to any one of E79 to E83, wherein the abnormality in one or more biomarkers of liver function is a grade 2 abnormality.

[0110] E85: The method according to any one of E79 to E83, wherein the abnormality in one or more biomarkers of liver function is a grade 3 abnormality.

[0111] E86: The method according to any one of E79 to E85, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin and alkaline phosphatase.

[0112] E87: The method according to any one of E79 to E85, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase and aspartate transaminase.

[0113] E88: The method according to any one of E79 to E87, wherein prior to step (a), administration of fenebrutinib or a pharmaceutically acceptable salt thereof is discontinued until the biomarker of liver function is within the normal range.

[0114] E89: The method according to any one of E79 to E87, wherein the period of step (a) continues until the biomarker of liver function falls within the normal range.

[0115] E90: The method of any one of E79 to E89, further comprising measuring one or more biomarkers of liver function before or during step (a).

[0116] E91: The method of any one of E1 to E90, wherein prior to said treatment, a sample from the patient is found to have elevated levels of one or more biomarkers selected from the group consisting of rheumatoid factor IgM, total IgM, total IgG, CXCL13 and CCL4.

[0117] E92: A method for identifying a human patient with moderately to severely active rheumatoid arthritis who is more likely to benefit from a treatment comprising fenebrutinib or a pharmaceutically acceptable salt thereof, said method comprising measuring the level of one or more biomarkers selected from the group consisting of rheumatoid factor IgM, total IgM, total IgG, CXCL13 and CCL4 in a sample from said patient, wherein an elevated level of one or more biomarkers in said sample indicates that said patient is more likely to benefit from said fenebrutinib treatment.

[0118] E93: The method of E92, wherein said patient has an inadequate response to previous treatment with one or more conventional non-biologic DMARDs.

[0119] E94: The method of E92, wherein said patient has exhibited an inadequate response or intolerance to previous treatment with one or more biologic rheumatoid arthritis drugs.

[0120] E95: The method of any one of E91 to E94, wherein said sample is known to have elevated levels of two of said biomarkers.

[0121] E96: The method of any one of E91 to E94, wherein said sample is known to have elevated levels of three of the biomarkers.

[0122] E97: The method of any one of E91 to E94, wherein the sample is found to have elevated levels of four of the biomarkers.

[0123] E98: The method of any one of E91 to E94, wherein the sample is known to have elevated levels of each of the biomarkers rheumatoid factor IgM, total IgM, total IgG, CXCL13 and CCL4.

[0124] E98a: The method of any one of E91 to E98, wherein at least one of the one or more biomarkers is rheumatoid factor IgM.

[0125] E98b: The method of E91 or E98a, wherein the elevated level of rheumatoid factor IgM in a blood sample from said patient is greater than 20 units RF / ml, or greater than or equal to 15 IU / ml RF IgM, or both.

[0126] E99: The method according to any one of E1 to E98, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0127] E100: The method according to any one of E1 to E98, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally in the form of one or more tablets or capsules.

[0128] E101: The method according to any one of E1 to E98, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is orally administered in the form of one or more tablets.

[0129] E102: The method of any one of E1 to E101, wherein the free base of fenebrutinib is administered.

[0130] E103: A compound for use in a method for treating moderately to severely active rheumatoid arthritis in a human patient, wherein the patient has had an inadequate response to prior treatment with one or more conventional non-biologic DMARDs, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the treatment is at a dose of about 150 mg to about 400 mg of fenebrutinib per day.

[0131] E104: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 200 mg, administered twice daily.

[0132] E104a: A compound for use in the method according to E103, wherein the daily dose of fenebrutinib is about 400 mg, administered twice a day as about 200 mg.

[0133] E105: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 200 mg, administered once a day.

[0134] E106: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 100 mg, administered twice daily.

[0135] E106a: A compound for use in the method according to E103, wherein the daily dose of fenebrutinib is about 200 mg, administered twice a day as about 100 mg.

[0136] E107: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 150 mg, administered once a day.

[0137] E108: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 150 mg to about 300 mg per day.

[0138] E109: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 200 mg to about 300 mg per day.

[0139] E110: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 200 mg to about 400 mg per day.

[0140] E111: A compound for use in the method according to E103, wherein the dose of fenebrutinib is about 150 mg to about 200 mg per day.

[0141] E112: A compound for use in the method according to any one of E103 and E108 to E111, wherein the daily dose is administered once or twice daily.

[0142] E113: A compound for use in the method according to E112, wherein when administered twice daily, each dose contains the same amount of fenebrutinib.

[0143] E114: A compound for use in the method according to any one of E103 to E113, wherein the conventional non-biologic DMARD in the previous treatment is methotrexate.

[0144] E115: A compound for use in the method according to any one of E103 to E113, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

[0145] E116: A compound for use in the method according to E115, wherein the additional therapeutic agent is methotrexate.

[0146] E117: A compound for use in the method of E115, wherein the additional therapeutic agent is a Janus kinase inhibitor.

[0147] E118: A compound for use in the method according to E117, wherein the Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, pefitinib, and upadatinib, and pharmaceutically acceptable salts thereof.

[0148] E119: A compound for use in the method according to E117, wherein the Janus kinase inhibitor is tofacitinib, or a pharmaceutically acceptable salt thereof.

[0149] E120: A compound for use in the method according to any one of E115 to E120, wherein both therapeutic agents are administered orally in a single tablet or capsule.

[0150] E121: A compound for use in the methods of E115 to E121, wherein methotrexate is also administered.

[0151] E122: A compound for use in the method according to any one of E103 to E121, wherein patients showing an inadequate response to previous treatment with one or more conventional non-biologic DMARDs are identified by RA disease activity by laboratory markers of inflammation and joint count, wherein inadequate response by joint count refers to ≧6 tender / painful joints on movement (68 joint count) and ≧6 swollen joints (66 joint count).

[0152] E123: A compound for use in the method of any one of E103 to E121, wherein patients showing an inadequate response to previous treatment with one or more conventional non-biologic DMARDs are identified by an hsCRP of 0.400 mg / dL or greater.

[0153] E124: A compound for use in the method of any one of E103 to E121, wherein a patient who has an inadequate response to prior treatment with one or more conventional non-biologic DMARDs is identified as having tested positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both.

[0154] E125: A compound for use in the method according to any one of E103 to E121, wherein a patient having an inadequate response to prior treatment with one or more conventional non-biologic DMARDs is identified by: ·Having a diagnosis of adult-onset RA as defined by the 2010 ACR / European League Against Rheumatism Classification Criteria for RA; RA disease activity by joint count and laboratory markers of inflammation: ≥6 tender / painful joints on exercise (68 joint count) and ≥6 swollen joints (66 joint count); · hsCRP ≥ 0.400 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and -Received one or more conventional non-biologic DMARDs at a stable dose for at least 12 weeks prior to treatment with fenebrutinib.

[0155] E126: A compound for use in the method according to any one of E122 to E125, wherein the conventional non-biologic DMARD is methotrexate.

[0156] E127: A compound for use in a method for treating moderately to severely active rheumatoid arthritis in a human patient, wherein the patient has had an inadequate response to or intolerance to prior treatment with one or more biologic rheumatoid arthritis drugs, the compound being fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment being fenebrutinib at a dose of about 150 to about 400 mg daily.

[0157] E128: A compound for use in the method according to E127, wherein the dose of fenebrutinib is about 200 mg, administered twice daily.

[0158] E128a: A compound for use in the method according to E127, wherein the daily dose of fenebrutinib is about 400 mg, administered twice a day as about 200 mg.

[0159] E129: The compound for use in the method according to E127, wherein the dose of fenebrutinib is about 300 mg, administered once a day.

[0160] E130: A compound for use in the method according to E127, wherein the dose of fenebrutinib is about 100 mg, administered twice daily.

[0161] E130a: A compound for use in the method described in E127, wherein the daily dose of fenebrutinib is about 200 mg administered twice a day as about 100 mg.

[0162] E131: A compound for use in the method according to E127, wherein the dose of fenebrutinib is about 200 mg, administered once a day.

[0163] E132: A compound for use in the method according to E127, wherein the dose of fenebrutinib is about 150 mg administered twice daily.

[0164] E132a: The compound for use in the method according to E127, wherein the daily dose of fenebrutinib is about 300 mg administered twice a day as about 150 mg.

[0165] E133: A compound for use in the method according to E127, wherein the dose of fenebrutinib is about 150 mg, administered once a day.

[0166] E134: A compound for use in the method according to any one of E127 to E133, wherein the biological rheumatoid arthritis drug is selected from the group consisting of TNF-alpha inhibitors, abatacept, tocilizumab, sarilumab, sirumab, anakinra, and any biosimilar equivalents thereof.

[0167] E135: A compound for use in the method of E134, wherein the biological rheumatoid arthritis agent is a TNF-alpha inhibitor.

[0168] E136: A compound for use in the method according to E135, wherein said TNF-alpha inhibitor is selected from the group consisting of adalimumab, infliximab, etanercept, golimumab, certolizumab, or biosimilar equivalents thereof.

[0169] E137: A compound for use in the method according to E136, wherein said TNF-alpha inhibitor is adalimumab.

[0170] E138: A compound for use in the method according to any one of E127 to E137, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

[0171] E139: A compound for use in the method according to E138, wherein the additional therapeutic agent is methotrexate.

[0172] E140: A compound for use in the method according to E138, wherein the additional therapeutic agent is a Janus kinase inhibitor.

[0173] E141: A compound for use in the method according to E140, wherein the Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, pefitinib, and upadatinib, and pharmaceutically acceptable salts thereof.

[0174] E142: A compound for use in the method according to E141, wherein the Janus kinase inhibitor is tofacitinib or a pharmaceutically acceptable salt thereof.

[0175] E143: A compound for use in the method according to any one of E140 to E142, wherein both therapeutic agents are administered orally in a single tablet or capsule.

[0176] E144: A compound for use in the method according to any one of E140 to E143, wherein methotrexate is also administered.

[0177] E145: A compound for use in the method according to any one of E127 to E144, wherein patients who have an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs are identified by insufficient efficacy or loss of efficacy at doses and durations considered acceptable for adequate assessment of clinical response to prior treatment with at least one but not more than two biologic rheumatoid arthritis drugs according to the clinical practice of each institution.

[0178] E146: A compound for use in the method according to any one of E127 to E144, wherein a patient having an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs is identified by: Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0179] E147: A compound for use in the method of any one of E127 to E144, wherein a patient who has an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs is identified by: · hsCRP ≥ 0.650 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0180] E148: A compound for use in the method according to any one of E127 to E144, wherein a patient having an inadequate response to prior treatment with one or more biological rheumatoid arthritis drugs is identified by: RA disease activity by joint count and laboratory markers of inflammation: ≥6 tender / painful joints on exercise (68 joint count) and ≥6 swollen joints (66 joint count); · hsCRP ≥ 0.650 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0181] E149: A compound for use in the method according to any one of E127 to E144, wherein a patient who has an inadequate response to prior treatment with one or more biologic rheumatoid arthritis drugs is identified by: ·Having a diagnosis of adult-onset RA as defined by the 2010 ACR / European League Against Rheumatism Classification Criteria for RA; RA disease activity by joint count and laboratory markers of inflammation: ≥6 tender / painful joints on exercise (68 joint count) and ≥6 swollen joints (66 joint count); · hsCRP ≥ 0.650 mg / dL; Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both; and Experience of intolerance to, or insufficient efficacy or loss of efficacy of, prior treatment with at least one and no more than two biologic rheumatoid arthritis medications at doses and durations considered acceptable for adequate evaluation of clinical response, according to clinical practice at each institution.

[0182] E150: A compound for use in the method according to any one of E127 to E149, wherein the patient exhibits relief of one or more symptoms of rheumatoid arthritis after treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0183] E151: A compound for use in the method described in E150, wherein the relief of the patient's symptoms is measured by at least a 50% reduction in the patient's American College of Rheumatology score (ACR50).

[0184] E152: A compound for use in the method according to E150, wherein the relief of the patient's symptoms is measured by at least a 70% reduction in the patient's American College of Rheumatology score (ACR70).

[0185] E153: A compound for use in the method described in E150, wherein the relief of the patient's symptoms is measured by at least a 20% reduction in the patient's American College of Rheumatology score (ACR20).

[0186] E154: A compound for use in the method according to E150, wherein the alleviation of the patient's symptoms is a reduction in the patient's HAQ-DI score.

[0187] E155: A compound for use in the method according to E150, wherein the alleviation of the patient's symptoms is a reduction in the patient's DAS28 score.

[0188] E156: A compound for use in the method according to E150, wherein the alleviation of the patient's symptoms is a decrease in the patient's DAS28-3-CRP score.

[0189] E157: A compound for use in the method according to E150, wherein the alleviation of the patient's symptoms is a reduction in the patient's CRP relative to baseline.

[0190] E158: A compound for use in the method according to E150, wherein the alleviation of the patient's symptoms is a decrease in the patient's ESR relative to baseline.

[0191] E159: A compound for use in the method according to E150, wherein the alleviation of the patient's symptoms is a decrease in SF-36.

[0192] E160: A compound for use in the method according to E150, wherein the reduction in the patient's symptoms is a reduction in the patient's FACIT-Fatigue score.

[0193] E161: A compound for use in the method according to E150, wherein the relief of the patient's symptoms is relief from two or more of the measures set out in E151 to E160.

[0194] E162: A compound for use in the method according to any one of E151 to E153, wherein the relief of the patient's symptoms is also assessed by relief from one or more of the measures set out in E155 to E160.

[0195] E163: A compound for use in the method according to any one of E150 to E162, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at the second week of treatment.

[0196] E164: A compound for use in the method according to any one of E150 to E162, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at 4 weeks of treatment.

[0197] E165: A compound for use in the method according to any one of E150 to E162, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at 8 weeks of treatment.

[0198] E166: A compound for use in the method according to any one of E150 to E162, wherein relief of one or more symptoms of rheumatoid arthritis occurs within or at 12 weeks of treatment.

[0199] E167: A compound for use in the method according to any one of E103 to E166, further comprising measuring one or more clinical or laboratory endpoints in the patient to assess the effectiveness of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0200] E168: A compound for use in the method described in E167, wherein one or more clinical or laboratory endpoints are a patient's: ACR50 score, ACR70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-Fatigue score, the patient's CRP relative to baseline, and ESR relative to baseline.

[0201] E168a: A compound for use in the method according to E157 or E168, wherein the CRP baseline is the level of CRP in a sample from the patient before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0202] E168b: A compound for use in the method according to E158, E168 or E168a, wherein the ESR baseline is the level of ESR in a sample from the patient before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0203] E169: A compound for use in the method according to E167 or E168, wherein the clinical or laboratory endpoint is measured after 2 weeks of treatment.

[0204] E170: A compound for use in the method according to E167 or E168, wherein the clinical or laboratory endpoint is measured after 4 weeks of treatment.

[0205] E171: A compound for use in the method according to E167 or E168, wherein the clinical or laboratory endpoint is measured after 8 weeks of treatment.

[0206] E172: A compound for use in the method according to E167 or E168, wherein the clinical or laboratory endpoint is measured after 12 weeks of treatment.

[0207] E173: A compound for use in the method according to any one of E103 to E172, wherein the patient to be treated is positive for autoantibodies.

[0208] E174: A compound for use in a method according to any one of E103 to E172, the method comprising a first step of identifying in a blood sample from the patient (i) the presence of autoantibodies, and (ii) an elevated ESR level compared to baseline prior to administering fenebrutinib or a pharmaceutically acceptable salt thereof to a patient who has tested positive for the autoantibodies and an elevated ESR.

[0209] E175: A compound for use in a method according to any one of E103 to E172, the method comprising a first step of identifying (i) the presence of autoantibodies, and (ii) elevated CRP levels in a blood sample from the patient compared to baseline, prior to administering fenebrutinib or a pharmaceutically acceptable salt thereof to a patient who has tested positive for the autoantibodies and elevated CRP in a blood sample from the patient.

[0210] E176: A compound for use in a method according to any one of E103 to E172, the method comprising a first step of identifying in a blood sample from the patient (i) the presence of autoantibodies, (ii) an elevated level of CRP compared to baseline, and (iii) an elevated level of ESR compared to baseline prior to administering fenebrutinib or a pharmaceutically acceptable salt thereof to a patient who has tested positive for the autoantibodies and elevated CRP.

[0211] E176a: A compound for use in the method according to E174 or E176, wherein the baseline ESR is the level of ESR in a blood sample from a healthy subject without rheumatoid arthritis.

[0212] E176b: A compound for use in the method according to E175, E176, or E176a, wherein the baseline CRP is the level of CRP in a blood sample from a healthy subject without rheumatoid arthritis.

[0213] E177: A compound for use in the method according to any one of E173 to E176, wherein the autoantibody is selected from the group consisting of rheumatoid factor antibodies and anti-citrullinated peptide antibodies (ACPA).

[0214] E178: A compound for use in the method according to any one of E173 to E176, wherein the autoantibody comprises an IgM antibody.

[0215] E179: A compound for use in the method according to any one of E103 to E172, which method first comprises confirming that the patient is seropositive prior to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0216] E180: A compound for use in the method according to any one of E103 to E179, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0217] E181: A compound for use in the method according to any one of E103 to E180, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally in the form of one or more tablets or capsules.

[0218] E182: A compound for use in the method according to any one of E103 to E180, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally in the form of one or more tablets.

[0219] E183: A compound for use in the method according to any one of E103 to E182, wherein the compound is the free base of fenebrutinib.

[0220] E184: A method for treating a human patient with chronic spontaneous urticaria, wherein the patient is symptomatic despite previous treatment with an H1 antihistamine, comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 50 mg to about 400 mg per day.

[0221] E185: The method according to E184, wherein the dose of fenebrutinib is about 200 mg administered twice daily.

[0222] E185a: The method of E184, wherein the daily dose of fenebrutinib is about 400 mg, administered twice daily as about 200 mg.

[0223] E186: The method according to E184, wherein the dose of fenebrutinib is about 200 mg and is administered once a day.

[0224] E187: The method according to E184, wherein the dose of fenebrutinib is about 150 mg and is administered once a day.

[0225] E188: The method according to E184, wherein the dose of fenebrutinib is about 100 mg and is administered once a day.

[0226] E189: The method according to E184, wherein the dose of fenebrutinib is about 100 mg administered twice daily.

[0227] E189a: The method of E184, wherein the daily dose of fenebrutinib is about 200 mg, administered twice daily as about 100 mg.

[0228] E190: The method according to E184, wherein the dose of fenebrutinib is about 50 mg and is administered once a day.

[0229] E191: The method according to E184, wherein the dose of fenebrutinib is about 50 mg administered twice daily.

[0230] E191a: The method of E184, wherein the daily dose of fenebrutinib is about 100 mg, administered twice daily as about 50 mg.

[0231] E192: The method according to any one of E184 to E191, wherein the patient exhibits a reduction in the average weekly itch severity score from baseline after treatment.

[0232] E193: The method of E192, wherein the mean decrease is at least a 3 point mean decrease in change from baseline.

[0233] E194: The method of E192, wherein the mean decrease is at least a 5 point mean decrease in change from baseline.

[0234] E195: The method according to any one of E184 to E194, wherein the patient exhibits a decrease in Urticaria Activity Score (UAS7) from baseline after treatment.

[0235] E196: The method according to E195, wherein the patient's UAS7 is 6 or less after treatment.

[0236] E197: The method according to E195, wherein the patient's UAS7 is 4 or less after treatment.

[0237] E198: The method according to E195, wherein the patient exhibits a decrease in UAS7 of at least 11 points after treatment.

[0238] E199: The method according to any one of E184 to E198, wherein said patient exhibits a reduction in weekly urticaria counts from baseline after treatment.

[0239] E200: A reduction of at least 6 points in weekly urticaria counts from baseline, as measured by E199.

[0240] E201: The method according to any one of E192 to E200, wherein the reduction from baseline occurs within or at week 4 of treatment.

[0241] E202: The method according to any one of E192 to E200, wherein the reduction from baseline occurs within or at 8 weeks of treatment.

[0242] E203: The method according to any one of E192 to E200, wherein the reduction from baseline occurs within or at 12 weeks of treatment.

[0243] E203a: The method according to any one of E192 to E203, wherein the baseline is a value assessed in the patient before initiation of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0244] E204: The method according to any one of E184 to E203, wherein the patient is simultaneously administered an H1 antihistamine.

[0245] E205: The method according to E204, wherein said H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, diphenhydramine, hydroxyzine, chlorpheniramine and cyproheptadine.

[0246] E206: The method according to E204, wherein said H1 antihistamine is selected from the group consisting of cetirizine, fexofenadine, loratadine and desloratadine.

[0247] E207: The method described in any one of E184 to E206, which first comprises a step of determining the presence of an autoantibody in a blood sample from a patient having said autoantibody before administering fenebrutinib or a pharmaceutically acceptable salt thereof to said patient.

[0248] E208: The method according to E207, wherein the autoantibody can activate mast cells and / or basophils.

[0249] E209: The method described in E207, wherein the autoantibody identified in the sample is selected from the group consisting of an IgE antibody that binds to TPO, an IgE antibody that binds to IL24, an IgG antibody that binds to IgE, and an IgG antibody that binds to FcERI.

[0250] E210: The method according to any one of E207 to E209, wherein the presence of autoantibodies is measured by the CU index method.

[0251] E210-i: The method according to any one of E207 to E210, wherein the identified autoantibody comprises an IgG antibody that binds to FcERI.

[0252] E210-i: The method of E210-i, wherein the level of IgG antibodies that bind to FcERI in the sample is elevated compared to the level in a healthy subject without chronic spontaneous urticaria.

[0253] E211: A method for identifying a human patient with chronic spontaneous urticaria, said patient being symptomatic of the disease despite previous treatment with an H1 antihistamine; (i) determining that a sample from the patient has an elevated level of one or more biomarkers selected from the group consisting of an IgE antibody that binds to TPO, an IgE antibody that binds to IL24, an IgG antibody that binds to IgE, and an IgG antibody that binds to FcERI; and (ii) A method comprising the step of administering to a patient about 50 mg to about 400 mg of fenebrutinib or a pharmaceutically acceptable salt thereof per day.

[0254] E212: A method for identifying human patients with chronic spontaneous urticaria who are more likely to benefit from treatment comprising fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the patient is symptomatic for the disease despite previous treatment with an H1 antihistamine, and the method determines the level of one or more biomarkers selected from the group consisting of IgE antibodies that bind to TPO, IgE antibodies that bind to IL24, IgG antibodies that bind IgE, and IgG antibodies that bind to FcERI, whereby an elevated level of the one or more biomarkers in the sample indicates that the patient is more likely to benefit from the fenebrutinib treatment.

[0255] E212-i: The method according to any one of E211 to E212, wherein the sample from the patient exhibits elevated levels of IgG antibodies that bind to FcERI.

[0256] E212-ii: The method of any one of E211 to E212-i, wherein the elevated levels of one or more biomarkers are elevated compared to a healthy subject without chronic spontaneous urticaria.

[0257] E213: A method of treating a human patient with chronic spontaneous urticaria by administering fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the patient is symptomatic of the disease despite previous treatment with an H1 antihistamine, and the patient exhibits abnormalities in one or more biomarkers of liver function after administration of fenebrutinib, the method comprising: (a) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to less than about 400 mg per day for a period of time; and thereafter (b) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to about 400 mg per day.

[0258] E214: The method according to E213, wherein the dosage in step (a) is about 200 mg / day or less.

[0259] E215: The method according to E213, wherein the dosage in step (a) is about 150 mg / day or less.

[0260] E216: The method according to any one of E213 to E215, wherein the dose in step (b) is the same as the dose in step (a).

[0261] E217: The method according to any one of E213 to E215, wherein the dose in step (b) is lower than the dose in step (a).

[0262] E218: The method according to any one of E213 to E217, wherein the abnormality in one or more biomarkers of liver function is a grade 2 abnormality.

[0263] E219: The method according to any one of E213 to E217, wherein the abnormality in one or more biomarkers of liver function is a grade 3 abnormality.

[0264] E220: The method according to any one of E213 to E219, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin and alkaline phosphatase.

[0265] E221: The method according to any one of E213 to E219, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase and aspartate transaminase.

[0266] E222: The method according to any one of E213 to E221, wherein prior to step (a), administration of fenebrutinib or a pharmaceutically acceptable salt thereof is discontinued until the biomarker of liver function is within the normal range.

[0267] E223: The method according to any one of E213 to E222, wherein the period of step (a) continues until the biomarker of liver function falls within the normal range.

[0268] E224: The method according to any one of E213 to E223, further comprising measuring one or more biomarkers of liver function before or during step (a).

[0269] E225: The method according to any one of E184 to E224, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0270] E226: The method according to any one of E184 to E225, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is orally administered in the form of one or more tablets or capsules.

[0271] E227: The method according to any one of E184 to E226, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is orally administered in the form of one or more tablets.

[0272] E228: The method according to any one of E184 to E227, wherein said compound is the free base of fenebrutinib.

[0273] E229: A compound for use in a method of treating a human patient with chronic spontaneous urticaria, wherein the patient is symptomatic despite previous treatment with an H1 antihistamine, the compound being fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment is fenebrutinib at a dose of about 50 mg to about 400 mg per day.

[0274] E230: A compound for use in the method according to E229, wherein the dose of fenebrutinib is about 200 mg, administered twice daily.

[0275] E230a: A compound for use in the method according to E229, wherein the daily dose of fenebrutinib is about 400 mg, administered twice a day as about 200 mg.

[0276] E231: A compound for use in the method according to E229, wherein the dose of fenebrutinib is about 200 mg, administered once a day.

[0277] E232: A compound for use in the method according to E229, wherein the dose of fenebrutinib is about 150 mg, administered once a day.

[0278] E233: The compound for use in the method according to E229, wherein the dose of fenebrutinib is about 100 mg, administered once a day.

[0279] E234: A compound for use in the method according to E229, wherein the dose of fenebrutinib is about 100 mg, administered twice daily.

[0280] E234a: A compound for use in the method according to E229, wherein the daily dose of fenebrutinib is about 200 mg, administered twice a day as about 100 mg.

[0281] E235: A compound for use in the method according to E229, wherein the dose of fenebrutinib is about 50 mg, administered once a day.

[0282] E236: A compound for use in the method according to E229, wherein the dose of fenebrutinib is about 50 mg, administered twice daily.

[0283] E236a: A compound for use in the method according to E229, wherein the daily dose of fenebrutinib is about 100 mg, administered twice daily as 50 mg.

[0284] E237: A compound for use in the method according to any one of E229 to E236, wherein the patient exhibits a reduction in the mean weekly itch severity score from baseline after treatment.

[0285] E238: A compound for use in the method according to E237, wherein the mean decrease is at least a 3 point mean decrease in change from baseline.

[0286] E239: A compound for use in the method according to E237, wherein the mean decrease is at least a 5 point mean decrease in change from baseline.

[0287] E240: A compound for use in the method of any one of E229 to E239, wherein said patient exhibits a decrease in Urticaria Activity Score (UAS7) from baseline after treatment.

[0288] E241: A compound for use in the method according to E240, wherein the patient's UAS7 is 6 or less after treatment.

[0289] E242: A compound for use in the method according to E240, wherein the patient's UAS7 is 4 or less after treatment.

[0290] E243: A compound for use in the method described in E240, wherein the patient exhibits a UAS7 reduction of at least 11 points following treatment.

[0291] E244: A compound for use in the method according to any one of E229 to E243, wherein said patient exhibits a reduction in weekly urticaria counts from baseline following treatment.

[0292] E245: A compound for use in the method described in E244, wherein weekly urticaria counts are reduced by at least 6 points from baseline.

[0293] E246: A compound for use in the method of any one of E237 to E245, wherein the reduction from baseline occurs within or at 4 weeks of treatment.

[0294] E247: A compound for use in the method of any one of E237 to E245, wherein the reduction from baseline occurs within or at 8 weeks of treatment.

[0295] E248: A compound for use in the method of any one of E237 to E245, wherein the reduction from baseline occurs within or at 12 weeks of treatment.

[0296] E248a: A compound for use in the method according to any one of E237 to E248, wherein the baseline is a value determined in the patient before the start of administration of fenebrutinib or a pharmaceutically acceptable salt thereof.

[0297] E249: A compound for use in the method according to any one of E229 to E248, wherein the patient is simultaneously administered an H1 antihistamine.

[0298] E250: A compound for use in the method according to E249, wherein the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, diphenhydramine, hydroxyzine, chlorpheniramine and cyproheptadine.

[0299] E251: A compound for use in the method according to E249, wherein said H1 antihistamine is selected from the group consisting of cetirizine, fexofenadine, loratadine and desloratadine.

[0300] E252: A compound for use in the method according to any one of E229 to E251, which method first comprises a step of determining the presence of an autoantibody in a blood sample from a patient having said autoantibody before administering fenebrutinib or a pharmaceutically acceptable salt thereof to said patient.

[0301] E253: A compound for use in the method according to E252, wherein the autoantibody is capable of activating mast cells and / or basophils.

[0302] E254: A compound for use in the method described in E252, wherein the autoantibody identified in the sample is selected from the group consisting of an IgE antibody that binds to TPO, an IgE antibody that binds to IL24, an IgG antibody that binds to IgE, and an IgG antibody that binds to FcERI.

[0303] E254-i: A compound for use in the methods described in E252 to E254, wherein the autoantibodies identified in the sample include IgG antibodies that bind to FcERI.

[0304] E255: A compound for use in the method according to any one of E252 to E254, wherein the presence of autoantibodies is measured by the CU index method.

[0305] E256: A compound for use in the method according to any one of E229 to E255, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally.

[0306] E257: A compound for use in the method according to any one of E229 to E256, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is orally administered in the form of one or more tablets or capsules.

[0307] E258: A compound for use in the method according to any one of E229 to E257, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is orally administered in the form of one or more tablets.

[0308] E259: A compound for use in the method according to any one of E229 to E258, wherein said compound is the free base of fenebrutinib.

[0309] E260: A method for treating a human patient with moderately to severely active systemic lupus erythematosus whose disease is symptomatic despite previous standard oral SLE treatment, comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to about 400 mg per day.

[0310] E261: The method according to E260, wherein the dose of fenebrutinib is about 200 mg administered twice daily.

[0311] E261a: The method according to E260, wherein the daily dose of fenebrutinib is about 400 mg, administered twice daily as about 200 mg.

[0312] E262: The method according to E260, wherein the dose of fenebrutinib is about 200 mg and is administered once a day.

[0313] E263: The method according to E260, wherein the dose of fenebrutinib is about 100 mg and is administered twice daily.

[0314] E263a: The method according to E260, wherein the daily dose of fenebrutinib is about 200 mg, administered twice daily as about 100 mg.

[0315] E264: The method according to E260, wherein the dose of fenebrutinib is about 150 mg and is administered once a day.

[0316] E265: The method according to E260, wherein the dose of fenebrutinib is about 150 mg to about 300 mg per day.

[0317] E266: The method according to E260, wherein the dose of fenebrutinib is about 200 mg to about 300 mg per day.

[0318] E267: The method according to E260, wherein the dose of fenebrutinib is about 200 mg to about 400 mg per day.

[0319] E268: The method according to E260, wherein the dose of fenebrutinib is about 150 mg to about 200 mg per day.

[0320] E269: The method according to any one of E260 to E268, wherein when administered twice daily, each dose contains the same amount of fenebrutinib.

[0321] E270: The method according to any one of E260 to E269, wherein said standard oral SLE treatment is selected from the group consisting of oral corticosteroids, antimalarials and immunosuppressants.

[0322] E271: The method according to any one of E260 to E269, wherein the standard oral SLE treatment is selected from the group consisting of oral corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, mycophenolate sodium, hydroxychloroquine, chloroquine and quinacrine.

[0323] E272: The method according to any one of E260 to E271, wherein the administration is in combination with oral corticosteroids.

[0324] E273: The method according to any one of E260 to E272, wherein the patient exhibits a reduction in one or more clinical symptoms of SLE after treatment.

[0325] E274: The method according to E273, wherein the alleviation of the patient's clinical symptoms is measured by the patient's SLE Responder Index (SRI-4) score.

[0326] E275: The method of E273 or E274, wherein the reduction in the patient's clinical symptoms is measured by the patient's British Isles Lupus Activity Group-based Composite Lupus Assessment (BICLA) score.

[0327] E276: The method according to any one of E273 to E275, wherein the alleviation of one or more clinical symptoms of SLE occurs within or at 24 weeks of treatment.

[0328] E277: The method according to any one of E273 to E275, wherein the alleviation of one or more clinical symptoms of SLE occurs within or at 48 weeks of treatment.

[0329] E278: The method according to any one of E260 to E277, further comprising measuring one or more clinical endpoints for the patient to assess the effectiveness of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0330] E279: The method according to E278, wherein the clinical endpoint is the patient's SRI-4 score.

[0331] E280: The method according to E278 or E279, wherein the clinical endpoint is the patient's BICLA score.

[0332] E281: The method according to any one of E278 to E280, wherein the clinical endpoint is measured after 24 weeks of treatment.

[0333] E282: The method of any one of E278 to E280, wherein the clinical endpoint is measured after 48 weeks of treatment.

[0334] E283: The method according to any one of E260 to E282, which first comprises identifying the presence of one or more biomarkers in a blood sample of the patient prior to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the one or more biomarkers are selected from the group consisting of CCL3, CCL4, CCL20, CXCL13 and autoantibodies.

[0335] E284: A method according to any one of E260 to E282, which first comprises identifying the presence of one or more biomarkers in a patient's blood sample prior to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the biomarkers include IgJ, MZB1 and TXNDC5.

[0336] E284a: A method according to any one of E260 to E282, which first comprises identifying the presence of one or more biomarkers selected from the group consisting of IgJ, MZB1 and TXNDC5 in a patient's blood sample prior to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0337] E285: A method of treating a human patient with moderate to severe active systemic lupus erythematosus who is symptomatic despite previous standard oral SLE treatment, wherein a sample from the patient has been found to have elevated levels of one or more biomarkers selected from the group consisting of CCL3, CCL4, CCL20, CXCL13 and autoantibodies, the method comprising administering to the patient about 150 mg to about 400 mg of fenebrutinib or a pharmaceutically acceptable salt thereof per day.

[0338] E286: A method for treating a human patient with moderate to severe active systemic lupus erythematosus who is symptomatic despite previous standard oral SLE treatment, comprising: (i) determining that a sample from the patient has elevated levels of one or more biomarkers selected from the group consisting of CCL3, CCL4, CCL20, CXCL13 and autoantibodies; and (ii) A method comprising the step of administering to a patient about 150 to about 400 mg of fenebrutinib or a pharmaceutically acceptable salt thereof per day.

[0339] E287: A method for identifying SLE patients who are more likely to benefit from treatment comprising fenebrutinib or a pharmaceutically acceptable salt thereof by determining the level of one or more biomarkers selected from the group consisting of CCL3, CCL4, CCL20, CXCL13 and autoantibodies in a sample from the patient, wherein an elevated level of one or more biomarkers in the sample indicates that the patient is more likely to benefit from fenebrutinib treatment.

[0340] E288: A compound for use in a method of treating a human patient with moderate to severe active systemic lupus erythematosus, wherein the patient is symptomatic for the disease despite previous standard oral SLE treatment, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the fenebrutinib is administered to the patient at a dose of about 150 mg to about 400 mg daily.

[0341] E289: A compound for use in the method according to E288, wherein the dose of fenebrutinib is about 200 mg, administered twice daily.

[0342] E289a: A compound for use in the method described in E288, wherein the daily dose of fenebrutinib is about 400 mg, administered twice a day as about 200 mg.

[0343] E290: A compound for use in the method according to E288, wherein the dose of fenebrutinib is about 200 mg, administered once a day.

[0344] E291: A compound for use in the method according to E288, wherein the dose of fenebrutinib is about 100 mg, administered twice daily.

[0345] E291a: The compound for use in the method described in E288, wherein the daily dose of fenebrutinib is about 200 mg, administered twice a day as about 100 mg.

[0346] E292: A compound for use in the method according to E288, wherein the dose of fenebrutinib is about 150 mg, administered once a day.

[0347] E293: The compound for use in the method according to E288, wherein the dose of fenebrutinib is about 150 mg to about 300 mg per day.

[0348] E294: The compound for use in the method according to E288, wherein the dose of fenebrutinib is about 200 mg to about 300 mg per day.

[0349] E295: The compound for use in the method according to E288, wherein the dose of fenebrutinib is about 200 mg to about 400 mg per day.

[0350] E296: The compound for use in the method according to E288, wherein the dose of fenebrutinib is about 150 mg to about 200 mg per day.

[0351] E297: A compound for use in the method according to any one of E288 to E296, wherein when administered twice daily, each dose contains the same amount of fenebrutinib.

[0352] E298: A compound for use in the method according to any one of E288 to E297, wherein the standard oral SLE treatment is selected from the group consisting of oral corticosteroids, antimalarials and immunosuppressants.

[0353] E299: A compound for use in the method according to any one of E288 to E297, wherein the standard oral SLE treatment is selected from the group consisting of oral corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, mycophenolate sodium, hydroxychloroquine, chloroquine and quinacrine.

[0354] E300: A compound for use in the method according to any one of E288 to E299, wherein the administration is in combination with an oral corticosteroid.

[0355] E301: A compound for use in the method according to any one of E288 to E300, wherein the patient shows a reduction in one or more clinical symptoms of SLE after treatment.

[0356] E302: A compound for use in the method according to E301, wherein the alleviation of the patient's clinical symptoms is measured by the patient's SLE Responder Index (SRI-4) score.

[0357] E303: A compound for use in the method of E302 or E303, wherein the alleviation of clinical symptoms in said patient is measured by the patient's British Isles Lupus Activity Group-based Composite Lupus Assessment (BICLA) score.

[0358] E304: A compound for use in the method of any one of E301 to E303, wherein the alleviation of one or more clinical symptoms of SLE occurs within or at 24 weeks of treatment.

[0359] E305: A compound for use in the method of any one of E301 to E303, wherein the alleviation of one or more clinical symptoms of SLE occurs within or at 48 weeks of treatment.

[0360] E306: A compound for use in the method according to any one of E288 to E305, further comprising measuring one or more clinical endpoints for the patient to assess the effectiveness of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0361] E307: A compound for use in the method according to E306, wherein the clinical endpoint is the patient's SRI-4 score.

[0362] E308: A compound for use in the method according to E306 or E307, wherein the clinical endpoint is the patient's BICLA score.

[0363] E309: A compound for use in the method according to any one of E305 to E308, wherein the clinical endpoint is measured after 24 weeks of treatment.

[0364] E310: A compound for use in the method according to any one of E305 to E308, wherein the clinical endpoint is measured after 48 weeks of treatment.

[0365] E311: A compound for use in the method described in any one of E288 to E310, wherein the method first comprises identifying the presence of one or more biomarkers in a blood sample from a patient having the autoantibody before treating the patient with fenebrutinib or a pharmaceutically acceptable salt thereof, and the one or more biomarkers are selected from the group consisting of CCL3, CCL4, CCL20, CXCL13 and an autoantibody.

[0366] E312: A compound for use in the method described in any one of E288 to E310, wherein the method first comprises identifying the presence of one or more biomarkers in a patient's blood sample prior to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof, the biomarkers including IgJ, MZB1 and TXNDC5.

[0367] E313: Fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating moderately to severely active rheumatoid arthritis in a human patient, wherein the patient shows abnormalities in one or more biomarkers of liver function after administration of fenebrutinib, the method comprising the steps of: (a) administering to the patient about 150 mg to about 400 mg of fenebrutinib or a pharmaceutically acceptable salt thereof per day for a certain period of time; and subsequently (b) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to about 400 mg per day.

[0368] E314: Fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating a human patient with chronic spontaneous urticaria, wherein the patient is symptomatic of disease despite previous treatment with an H1 antihistamine, the patient exhibits abnormalities in one or more biomarkers of liver function following administration of fenebrutinib, and the patient is administered fenebrutinib or a pharmaceutically acceptable salt thereof at a dose lower than about 50 mg to about 400 mg per day for a period of time, followed by (b) administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 50 mg to about 400 mg per day to the patient.

[0369] E315: Fenebrutinib or a pharmaceutically acceptable salt thereof for use in treating a human patient with moderate to severe active systemic lupus erythematosus, wherein the patient exhibits abnormalities in one or more biomarkers of liver function after administration of fenebrutinib, the method comprising: (a) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of less than about 150 mg to about 400 mg per day for a fixed period of time, followed by (b) administering to the patient fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to about 400 mg per day.

[0370] E316: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E315, wherein the dose in step (a) is about 200 mg or less per day.

[0371] E317: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E315, wherein the dose in step (a) is about 150 mg or less per day.

[0372] E318: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E317, wherein the dose in step (b) is the same as the dose in step (a).

[0373] E319: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E317, wherein the dose in step (b) is lower than the dose in step (a).

[0374] E320: Fenebrutinib or a pharmaceutically acceptable salt thereof for the use according to any one of E313 to E319, wherein the abnormality in one or more biomarkers of liver function is grade 2 abnormality.

[0375] E321: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E319, wherein the abnormality in one or more biomarkers of liver function is grade 3 abnormality.

[0376] E322: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E321, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin and alkaline phosphatase.

[0377] E323: Fenebrutinib or a pharmaceutically acceptable salt thereof for use according to any one of E313 to E321, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase and aspartate transaminase.

[0378] Also provided herein is a compound, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for any one of the methods of treatment described in the preceding embodiments.

[0379] In addition to the specific embodiments described above, any one of the embodiments of the present invention may be combined.

[0380] It should be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the present invention will be apparent to those skilled in the art. These and other embodiments of the present invention are further described in the detailed description that follows. [Brief explanation of the drawings]

[0381] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the U.S. Patent and Trademark Office upon request and payment of the necessary fee.

[0382] [Figure 1] FIG. 1 shows ACR50 scores over time for Cohort 1 of the RA study with fenebrutinib in Example 1.

[0383] [Figure 2] FIG. 2 shows ACR50 scores over time for Cohort 2 of the RA study with fenebrutinib in Example 1.

[0384] [Figure 3]FIG. 3 shows the ACR scores at week 12 by treatment group in the clinical trial of the study using fenebrutinib in Example 1.

[0385] [Figure 4] FIG. 4 shows the ACR core parameter HAQ-DI for Cohort 1 of the RA study with fenebrutinib in Example 1.

[0386] [Figure 5] FIG. 5 shows Patient Global Assessment ("Patient GA") scores over time for Cohort 1 of the fenebrutinib RA study of Example 1.

[0387] [Figure 6] FIG. 6 shows the Physician Global Assessment ("Physician GA") scores over time for Cohort 1 of the RA study with fenebrutinib in Example 1.

[0388] [Figure 7] FIG. 7 shows the total swollen joint count (“SJC”) scores in Cohort 1 of the fenebrutinib RA study of Example 1.

[0389] [Figure 8] FIG. 8 shows the total tender joint (“TJC”) scores in Cohort 1 of the fenebrutinib RA study of Example 1.

[0390] [Figure 9] FIG. 9 shows pain over time for patients in Cohort 1 of the fenebrutinib RA study of Example 1.

[0391] [Figure 10] FIG. 10 shows the total HAQ-DI for Cohort 1 of the clinical study of the RA trial with fenebrutinib in Example 1.

[0392] [Figure 11]FIG. 11 shows TJC scores in Cohort 2 of the RA study using fenebrutinib in Example 1.

[0393] [Figure 12] FIG. 12 shows the SJC scores in Cohort 2 of the RA study with fenebrutinib in Example 1.

[0394] [Figure 13] FIG. 13 shows patient GA over time in Cohort 2 of the fenebrutinib RA study of Example 1.

[0395] [Figure 14] FIG. 14 shows physician GA over time in Cohort 2 of the fenebrutinib RA study of Example 1.

[0396] [Figure 15] FIG. 15 shows pain over time in patients in Cohort 2 of the fenebrutinib RA study of Example 1.

[0397] [Figure 16] FIG. 16 shows DAS28-3-CRP scores over time in Cohort 1 of the fenebrutinib RA study of Example 1.

[0398] [Figure 17] FIG. 17 shows DAS28-3-CRP scores over time in Cohort 2 of the fenebrutinib RA study of Example 1.

[0399] [Figure 18] FIG. 18 shows the reduction in CRP over time in Cohort 1 of the RA study with fenebrutinib of Example 1.

[0400] [Figure 19] FIG. 19 shows the decline in ESR over time in Cohort 1 of the RA pilot study using fenebrutinib in Example 1.

[0401] [Figure 20] FIG. 20 shows the mean change in UAS7 from baseline over time in Cohort 1 of the CSU study with fenebrutinib in Example 2.

[0402] [Figure 21A] FIG. 21A shows ACR50 responses by visit for cohorts 1 and 2 of the RA study with fenebrutinib in Example 1. [Figure 21B] FIG. 21B shows the mean change in baseline DAS28-4-CRP by visit for cohorts 1 and 2 of the study of RA with fenebrutinib in Example 1. [Figure 21C] Figure 21C shows the mean change from baseline in HAQ-DI by visit for Cohorts 1 and 2 of the study of RA with fenebrutinib in Example 1. Legend for all graphs is provided in Figure 21C.

[0403] [Figure 22A] FIG. 22A shows the absolute change from baseline in total IgM and IgG at week 12 for Cohort 1 in the fenebrutinib RA study of Example 1. [Figure 22B] Figure 22B shows the percent change from baseline in rheumatoid factor (RF) and ACPA levels for Cohort 1 in the fenebrutinib RA study of Example 1. Significance versus placebo is indicated by *. The x-axis for each graph is from left to right: placebo, 50 mg qd, 150 mg qd, 200 mg bid, ADA.

[0404] [Figure 23A] FIG. 23A shows the percent change in CCL4 from baseline to week 12 for Cohort 1 in the RA study with fenebrutinib in Example 1. [Figure 23B]FIG. 23B shows the percent change from baseline to week 12 in IL-6 for Cohort 1 in the fenebrutinib RA study of Example 1. [Figure 23C] FIG. 23C shows the percent change in CD19+ B cells from baseline to week 12 for Cohort 1 in the fenebrutinib RA study of Example 1. [Figure 23D] Figure 23D shows the percent change from baseline to week 12 in CD3+ T cells for Cohort 1 in the fenebrutinib RA study of Example 1. Significance versus placebo is indicated by *.

[0405] [Figure 24A] FIG. 24A shows ACR20 (FIG. 24A) responses from week 1 to week 12 for cohorts 1 and 2 of the fenebrutinib RA study of Example 1. [Figure 24B] FIG. 24B shows the ACR70 (FIG. 24A) responses from week 1 to week 12 for cohorts 1 and 2 of the fenebrutinib RA study of Example 1.

[0406] [Figure 25A] FIG. 25A shows the change in the ACR component of the SJC from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1. [Figure 25B] FIG. 25B shows the change in the ACR component of TJC from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1. [Figure 25C] FIG. 25C shows the change in the ACR component of the ESR from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1. [Figure 25D] FIG. 25D shows the change in the ACR component of CRP from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1.

[0407] [Figure 26A] FIG. 26A shows the change in the ACR component of the Physician's Global Assessment score from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1. [Figure 26B] FIG. 26B shows the change in the ACR component of the Patient Global Assessment score from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1. [Figure 26C] FIG. 26C shows the change in the ACR component of patient pain assessment scores from baseline to week 12 in cohorts 1 and 2 of the fenebrutinib RA study of Example 1.

[0408] [Figure 27] Figure 27 shows the absolute change from baseline in IgM and IgG (left) and the percent change from baseline in rheumatoid factor (RF) and ACPA (right) at week 12 for Cohort 2 of the fenebrutinib RA study in Example 1. Significance versus placebo is indicated by *.

[0409] [Figure 28A] FIG. 28A shows the percent change from baseline to week 12 in CCL4 from Cohort 2 of the fenebrutinib RA study of Example 1. [Figure 28B] FIG. 28B shows the percent change from baseline to week 12 in IL-6 from Cohort 2 of the RA study with fenebrutinib in Example 1. [Figure 28C] FIG. 28C shows the percent change from baseline to week 12 in CD19+ B cells from cohort 2 of the fenebrutinib RA study of Example 1. [Figure 28D] Figure 28D shows the percent change from baseline to week 12 in CD3+ T cells from Cohort 2 of the fenebrutinib RA study in Example 1. Significance versus placebo is indicated by *.

[0410] [Figure 29A] FIG. 29A shows the ACR50 response rate at week 12 as a function of baseline rheumatoid factor (RF) levels by quartile for Cohort 1 of the fenebrutinib RA study of Example 1. [Figure 29B] FIG. 29B shows the ACR50 response rate at week 12 as a function of baseline rheumatoid factor (RF) levels by quartile for Cohort 2 of the fenebrutinib RA study of Example 1.

[0411] [Figure 30A] FIG. 30A is a table summarizing the demographics and baseline characteristics of patients in the fenebrutinib RA study of Example 1. [Figure 30B] FIG. 30B is a table summarizing the demographics and baseline characteristics of patients in the fenebrutinib RA study of Example 1.

[0412] [Figure 31A] FIG. 31A is a table summarizing the primary and secondary efficacy endpoints at week 12 of the fenebrutinib RA study of Example 1. [Figure 31B] FIG. 31B is a table summarizing the primary and secondary efficacy endpoints at week 12 of the fenebrutinib RA study of Example 1.

[0413] [Figure 32] Figure 32 shows a heatmap reflecting the expression of genes regulated by BTK-dependent immune complex-mediated stimulation of Fcγ receptors.

[0414] [Figure 33] FIG. 33 shows a plot of UAS7 scores over time for subjects in Cohort 1 of the CSU study of Example 2, separated by subjects who tested positive for CUI or subjects who tested negative for CUI.

[0415] [Figure 34] Figure 34 shows a plot of UAS7 scores over time for subjects in Cohort 2 of the CSU study in Example 2, separated by subjects who tested positive for CUI or subjects who tested negative for CUI. UAS7 MID=9.5-10.5.

[0416] [Figure 35] Figure 35 is a plot of weekly itch at week 8 for both cohorts of the CSU study of Example 2. Shown are treatment differences for LS means for all participants in both cohorts, as well as treatment differences categorized by CUI-negative and CUI-positive groups.

[0417] [Figure 36] Figure 36 is a summary of the UAS7 scores at week 8 for both cohorts in the CSU study of Example 2, for all participants in both cohorts, categorized by CUI-negative (<10) and CUI-positive (> / =10) groups.

[0418] [Figure 37] Figure 37 is a plot of IgG anti-FcERI autoantibody levels in subjects from both Cohorts 1 and 2 of the CSU study of Example 2, divided into subjects receiving fenebrutinib (left) and subjects receiving placebo (right), from week 0 to week 8.

[0419] [Figure 38] Figure 38 shows a plot of UAS7 scores from week 0 to week 8 in individuals from Cohort 2 of the CSU study in Example 2, separated by those who tested positive for anti-FcERI autoantibodies (right) and those who tested negative for anti-FcERI autoantibodies (left). UAS7 MID=9.5-10.5. DETAILED DESCRIPTION OF THE INVENTION

[0420] I. Definition Before describing the present invention in detail, it is to be understood that this invention is not limited to particular compositions or biological systems, which can, of course, vary widely. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0421] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "one molecule" optionally includes a combination of two or more such molecules, and the like.

[0422] The term "about," as used herein, refers to a normal error range for the respective value, as would be readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the 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.

[0423] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0424] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredient is in a form such that it is effective and which does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. In some embodiments, such formulations are sterile. A "pharmaceutically acceptable" excipient (vehicle, additive) is one that can be reasonably administered to a mammalian subject to provide an effective dose of the active ingredient employed.

[0425] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of the individual or cells being treated during the course of clinical pathology. Desired effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and ameliorating or improving 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 are alleviated. The rate of degeneration or decline, or the rate of disease or disorder onset, is slowed or halted so that the disease is more tolerable to the patient; the progression of the disease or disorder is delayed or halted; or the degenerative end point is less debilitating. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are alleviated or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, alleviating symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, and / or prolonging the individual's survival. Treatment of a particular disease or disorder may, in some embodiments, include specific clinical or other endpoints, such as, but not limited to, those described in the examples provided herein.

[0426] An "effective amount" is at least the minimum amount necessary to achieve measurable improvement or prevention of a particular disorder. The effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the antibody to elicit a desired response in the individual. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of any treatment. For prophylactic use, beneficial or desired results include results such as elimination or reduction of the risk of disease, reduction of disease severity, or delay in the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifested during disease development. For therapeutic use, beneficial or desired results include clinical results such as alleviation of one or more symptoms caused by the disease, improvement in the quality of life of a person suffering from the disease, reduction in the dose of other drugs required to treat the disease, enhancement of the effect of another drug (e.g., by targeting), delay in disease progression, and / or prolongation of survival. An effective amount may be administered in a single dose or multiple doses. In the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As clinically understood, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when the desired result is obtained or achieved in combination with one or more other agents.

[0427] The dosage ranges provided herein refer to the amount of fenebrutinib in free form. Taking into account the molecular weight difference between fenebrutinib in free form and its salt form, it will be clear to those skilled in the art how to calculate the corresponding amount of fenebrutinib in pharmaceutical salt form. For example, in some embodiments provided herein, a patient is administered about 200 mg of fenebrutinib or a pharmaceutically acceptable salt thereof per day. In such embodiments, when a pharmaceutically acceptable salt form is administered, the total weight of the administered pharmaceutically acceptable salt of fenebrutinib is greater than 200 mg, but corresponds to about 200 mg of fenebrutinib in free form, due to the fact that the salt form has a higher molecular weight than fenebrutinib in free form.

[0428] As used herein, "inadequate response" refers to the lack of a sufficient response to the treatment of a disease as measured by clinical, laboratory, or other measures of disease activity, including its symptoms. An inadequate response may be defined by a specific clinical or other endpoint, as described in the examples provided herein. As provided herein, an inadequate response includes an outcome in which no discernible response to treatment is observed, and an outcome in which a response to treatment is observed but is considered insufficient to significantly alleviate symptoms or treat the disease.

[0429] As used herein, "intolerance" to treatment refers to the inability of a patient to continue receiving a drug or therapy due to one or more sensitivity or adverse reactions to the drug or therapy.Intolerance may require the patient to discontinue treatment for a certain period of time or indefinitely.Intolerance may be caused, for example, by the side effects of drug treatment in a particular patient or group of patients.

[0430] As used herein, "symptomatic disease" refers to a patient showing symptoms, signs or symptoms of disease. Such symptoms or signs of disease can be observed by a doctor or other caregiver, by the patient himself, or by one or more laboratory tests. A patient is symptomatic for disease when he shows such signs. In some embodiments, a patient is considered to be symptomatic for disease according to the specific patient inclusion criteria shown in the examples provided herein.

[0431] As used herein, "in combination with" or "in conjunction with" refers to the administration of one treatment modality (e.g., a drug therapy) in addition to another treatment modality. Thus, "in conjunction with" refers to the administration of one treatment modality before, during, or after the administration of the other treatment modality to a patient.

[0432] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including those pathological conditions that predispose a mammal to the disorder in question.

[0433] As used herein, "moderately to severely active rheumatoid arthritis," which may be used interchangeably with "moderately to severely active rheumatoid arthritis," refers to active RA as measured by criteria accepted in the field of rheumatology (e.g., DAS28, ACR50, SDAI, joint count). In some embodiments, patients with six or more tender joints and six or more swollen joints have moderately to severely active RA. In other embodiments, patients with (i) six or more tender joints and six or more swollen joints and (ii) elevated laboratory measures of inflammation have moderately to severely active RA. Such laboratory measures of inflammation may be CRP, ESR, autoantibodies (e.g., RF and ACPA), or a combination of these measures.

[0434] As used herein, "moderately to severely active systemic lupus erythematosus," which may be used interchangeably with "moderately to severely active systemic lupus erythematosus," refers to active SLE as measured by art-accepted criteria (e.g., SLEDAI-2K score and / or physician's global assessment). In some embodiments, patients with a clinical SLEDAI-2K score ≥ 4.0 (both at screening and on day 1), a SLEDAI-2K score ≥ 8 (at screening only), and a physician's global assessment ≥ 1.0 (out of 3) are considered to have moderately to severely active SLE. In some embodiments, patients with moderately to severely active SLE have the symptoms described above and are currently taking at least one standard oral treatment for SLE (e.g., corticosteroids, antimalarials, and / or immunosuppressants).

[0435] As used herein, the term "DMARD" refers to disease-modifying antirheumatic drugs.As used herein, DMARD includes traditional non-biological DMARD (such as methotrexate, azathioprine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, sulfasalazine, hydroxychloroquine and minocycline) and targeted non-biological DMARD, such as Janus kinase inhibitor (JAK inhibitor), SYK inhibitor, IRAK1 inhibitor, IRAK4 inhibitor, RIP1K inhibitor and apremilast.Exemplary traditional non-biological DMARD includes but is not limited to methotrexate, azathioprine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, sulfasalazine, hydroxychloroquine and minocycline. Exemplary target non-biological DMARDS include apremilast, tofacitinib, baricitinib, filgotinib, pefitinib, and upadatinib (including pharmaceutically acceptable salts thereof). In some embodiments, hydroxychloroquine is in sulfate form (i.e., hydroxychloroquine sulfate). Exemplary Janus kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib, pefitinib, and upadatinib, and pharmaceutically acceptable salts thereof.

[0436] As used herein, "biological rheumatoid arthritis drugs" refers to biological molecules such as proteins that interfere with or regulate the activity of cell receptors associated with inflammatory and / or autoimmune responses associated with rheumatoid arthritis, particularly TNF-alpha, B cell receptors, T cell receptors, cytokines (e.g., IL-1, IL-6, and IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Biological rheumatoid arthritis drugs include, but are not limited to, TNF-alpha inhibitors, B cell antagonists, T cell antagonists, IL-1 receptor antagonists, IL-6 receptor antagonists, IL-17 receptor antagonists, and GM-CSF receptor antagonists. Exemplary biologic rheumatoid arthritis drugs include, but are not limited to, abatacept, rituximab, tocilizumab, adalimumab, etanercept, anakinra, infliximab, sarilumab, golimumab, certolizumab, certolizumab pegol, and any biosimilar equivalents thereof. In some embodiments, the biologic rheumatoid arthritis drug is adalimumab, tocilizumab, or sarilumab.

[0437] In some embodiments, a "biologic rheumatoid arthritis drug" is any biologic or biosimilar equivalent that has the same mode of action as the listed drug, including a "non-TNFα inhibitor biologic," e.g., abatacept, tocilizumab, sarilumab, sirumab, anakinra, or an investigational biosimilar.

[0438] As used herein, "biological TNF-alpha inhibitor" refers to a biological agent (i.e., an antibody) that inhibits to some extent the biological function of tumor necrosis factor alpha (TNF-alpha), for example, by binding to TNF-alpha and neutralizing or reducing its activity. Examples of biological TNF-alpha inhibitors include, but are not limited to, adalimumab, etanercept, infliximab, golimumab, certolizumab, certolizumab pegol, and any biosimilar equivalents thereof.

[0439] As used herein, a "B cell antagonist" refers to a molecule that, upon binding to a B cell surface marker, destroys or depletes mammalian B cells and / or inhibits one or more B cell functions. Exemplary B cell antagonists include, but are not limited to, CD20 antibodies, CD22 antibodies, BR3 antibodies, and BR3-Fc immunoadhesins. Exemplary CD20 antibodies include rituximab, ocrelizumab, ofatumumab, tositumomab, obinutuzumab, ibritumomab, and any biosimilar equivalents thereof.

[0440] As used herein, a "T cell antagonist" is a molecule that, upon binding to a T cell surface marker, inhibits one or more T cell functions, such as activation, cell signaling, and / or differentiation. In some embodiments, the T cell antagonist is abatacept or a biosimilar equivalent thereof.

[0441] As used herein, "IL-6 receptor antagonist" refers to an agent that inhibits to some extent the biological function of interleukin-6 (IL-6), for example, by binding to the IL-6 receptor and neutralizing or reducing its activity. In some embodiments, the IL-6 receptor antagonist is tocilizumab, sarilumab, and any biosimilar equivalents thereof.

[0442] As used herein, "IL-1 receptor antagonist" refers to an agent that inhibits to some extent the biological function of interleukin-1 (IL-1), for example, by binding to the IL-1 receptor and neutralizing or reducing its activity. In some embodiments, the IL-1 binding antagonist is anakinra.

[0443] As used herein, "ACR" and "ACR score" refer to the American College of Rheumatology standard score for measuring a patient's rheumatoid arthritis activity. ACR20 refers to a 20% improvement on a 28-interval scale. ACR50 refers to a 50% improvement. ACR70 refers to a 70% improvement. See www.rheumatoidarthritis.org / treatment / acr-score (last visit August 7, 2018); Aletaha, D. et al. Ann. Rheum. Dis. 2010, 69(9):1580-8.

[0444] As used herein, "HAQ-DI" refers to the HAQ disability subscale, which consists of patient questions as a measure of functional disability and overall severity of rheumatoid arthritis. See B. Bruce, JF Fries, Health and Quality of Life Outcomes 2003, 1:20; Bardwell et al., Rheumatology 2002, 41(1):38-45.

[0445] As used herein, "DAS28" refers to the disease activity score measured by partially referencing 28 joints in patients with rheumatoid arthritis. See National Rheumatoid Arthritis Society (www.nras.org.uk / the-das28-score, last visit date August 7, 2018); J. Fransen, PLCM van Riel., Clin Exp Rheumatol 2005;23(Suppl.39):S93-S99. As used herein, "DAS28-3-CRP" refers to the DAS28 score measured by three variables: tender joint count, swollen joint count, and C-reactive protein ("CRP").

[0446] As used herein, "SF-36" refers to the widely used Medical Outcomes Health Survey "Short Form-36," which is used as a tool to monitor patient medical care outcomes. See Tarlov AR, et al., JAMA 1989, 262(7):925-30; Linde, L., et al., J Rheumatol, 35(2008), pp.1528-1537.

[0447] As used herein, "FACIT-Fatigue" or "FACIT-Fatigue scale" refers to the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) scale, a standard measure of patient fatigue in patient surveys, e.g., in patients with rheumatoid arthritis. See Cella, D., et al., J Rheumatol. 2005, 32(5):811-9.

[0448] As used herein, "CRP" refers to C-reactive protein, or a blood test for inflammation in the body that measures C-reactive protein in the blood. CRP, a protein produced in the liver, increases in blood levels in response to inflammation. CRP can be measured by a "hsCRP" test, which measures high-sensitivity CRP. In some embodiments, a positive result for elevated CRP is when the hsCRP test evaluates hsCRP > 0.400 mg / dL. In other embodiments, a positive result for elevated CRP is when the hsCRP test evaluates hsCRP > 0.650 mg / dL. CRP tests are widely available from a variety of suppliers (e.g., LabCorp, Quest Diagnostics, Life Line Screening, etc.).

[0449] As used herein, "ESR" refers to the "erythrocyte sedimentation rate," a test that indirectly measures the level of inflammation in the body by measuring how quickly red blood cells settle to the bottom of a test tube containing a patient's blood sample. See www.healthline.com / health / esr (last visit August 7, 2018). A positive ESR can be measured using the Westergren method according to specifications by the International Organization for Standardization in Hematology or by automated methods (e.g., Alifax's TEST1). See https: / / icsh.org / guidelines; Lou, JMet al., Int. Jnl. Lab. Hem. 2011, 33:125-132.

[0450] As used herein, "ACPA" refers to anti-citrullinated peptide antibodies or anti-citrullinated protein antibodies, also known as anti-cyclic citrullinated protein / peptide antibodies (i.e., anti-CCPs or ACPAs).

[0451] As used herein, "autoantibody positive" or "positive for autoantibodies" refers to patients with elevated levels of autoantibodies. Such patients test positive for one or both of these autoantibodies. In some embodiments, autoantibody positive includes seropositive patients. Test kits or assays for measuring autoantibodies in patient samples are commercially available (e.g., Anti-CCP Cobas e601 from Covance, Diastat from Axis-Shield, Immunoscan-CCP Plus from Eurodiagnostica, ELIA-CCP from Phadia, and Quanta Lite from Inova).

[0452] As used herein, "seropositive" refers to a patient who has elevated levels of the autoantibodies rheumatoid factor (RF), ACPA, or both. Such patients test positive for one or both of RF and ACPA. In some embodiments, a positive RF diagnosis means that the patient's blood sample has RF greater than 20 units / ml, and a positive ACPA diagnosis means that the patient's blood sample has ACPA greater than 5 units / ml. See Isaacs, JD, et al. Ann. Rheum. Dis. 2013, 72:329-336; Aggarwal, R. et al. Arthritis Rheum. 2009, 61(11):1472-83. In other embodiments, a positive RF diagnosis means that the patient's blood sample has RF IgM greater than 15 IU / ml, and a positive ACPA diagnosis means that the patient's blood sample has ACPA IgG greater than 17 U / ml. Test kits or assays are commercially available (Anti-CCP Cobas e601, Diastat, Immunoscan-CCP Plus, ELIA-CCP, and Quanta Lite).

[0453] As used herein, "seronegative" refers to patients who do not have elevated levels of both RF and ACPA (i.e., patients are negative by both measures).

[0454] As used herein, "UAS7" refers to a 7-day summed urticaria activity score that assesses, among other things, the number of urticaria and the severity of itching in CSU patients. UAS7 is further described in the clinical trial in Example 2.

[0455] As used herein, "H1 antihistamine" refers to a drug that is an antagonist of the H1-histamine receptor and is commonly prescribed for allergies, urticaria, and other allergic or hypersensitivity reactions or conditions. H1 antihistamines provided herein include alkylamine antihistamines, ethanolamine antihistamines, tricyclic antihistamines, and second-generation antihistamines. Exemplary alkylamine antihistamines include, but are not limited to, pheniramine, chlorpheniramine, dexchlorpheniramine, brompheniramine, dexbromopheniramine, triprolidine, dimethidene, acetaminophen / chlorpheniramine, acetaminophen / chlorpheniramine / phenylephrine, and chlorpheniramine / phenylephrine / dextromethorphan. Exemplary ethanolamine antihistamines include, but are not limited to, clemastine, diphenhydramine, and doxylamine. Exemplary tricyclic antihistamines include loratadine and desloratadine.Other H1 antihistamines include second-generation antihistamines such as cetirizine, levocetirizine and fexofenadine.In some embodiments, the H1 antihistamines provided herein include cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, diphenhydramine, hydroxyzine, chlorpheniramine and cyproheptadine.

[0456] As used herein, "CU Index" or "Chronic Urticaria Index" refers to a commercially available in vitro basophil histamine release assay in which patient serum is mixed with donor basophils and the released histamine level is measured by quantitative enzyme immunoassay. A CU Index value of 10 or greater indicates that the patient has an autoimmune basis for their urticaria (e.g., antibodies to either IgE, FcεRI, or anti-FcεRII) or another histamine-releasing factor. See Biagtan, MJ, et al., J Allergy Clin Immunol. 2011, 127(6):1626-27. A commercially available CU Index test is the CU Index® by Viracor (www.viracor-eurofins.com / 2103-cu-index, last visit on August 23, 2018).

[0457] As used herein, "standard oral SLE treatment" refers to oral medications commonly prescribed to SLE patients. In some embodiments, the standard oral SLE treatment is selected from corticosteroids, antimalarials, and immunosuppressants. In some embodiments, the standard oral SLE treatment is selected from oral corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, mycophenolate sodium, hydroxychloroquine, chloroquine, and quinacrine.

[0458] As used herein, "SRI-4" refers to SLE Responder Index response. The SRI-4 response criteria are commonly used in SLE testing and accepted by health authorities to measure the reduction in SLE disease activity, and are a composite measure that includes the SLE Disease Activity Index (SLEDAI-2K), the British Isles Lupus Activity Group (BILAG) 2004, and the Physician Global Assessment. See Luijten KM, Autoimmun. Rev. 2012, 11(5):326-9.

[0459] As used herein, "BICLA" refers to the BILAG-based Composite Lupus Assessment. BICLA response is a common secondary metric to SRI-4 as a meaningful measure of SLE disease activity. See Luijten KM, Autoimmun. Rev. 2012, 11(5):326-9.

[0460] "Oral corticosteroids" or "OCS," as defined herein, refer to glucocorticoids, steroids, and / or cortisol-like drugs suitable for oral administration for the treatment of the diseases provided herein, including, but not limited to, prednisone, cortisone, cortisone acetate, hydrocortisone, dexamethasone, prednisolone, and methylprednisolone.

[0461] A "patient" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the patient is a human.

[0462] The term "antibody" as used herein is used in the broadest sense and specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.

[0463] The term "biomarker" as used herein refers to an indicator, e.g., a predictive, diagnostic, and / or prognostic indicator, that can be detected in a sample. A biomarker can serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer) characterized by certain molecular, pathological, histological, and / or clinical characteristics. In some embodiments, the biomarker is a gene. Biomarkers include, but are not limited to, polynucleotide (e.g., DNA and / or RNA), polypeptide, polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrate, and / or glycolipid-based molecular markers. The "amount" or "level" of a biomarker associated with an increased clinical benefit to an individual is a detectable level in a biological sample. These can be measured by methods known to those skilled in the art and disclosed herein. In some embodiments, the expression level or amount of the assessed biomarker can be used to determine a response to treatment. In certain embodiments, the expression level or amount of one or more biomarkers is associated with a particular response to treatment.

[0464] The term "sample" as used herein refers to a composition obtained or derived from a subject and / or individual of interest that contains cellular and / or other molecular entities to be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological properties. For example, the phrase "disease sample" and variations thereof refer to any sample obtained from a subject of interest that is expected to contain or is known to contain the cellular and / or molecular entities to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts, e.g., homogenized tissue, tumor tissue, cell extracts, and combinations thereof.

[0465] A "tissue sample" or "cell sample" refers to a collection of similar cells obtained from the tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue, such as from fresh, frozen, and / or preserved organs, biopsies, and / or aspirates; blood or any blood constituents, such as plasma; bodily fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any time during a subject's pregnancy or development. A tissue sample may also be primary or cultured cells or cell lines. In some cases, a tissue or cell sample is obtained from a diseased tissue / organ. A tissue or cell sample may contain compounds not naturally mixed with native tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc.

[0466] 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 comparison purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased part (e.g., tissue or cell) of the body of the same subject or individual. For example, a healthy and / or non-diseased cell or tissue adjacent to a diseased cell or tissue (e.g., a cell or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from an untreated tissue and / or cell of the body of the same subject or individual. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased part (e.g., tissue or cell) of the body of an individual other than the subject or individual. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from intact tissues and / or cells from the body of an individual who is not the subject or individual.

[0467] The term "diagnosis" is used herein to refer to the identification or classification of a molecular or pathological state, disease, or condition. For example, "diagnosis" can refer to the identification of a specific type of disease. "Diagnosis" can also refer to the classification of a specific subtype, for example, by histopathological criteria or by molecular characteristics (e.g., a subtype characterized by the expression of a biomarker or a combination of biomarkers (e.g., a specific gene or protein encoded by the gene)).

[0468] A patient's "effective response" or patient "responsiveness" to treatment with a pharmaceutical agent, and similar terms, refers to a clinical or therapeutic benefit conferred on a patient at risk for or suffering from a disease or disorder, such as cancer. In one embodiment, such benefit includes one or more of: extending survival (including overall survival and progression-free survival); producing an objective response (including a complete or partial response); or ameliorating signs or symptoms of cancer. In some embodiments, the disease or disorder is rheumatoid arthritis, CSU, or SLE. In certain embodiments, an "effective response" or patient "responsiveness" to treatment of a particular disorder or condition may be assessed using one or more standardized assessments, such as, for example, the standardized assessments described herein.

[0469] A patient who "does not respond effectively" to treatment refers to a patient who does not have any of the following: prolonged survival (including overall survival and progression-free survival), an objective response (including a complete or partial response), or an improvement in signs or symptoms of cancer. In some embodiments, a patient who "does not respond effectively" to treatment refers to a patient who does not have an improvement in one or more signs or symptoms of a disorder or disease, such as SLE, CSU, or RA. II. Pharmaceutical Compositions and Formulations

[0470] Also provided herein are pharmaceutical compositions and formulations comprising fenebrutinib or a pharmaceutically acceptable salt thereof for use in the methods of treatment described herein (e.g., RA, CSU, and / or SLE). In some embodiments, the pharmaceutical compositions and formulations further comprise one or more pharmaceutically acceptable carriers. International Publication No. 2017 / 148837, incorporated herein by reference in its entirety, discloses formulations and dosage forms comprising fenebrutinib and pharmaceutically acceptable salts thereof. In some embodiments, the formulations described in International Publication No. 2017 / 148837 are used to deliver fenebrutinib to a patient according to one or more of the methods provided herein.

[0471] Fenebrutinib or a pharmaceutically acceptable salt thereof may be administered by any suitable means, including oral, parenteral, pulmonary, and intranasal administration, and, if desired for local treatment, intralesional administration. In a preferred embodiment, oral administration is preferred.

[0472] Pharmaceutically acceptable salts of fenebrutinib may be used in the methods herein. As used herein, the term "pharmaceutically acceptable salts" refers to salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either directly or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunolonic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science (1977) Vol. 66, pp. 1-19). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0473] In some embodiments provided herein, an oral dose of fenebrutinib or a pharmaceutically acceptable salt thereof, preferably in tablet or capsule form, contains about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, or 200 mg of the active ingredient. In some embodiments of a dosage form comprising a pharmaceutically acceptable salt of fenebrutinib, the oral dosage form contains the pharmaceutically acceptable salt form in an amount equivalent to about 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, or 200 mg of fenebrutinib free form.

[0474] In some embodiments, the daily dose of fenebrutinib or a pharmaceutically acceptable salt thereof includes about 50 to 400 mg per day; about 150 to 400 mg per day; about 200 to 400 mg per day; about 250 to 400 mg per day; about 300 to 400 mg per day; about 50 to 300 mg per day; about 100 to 300 mg per day; about 150 to 300 mg per day; about 250 to 300 mg per day; about 50 to 200 mg per day; about 100 to 200 mg per day; about 150 to 200 mg per day; and about 200 to 300 mg per day. In some embodiments, the oral dose is 50 mg once daily, 100 mg once daily, 150 mg once daily, 200 mg once daily, 250 mg once daily, 300 mg once daily, 100 mg twice daily, 150 mg twice daily, or 200 mg twice daily. In some embodiments in which a pharmaceutically acceptable salt form of fenebrutinib is administered, the daily dose is an amount equivalent to a dosage or dosage range of the free form of fenebrutinib as described herein (e.g., equivalent to about 50-400 mg daily, about 150-400 mg daily, or about 200-400 mg daily of the free form of fenebrutinib).

[0475] In some embodiments, the compositions and formulations herein may also contain one or more active ingredients necessary for the particular indication being treated (e.g., RA, CSU, and / or SLE), preferably those with complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts effective for the intended purpose. In some such embodiments, the formulation is an oral tablet or capsule containing fenebrutinib or a pharmaceutically acceptable salt thereof and a Janus kinase inhibitor, preferably selected from the group consisting of tofacitinib, baricitinib, filgotinib, pefitinib, and upadacitinib. In some embodiments, the tablet or capsule contains fenebrutinib or a pharmaceutically acceptable salt thereof and tofacitinib. III. Treatment Methods

[0476] Provided herein are methods for treating RA, CSU, or SLE in specific patient populations described herein by administering fenebrutinib or a pharmaceutically acceptable salt thereof. In one embodiment, provided herein are methods for treating patients with moderately to severely active RA, wherein the patient has shown an inadequate response to prior treatment with one or more conventional non-biologic DMARDs. In another embodiment, the patient has shown an inadequate response or intolerance to prior treatment with one or more biologic rheumatoid arthritis drugs. More specific embodiments of these treatment methods are described in the Summary of the Disclosure (i.e., E1, E2, etc.). In the clinical trial results provided herein, fenebrutinib was found to be safe and effective in treating RA in the above patient populations.

[0477] In another aspect, provided herein are methods for treating CSU patients who remain symptomatic despite previous treatment with H1 antihistamines. In the clinical trial results provided herein, fenebrutinib was found to be safe and effective in treating CSU in this patient population. More specific embodiments of these treatment methods are described in the Summary of the Disclosure.

[0478] In another aspect, provided herein are methods for treating patients with moderately to severely active SLE who are symptomatic despite previous standard oral SLE treatments.Fenebrutinib has been found to be safe and effective in treating SLE in this patient population in the clinical trial results provided herein.More specific aspects of these treatment methods are described in the Summary of the Disclosure.

[0479] Also provided herein is a method for treating RA, CSU or SLE in certain patient populations described herein by administering fenebrutinib or its pharmaceutically acceptable salt, and these patients are monitored after treatment for elevated liver enzymes associated with hepatotoxicity.It has been found that at certain doses of fenebrutinib, some patients experience elevated liver enzymes associated with hepatotoxicity, and therefore it is desirable to monitor such occurrences during treatment, and in some cases, stop treatment for a period of time or reduce the dose of fenebrutinib if necessary.In some embodiments, when a patient shows signs of elevated liver enzymes associated with hepatotoxicity, the administration of fenebrutinib is discontinued, stopped for a certain period of time, and then resumed or continued at a lower dose.More specific aspects of these treatment methods are described in the Summary of the Disclosure.

[0480] Fenebrutinib or its pharmaceutically acceptable salts can be used alone or in combination with other drugs in the treatment methods described herein.For example, the additional therapeutic agent can be an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a proapoptotic agent, a neurotropic factor, a drug for treating cardiovascular disease, a drug for treating liver disease, an antiviral agent, a drug for treating blood disorders, a drug for treating diabetes, and a drug for treating immunodeficiency disorders.The second therapeutic agent can be an NSAID anti-inflammatory agent.The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activity to fenebrutinib or its pharmaceutically acceptable salts so as not to adversely affect each other.More specific embodiments of these treatment methods using combination therapies are described in the Summary of the Disclosure.

[0481] In some embodiments, the additional therapeutic agent is a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone); a disease-modifying antirheumatic drug ("DMARD", e.g., an immunosuppressant or anti-inflammatory agent); an antimalarial (e.g., hydroxychloroquine and chloroquine); an immunosuppressant (e.g., cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate); an anti-inflammatory agent (e.g., aspirin, an NSAID (e.g., ibuprofen, naproxen, indomethacin, nabumetone, celecoxib)); an antihypertensive agent (e.g., a calcium channel blocker (e.g., , amlodipine, nifedipine) and diuretics (e.g., furosemide)); statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin); anti-B cell agents (e.g., anti-CD20 (e.g., rituximab), anti-CD22); anti-B lymphocyte stimulating agents ("anti-BLyS", e.g., belimumab, blisibimod); type 1 interferon receptor antagonists (e.g., anifrolumab); T cell modifying agents (e.g., ligelimod); abatacept; anticoagulants (e.g., heparin, warfarin); and vitamin D supplements.

[0482] In other aspects, patients treated with the methods provided herein have a disease that expresses (e.g., is shown to express in a diagnostic test) one or more biomarkers. In some embodiments, the patient's disease expresses lower levels of the biomarker. In some embodiments, the patient's disease expresses higher levels of the biomarker. Particular biomarkers are described in the Summary of the Disclosure and in any of the Examples below. In some embodiments of any of the methods, assays, and / or kits provided herein, one or more biomarkers are present in a sample if it comprises more than 0% of the sample. In some embodiments, the biomarker is present in at least 1% of the sample. In some embodiments, the biomarker is present in at least 5% of the sample. In some embodiments, the biomarker is present in at least 10% of the sample. In certain embodiments, e.g., in certain embodiments where the disorder is SLE, the one or more biomarkers are selected from the group consisting of IgJ, MZB1, and TXNDC5. In other embodiments, e.g., in certain embodiments where the disorder is SLE, the one or more biomarkers are selected from the group consisting of CCL3, CCL4, CCL20, CXCL13, and autoantibodies. In still further embodiments, for example, in certain embodiments where the disorder is CSU, the one or more biomarkers are selected from the group consisting of an IgE antibody that binds to TPO, an IgE antibody that binds to IL24, an IgG antibody that binds to IgE, and an IgG antibody that binds to FcERI. In still further embodiments where the disorder is CSU, the one or more biomarkers include an IgG antibody that binds to FcERI (e.g., including at least an IgG antibody that binds to FcERI, which may or may not further include one or more other biomarkers). In still further embodiments, for example, in certain embodiments where the disorder is CSU, the one or more biomarkers are one or more autoantibodies assessed using the CU index method. In some embodiments, a CU index value of 10 or greater indicates elevated levels of one or more biomarkers (e.g., autoantibodies).In certain embodiments, elevated levels of one or more of these biomarkers (e.g., one or more biomarkers in SLE patients, or one or more biomarkers in CSU patients) indicate that the patient is more likely to benefit from treatment with fenebrutinib or a pharmaceutically acceptable salt thereof than subjects without elevated levels, e.g., subjects with the same disorder but without elevated biomarker levels, or healthy subjects without the disorder, or subjects with levels approximately equal to a baseline level as determined by one of skill in the art (such as the average of a population or a subset thereof). In some embodiments, a patient "more likely to benefit" includes having a better response (e.g., greater relief of one or more symptoms, or relief of more symptoms) to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof, compared to a subject with the same disorder who is administered the same dose of fenebrutinib or a pharmaceutically acceptable salt thereof but who does not have elevated levels of one or more biomarkers.

[0483] In some embodiments of the methods provided herein, the patient has CSU and tests positive for the CU index. In certain embodiments, such CU index-positive patients are more likely to benefit (e.g., have a better response) from treatment with fenebrutinib or a pharmaceutically acceptable salt thereof than patients who test negative for CSU in the CU index. In certain embodiments, CU index-positive CSU patients are more likely to show a greater reduction in one or more symptoms or symptom measures when treated with fenebrutinib or a pharmaceutically acceptable salt thereof than CU index-negative CSU patients. In yet further embodiments, CU index-positive CSU patients are more likely to show a response (e.g., by reducing one or more symptoms or symptom measures) to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof at a lower dose than CU index-negative patients. Therefore, in some embodiments, the present invention provides a method for reducing the level of fenebrutinib or a pharmaceutically acceptable salt thereof administered to a patient with CSU who requires fenebrutinib or a pharmaceutically acceptable salt thereof, comprising: determining whether the patient is a CU index-positive patient; and administering a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof to the CU index-positive patient compared to a CU index-negative patient. In certain embodiments, the greater response or greater reduction in one or more symptoms or symptom measures is a decrease in UAS7, a decrease in weekly itch score, or both. In certain embodiments, CU index-positive patients show a greater decrease in UAS7, a greater decrease in weekly itch score, or both, compared to CU index-negative patients administered the same dose of fenebrutinib or a pharmaceutically acceptable salt thereof. In still further embodiments, CU Index-positive patients exhibit a substantially equal reduction in UAS7, or a substantially equal reduction in weekly itch scores, or both, compared to CU Index-negative patients administered a higher dose of fenebrutinib or a pharmaceutically acceptable salt thereof.In certain embodiments, the UAS7 score, or the weekly itch score, or both, are assessed over 4 weeks, or over 8 weeks, or over 12 weeks.

[0484] In some embodiments of the methods provided herein, patients have CSU and test positive for IgG antibodies that bind to FcERI (e.g., IgG anti-FcERI autoantibodies). In certain embodiments, patients who test positive for IgG antibodies that bind to FcERI are more likely to benefit (e.g., have a better response) from treatment with fenebrutinib or a pharmaceutically acceptable salt thereof, compared with CSU patients who test negative for IgG antibodies that bind to FcERI. In certain embodiments, patients who test positive for IgG antibodies that bind to FcERI are more likely to show a reduction in one or more symptoms or symptom assessments when treated with fenebrutinib or a pharmaceutically acceptable salt thereof, compared with patients who test negative for said antibodies. In yet a further embodiment, CSU patients who test positive for IgG antibodies that bind to FcERI are more likely to respond to treatment with a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., by reducing one or more symptoms or symptom ratings) than CSU patients who test negative for the antibody. Thus, in some embodiments, provided herein is a method for reducing the level of fenebrutinib or a pharmaceutically acceptable salt thereof administered to patients with CSU who require fenebrutinib or a pharmaceutically acceptable salt thereof, comprising determining whether the patient tests positive for IgG antibodies that bind to FcERI, and administering a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof to the antibody-positive patient compared to patients who test negative for IgG antibodies that bind to FcERI. In certain embodiments, the greater response or greater reduction in one or more symptoms or symptom measures is a decrease in UAS7, or a decrease in weekly itch score, or both.In certain embodiments, patients who test positive for an IgG antibody that binds FcERI exhibit a greater decrease in UAS7, or a greater decrease in weekly itch scores, or both, compared to patients who test negative for said antibody and are administered the same dose of fenebrutinib or a pharmaceutically acceptable salt thereof. In yet further embodiments, patients who test positive for an IgG antibody that binds FcERI exhibit a roughly equal decrease in UAS7, or a roughly equal decrease in weekly itch scores, or both, compared to patients who test negative for said antibody and are administered a higher dose of fenebrutinib or a pharmaceutically acceptable salt thereof. In certain embodiments, the UAS7 score, or weekly itch score, or both, are assessed over 4 weeks, or over 8 weeks, or over 12 weeks.

[0485] In some embodiments, patients with a disorder have elevated levels of one or more biomarkers (e.g., high levels of one or more antibodies, such as IgG antibodies that bind to FcERI; or a positive CU index test), and the levels are elevated compared to healthy subjects without the disorder. In other embodiments, the levels are elevated compared to a baseline, e.g., a baseline determined by population or subpopulation assessment, or a baseline provided by the manufacturer of a biomarker test, or a lower limit of quantitation. In some embodiments, the baseline is the mean of a group of patients with the disorder or the mean of a group of healthy subjects. In some embodiments, the baseline is the mean plus one standard deviation, the mean plus two standard deviations, or the mean plus three standard deviations of a group of patients with the disorder or a group of healthy subjects.

[0486] In some embodiments of any of these methods, assays, and / or kits, the biomarkers are detected in the sample using a method selected from the group consisting of FACS, Western blot, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, dot blotting, immunodetection methods, HPLC, surface plasmon resonance, optical spectroscopy, mass spectroscopy, HPLC, qPCR, RT-qPCR, multiplex qPCR or RT-qPCR, RNA-seq, microarray analysis, SAGE, MassARRAY techniques, and FISH, and combinations thereof.

[0487] In some embodiments of any of these methods, assays, and / or kits, the biomarker is detected in the sample by protein expression. In some embodiments, protein expression is determined by immunohistochemistry (IHC). In some embodiments, the biomarker is detected using an antibody. In some embodiments, the biomarker is detected by IHC as weak staining intensity. In some embodiments, the biomarker is detected by IHC as medium staining intensity. In some embodiments, the biomarker is detected by IHC as strong staining intensity. In some embodiments, the staining is membranous staining, cytoplasmic staining, or a combination thereof. IV. Biomarkers, Detection and Diagnostic Methods

[0488] Also provided herein are methods for detecting and diagnosing one or more of the diseases described herein (i.e., RA, CSU, or SLE) in patients who have been or will be treated with fenebrutinib. In some embodiments, the methods include obtaining a sample from a patient who is being treated with fenebrutinib or who will be treated with fenebrutinib. Further embodiments of biomarkers, detection, and diagnostic methods are provided in the Summary of the Disclosure above.

[0489] The SLE biomarkers IgJ, MZB1 and TXNDC5, and their relationship to BTK inhibition and fenebrutinib in particular, are described in WO 2018 / 175863, the entire contents of which are incorporated herein by reference.

[0490] In some aspects, the sample obtained from a patient to be treated or currently being treated is whole blood. In some embodiments, the whole blood contains immune cells, circulating cells, and any combination thereof. In some embodiments, the sample is taken from the patient's plasma.

[0491] The presence and / or expression level / amount of a biomarker can be detected qualitatively and / or quantitatively based on any suitable criteria known in the art, including, but not limited to, DNA, mRNA, cDNA, protein, protein fragment, and / or gene copy number. In certain embodiments, the presence and / or expression level / amount of a biomarker in a first sample is increased or elevated compared to its presence / absence and / or expression level / amount in a second sample. In certain embodiments, the presence / absence and / or expression level / amount of a biomarker in a first sample is decreased or reduced compared to its presence and / or expression level / amount in a second sample. In certain embodiments, the second sample is a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue. Further disclosure for determining the presence / absence and / or expression level / amount of a gene is described herein.

[0492] In some embodiments of any of these methods, elevated expression refers to an overall increase of about any 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more in the level of a biomarker (e.g., a protein or nucleic acid (e.g., a gene or mRNA)) as detected by standard art-known methods, such as those described herein, compared to a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue. In certain embodiments, elevated expression refers to an increase in the expression level / amount of a biomarker in a sample, which increase is at least about any of a 1.5-fold, 1.75-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 25-fold, 50-fold, 75-fold, or 100-fold increase in the expression level / amount of the respective biomarker in the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue. In some embodiments, elevated expression refers to an overall increase of greater than about 1.5-fold, about 1.75-fold, about 2-fold, about 2.25-fold, about 2.5-fold, about 2.75-fold, about 3.0-fold, or about 3.25-fold compared to a reference sample, reference cell, reference tissue, control sample, control cell, control tissue, or internal control (e.g., housekeeping gene).

[0493] In some embodiments of any of these methods, reduced expression refers to an overall reduction of about any of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more in the level of a biomarker (e.g., a protein or nucleic acid (e.g., a gene or mRNA)) as detected by standard art-known methods, such as those described herein, compared to a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue. In certain embodiments, reduced expression refers to a decrease in the expression level / amount of a biomarker in a sample, which decrease is at least about 0.9-fold, 0.8-fold, 0.7-fold, 0.6-fold, 0.5-fold, 0.4-fold, 0.3-fold, 0.2-fold, 0.1-fold, 0.05-fold, or 0.01-fold the expression level / amount of the respective biomarker in the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue.

[0494] In some embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is from one or more subjects who do not have the disorder or disease being treated in the patient. In other embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from the patient before treatment. For example, in some embodiments of the methods provided herein, treatment of the patient results in a decrease in expression of one or more biomarkers compared to the level of the one or more biomarkers in the same patient before treatment. In other embodiments of the methods provided herein, the patient has a disorder or disease (such as a disorder or disease described herein), and the patient has elevated expression of one or more biomarkers compared to a subject without the disorder or disease. In certain embodiments, the patient has a disorder or disease (such as a disorder or disease described herein), and the patient has elevated expression of one or more biomarkers compared to another subject who also has the disorder or disease.

[0495] The presence and / or expression levels / amounts of various biomarkers in a sample can be analyzed by several methodologies, many of which are known in the art and understood by those of skill in the art, including, but not limited to, immunohistochemistry ("IHC"), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting ("FACS"), MassARRAY, proteomics, quantitative blood-based assays (e.g., serum ELISA), biochemical enzyme activity assays, in situ hybridization, Southern analysis, Northern analysis, whole genome sequencing, polymerase chain reaction ("PCR"), e.g., quantitative real-time PCR ("qRT-PCR") and other amplification-based detection methods, e.g., branched DNA, SISBA, TMA, etc.), RNA-Seq, FISH, microarray analysis, gene expression profiling, and / or serial analysis of gene expression ("SAGE"), as well as any of a wide variety of assays that can be performed by protein, gene, and / or tissue array analysis. Exemplary protocols for assessing the status of genes and gene products are found, for example, in Ausubel et al. (1995) "Current Protocols In Molecular Biology," Part 2 (Northern blotting), Part 4 (Southern blotting), Part 15 (immunoblotting), and Part 18 (PCR analysis). Multiplexed immunoassays, such as those available from Rules Based Medicine or Mes·Scale Discovery ("MSD"), can also be used.

[0496] In some embodiments, the presence and / or expression level / amount of the biomarkers is determined using a method comprising: (a) performing gene expression profiling, PCR (such as rtPCR or qRT-PCR), RNA-seq, microarray analysis, SAGE, MassARRAY techniques, or FISH on a sample (such as a subject cancer sample); and b) determining the presence and / or expression level / amount of the biomarkers in the sample. In some embodiments, the microarray method comprises the use of a microarray chip having one or more nucleic acid molecules capable of hybridizing under stringent conditions to nucleic acid molecules encoding the above-mentioned genes or having one or more polypeptides (such as peptides or antibodies) capable of binding to one or more of the proteins encoded by the above-mentioned genes. In one embodiment, the PCR method is qRT-PCR. In one embodiment, the PCR method is multiplex PCR. In some embodiments, gene expression is measured by microarray. In some embodiments, gene expression is measured by qRT-PCR. In some embodiments, expression is measured by multiplex PCR.

[0497] Methods for assessing mRNA in cells are well known and include, for example, hybridization assays using complementary DNA probes (such as in situ hybridization, Northern blots, and related techniques using labeled riboprobes specific for one or more genes), and various nucleic acid amplification assays (such as RT-PCR using complementary primers specific for one or more of the genes, and other amplification-based detection methods such as branched DNA, SISBA, TMA, etc.).

[0498] The sample from mammal can be conveniently assayed for mRNA using Northern blot, dot blot or PCR analysis.In addition, such method can include one or more steps that allow determining the level of target mRNA in biological sample (for example, by simultaneously testing the level of a control mRNA sequence of "housekeeping" gene such as actin family member).Optionally, the sequence of amplified target cDNA can be determined.

[0499] Any of the methods includes a protocol for testing or detecting mRNA, such as target mRNA, in a tissue or cell sample using microarray technology. Using nucleic acid microarrays, test and control mRNA samples from test and control tissue samples are reverse transcribed and labeled to generate cDNA probes. The probes are then hybridized to an array of nucleic acids immobilized on a solid support. The array is configured so that the sequence and location of each array member are known. For example, a selection of various genes whose expression correlates with increased or decreased clinical benefit of antiangiogenic therapy can be arrayed on a solid support. Hybridization of a labeled probe with a particular array member indicates that the sample from which the probe was derived expresses that gene.

[0500] According to some embodiments, the presence and / or expression level / amount is measured by observing the protein expression level of the aforementioned genes. In certain embodiments, the method comprises contacting a biological sample with an antibody that specifically binds to a biomarker described herein under conditions that allow binding of the biomarker, and detecting whether a complex is formed between the antibody and the biomarker. Such methods may be in vitro or in vivo methods.

[0501] The presence and / or expression level / amount of a selected biomarker in a tissue or cell sample can also be tested by functional or activity-based assays. For example, if the biomarker is an enzyme, assays known in the art can be performed to determine or detect the presence of a given enzymatic activity in a tissue or cell sample.

[0502] In certain embodiments, samples are normalized for both differences in the amount of assayed biomarkers and variations in the quality of the samples used, as well as variations between assay runs. Such normalization can be achieved by detecting and incorporating the expression of certain normalization biomarkers, such as well-known housekeeping genes. Alternatively, normalization can be based on the average signal or median signal of all assayed genes or a large subset thereof (global normalization approach). For each gene, the measured normalized amount of the subject's mRNA or protein is compared to the amount found in a reference set. The normalized expression level of each tested mRNA or protein for each subject can be expressed as a percentage of the measured expression level in the reference set. The measured presence and / or expression level / amount in the specific subject sample being analyzed is expressed as a percentage within this range, which can be determined by methods well known in the art.

[0503] In one embodiment, the sample is a clinical sample. In another embodiment, the sample is used in a diagnostic assay. In some embodiments, the sample is obtained from a patient's tissue, urine, sputum, serum, or plasma. The same techniques discussed above for detecting target genes or gene products in cancerous samples can be applied to other body samples. By screening such body samples, simple and early diagnosis of these cancers can be achieved. In addition, progress in therapy can be more easily monitored by testing such body samples for target genes or gene products.

[0504] In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a single sample or a combination of multiple samples from the same subject or individual obtained at one or more time points different from when the test sample is obtained. For example, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from the same subject or individual at an earlier time point than when the test sample is obtained. In certain embodiments, the reference sample, control cell, or control tissue is a combination of multiple samples from one or more healthy individuals who are not the subject or individual. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a combination of multiple samples from one or more individuals with a disease or disorder who are not the subject or individual. In certain embodiments, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a pooled RNA sample from normal tissue, or a pooled plasma or serum sample from one or more individuals who are not the subject or individual.

[0505] Certain aspects of the present disclosure relate to measuring the expression levels of one or more genes or one or more proteins in a sample. In some embodiments, the sample may include white blood cells. In some embodiments, the sample may be a peripheral blood sample. The peripheral blood sample may include white blood cells, PBMCs, etc. Any technique known in the art for isolating white blood cells from a peripheral blood sample may be used. For example, a blood sample may be drawn, red blood cells may be lysed, and a white blood cell pellet may be isolated and used for the sample. In another example, density gradient separation may be used to separate white blood cells (e.g., PBMCs) from red blood cells. In some embodiments, a fresh peripheral blood sample (i.e., a peripheral blood sample not prepared by the methods described above) may be used. In some embodiments, the peripheral blood sample may be prepared by incubation in a solution to preserve the integrity of the mRNA and / or protein. V. Product or Kit

[0506] In another embodiment of the present invention, a product or kit is provided that includes fenebrutinib or a pharmaceutically acceptable salt thereof and a second therapeutic agent. In some embodiments, the product or kit further includes a package insert that includes instructions for using fenebrutinib or a pharmaceutically acceptable salt thereof in combination with the second therapeutic agent to treat a disease provided herein (e.g., RA, CSU and / or SLE).

[0507] In some embodiments, fenebrutinib or its pharmaceutically acceptable salt and the second therapeutic agent are contained in the same capsule or tablet, or in separate capsules or tablets with the kit. Suitable containers for the kit include, for example, bottles or boxes. In some embodiments, the container holds the formulation, and the label on or associated with the container can indicate instructions for use. The product or kit can further include other materials that are desirable from a commercial and user perspective, such as a package insert with instructions for use.

[0508] The specification is considered to be sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. [Example]

[0509] The present disclosure will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention. It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested to those skilled in the art in light of these, which should be included within the spirit and scope of the present application and the scope of the appended claims. Example 1 A two-cohort, randomized, phase II, double-blind, parallel-group study evaluating the efficacy and safety of fenebrutinib compared with placebo and adalimumab in patients with an inadequate response to prior methotrexate therapy (cohort 1) and compared with placebo in patients with an inadequate response or intolerance to prior TNF therapy (cohort 2) in patients with active rheumatoid arthritis.

[0510] This study was designed to evaluate the efficacy and safety of fenebrutinib in combination with methotrexate (MTX) compared with placebo (Cohorts 1 and 2) and adalimumab (ADA) (Cohort 1) in patients with moderately to severely active rheumatoid arthritis (RA). The specific objectives of the study and corresponding endpoints are outlined below. Test objectives

[0511] The primary efficacy objective of Cohort 1 of this study was to evaluate the efficacy of fenebrutinib at three dose levels compared with placebo used in combination with a stable dose of MTX in patients with active RA who had an inadequate response to MTX and were TNF-naive.

[0512] The primary efficacy objective of Cohort 2 of this study was to evaluate the efficacy of fenebrutinib compared with placebo used in combination with a stable dose of MTX in patients with active RA who had an inadequate response or intolerance to one or two TNF inhibitors and had been previously exposed to one or less non-TNF biologics.

[0513] The secondary efficacy objectives of this study were: To evaluate the efficacy of fenebrutinib compared with ADA in combination with a stable dose of MTX in patients with active RA who have had an inadequate response to MTX and who have not received TNF therapy. To assess the efficacy of fenebrutinib over time using multiple standardized assessments (e.g., ACR20, ACR50, ACR70, DAS28, DAS28-3-CRP) and based on the individual components of the ACR (tender / painful joint count, swollen joint count, patient assessment of arthritis pain, patient global assessment of arthritis, physician global assessment of arthritis, CRP, HAQ-DI). To evaluate the efficacy of fenebrutinib over time (ACR50 response rate at days 7, 14, 28 and 56). To assess DAS28 remission (<2.6) and LDA (<3.2) status at days 7, 14, 28, 56, and 84. At days 7, 14, 28, 56, and 84, ACR / EULAR remission will be assessed according to Boolean definitions (tender joint count ≤ 1, swollen joint count ≤ 1, CRP ≤ 1, and Patient Global Assessment ≤ 1). To assess remission according to SDAI (defined as ≦3.3 for ACR / EULAR remission) and remission according to CDAI (defined as ≦2.8) at days 7, 14, 28, 56, and 84. To assess the effect of fenebrutinib compared with placebo on health-related quality of life (SF-36, standard, version 2, questionnaire at day 84). To assess the effect of fenebrutinib compared to placebo on fatigue (FACIT-Fatigue Assessment at day 84).

[0514] The safety objective of this study was to evaluate the safety of fenebrutinib administered in combination with MTX in patients with moderate to severe RA.

[0515] The pharmacokinetic objective for this study was to characterize the pharmacokinetics of fenebrutinib in patients using a population PK approach. PK exploration objectives included the relationship between drug exposure and the pharmacological action, efficacy, and safety of fenebrutinib; the effects of selected covariates on measures of exposure and / or response to fenebrutinib; and the effects of genetic polymorphisms on measures of fenebrutinib exposure.

[0516] The biomarker exploration objectives of this study are as follows: ·To evaluate the effect of fenebrutinib on biomarkers that help define MOA. To assess the relationship between biomarker changes and efficacy. To assess whether baseline biomarkers identify subsets of patients who may derive increased clinical benefit from fenebrutinib. Study design

[0517] This study was a multicenter, phase II, randomized, double-blind, placebo-controlled, activity-specific (Cohort 1 only), parallel-group, dose-ranging study to evaluate the efficacy and safety of fenebrutinib in patients with moderately to severely active RA who had an inadequate response to prior MTX therapy (Cohort 1) or who had an inadequate response to MTX and TNF therapy and who may have been exposed to one or fewer non-TNF inhibitor biologics (Cohort 2). Moderately to severely active RA was defined by ≥6 tender / painful joints (68 joint counts) and ≥6 swollen joints (66 joint counts) on exercise and high-sensitivity C-reactive protein (hsCRP) ≥0 at both screening and Day 1 (randomization). At screening, hsCRP ≥400 mg / dL for Cohort 1 and ≥0.650 mg / dL for Cohort 2.

[0518] The study enrolled 578 patients. In cohort 1, 480 patients with MTX-IR were randomized to placebo (110 patients), ADA (111 patients), or one of three doses of fenebrutinib: 50 mg once daily (40 patients), 150 mg once daily (109 patients), or 200 mg twice daily (110 patients). In cohort 2, 98 patients with TNF-IR were randomized to placebo or 200 mg twice daily bi-dose fenebrutinib. After a screening period of up to 28 days, patients in both cohorts received blinded study medication (oral fenebrutinib or matching placebo) for 12 weeks, after which they had the option to participate in an 8-week follow-up period or enroll in an open-label extension (OLE) study. In addition to the study drug, patients in Cohort 1 were also treated with subcutaneous (SC) comparator drugs (ADA or placebo).

[0519] Cohort 1 Treatment Regimen. Patients in Cohort 1 will be randomly assigned in a 1:1:1:1:1:1 fashion to one of five parallel treatment arms. Once enrollment in Arm A is complete, patients will be randomized 1:1:1:1 to the remaining four treatment arms. Group A: 50 mg fenebrutinib once daily (BID tablet) + placebo injection SC every 2 weeks (Q2W) (n=40) Group B: 150 mg fenebrutinib once daily (BID tablet) + placebo injection SC every 2 weeks (Q2W) (n=109) Group C: 200 mg fenebrutinib twice daily (BID tablets) + placebo injection SC every 2 weeks (Q2W) (n=110) Group D: Placebo (BID tablet) + placebo injection SC Q2W (n=110) Group E: Placebo (BID tablet) + 40 mg ADA injection SC Q2W (n=111)

[0520] Cohort 2 Treatment Regimen. Patients in Cohort 2 are randomly assigned in a 1:1 fashion to one of two parallel treatment groups. Group A: 200 mg fenebrutinib once daily (BID tablets, n=49) Group B: Placebo (BID tablets, n=49)

[0521] Patients must continue stable MTX treatment and a stable dose of folic acid throughout the study. For patients taking chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and / or corticosteroids, continued use of a stable (at least 2 weeks prior to randomization) oral NSAID and / or stable (at least 6 weeks prior to randomization) oral corticosteroid (≤10 mg / day prednisone equivalent) dose is permitted and should be continued unchanged throughout the study unless adjustment is required for safety reasons. Patients taking proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) should be stabilized on a regimen starting at least 2 weeks prior to randomization and continuing throughout the study. Selection Criteria

[0522] Patients must meet the following study entry criteria: Age 18-75 years at screening. ·Ability and willingness to provide written informed consent and comply with the requirements of the protocol. -Having a diagnosis of adult-onset RA as defined by the 2010 ACR / European League Against Rheumatism classification criteria: RA disease activity by joint count and laboratory markers of inflammation: ≥ 6 tender / painful joints on exercise (68 joint count) and ≥ 6 swollen joints (66 joint count) at both screening and day 1 (randomization). At screening, hsCRP must be as follows: Cohort 1: ≥ 0.400 mg / dL (may be repeated once); Cohort 2: ≥ 0.650 mg / dL (may be repeated once). Positive for anti-cyclic citrullinated protein / peptide antibodies (anti-CCP or ACPA), rheumatoid factor, or both (based on historical data, requiring documentation of previous positive test values ​​in an electronic case report form). Patients must have received MTX for at least 12 weeks immediately prior to randomization, with a stable dose between 7.5 and 25 mg / week (oral or parenteral) for the last 8 weeks before randomization. For patients entering the study on a dose <15 mg MTX / week, there must be clear documentation in the medical record that a higher dose was not tolerated or that the MTX dose was the highest dose tolerated based on local clinical practice guidelines. Discontinue all non-biologic disease-modifying antirheumatic drugs (DMARDs) other than MTX and leflunomide at least 4 weeks before randomization. Patients previously taking leflunomide must have discontinued it ≥8 weeks before randomization or discontinued it at least 28 days before randomization with the following exclusion procedures: Cholestyramine or activated charcoal should be taken at standard doses for a minimum of 6 days, ideally for the standard 11 days (Arava® US package insert; Arava® Summary of Product Characteristics). - Willingness to receive adequate and stable folic acid treatment (≥5 mg total dose weekly) during the study. For patients currently taking oral corticosteroids only: Treatment must be at a stable dose of ≤10 mg / d prednisone (or equivalent) for 6 weeks prior to randomization and plan to maintain the stable dose for the duration of the study. For patients currently taking an NSAID regularly (not as needed) only: Treatment must be on a stable dose for 2 weeks prior to randomization and plan to maintain a stable dose for the duration of the study. For patients currently taking a PPI or H2RA only: Treatment must be on a stable dose for 2 weeks prior to randomization and plan to maintain a stable dose for the duration of the study. · No evidence of inappropriate treatment of Mycobacterium tuberculosis (TB) infection, either active or covert. ·For women of childbearing potential (including those who have had a tubal ligation): Agree to maintain abstinence (abstain from heterosexual intercourse) or use a method of contraception that results in a failure rate of <1% per year, in accordance with the ADA local prescription label, for the duration of treatment and for at least 60 days after the last dose of study drug, or longer if needed. For men: Agree to maintain abstinence (abstain from heterosexual intercourse) or use contraception and refrain from donating sperm.

[0523] To be enrolled in Cohort 2, patients must also meet the following criteria: Have experienced an inadequate response or intolerance to prior treatment with at least one and no more than two biologic TNFα inhibitors (e.g., infliximab, etanercept, adalimumab, golimumab, or certolizumab, or biosimilar equivalents) and, in the investigator's opinion, are either of the following (this must be recorded on the eCRF): Insufficient efficacy or loss of efficacy was experienced at a dose and duration considered acceptable for adequate evaluation of clinical response according to local clinical practice. - have experienced intolerance to such treatments · Potential exposure to one or less non-TNF-alpha inhibitor biologics (e.g., abatacept, tocilizumab, sarilumab, sirumab, anakinra, or any biologic or biosimilar equivalent with the same mode of action as the listed drugs, including investigational biosimilars). Exclusion criteria

[0524] Patients who met the following criteria were excluded from the study: ·A history or current medical history of inflammatory joint disease or other systemic autoimmune disorders other than RA · Clinically significant organ dysfunction or systemic involvement secondary to RA that poses an increased risk for study participation, as determined by the investigator. Functional class IV according to the ACR 1991 revised criteria for global functional status in rheumatoid arthritis Planned bone / joint surgery (e.g., joint fusion) within 8 weeks prior to screening or major surgery, including joint surgery, within 12 weeks after randomization Prior treatment with fenebrutinib or other BTK inhibitors Previous treatment with cell-depleting therapy, including B-cell-depleting therapy (e.g., anti-CD20 directed therapy such as rituximab) Prior treatment with any non-TNF inhibitor biologic DMARD (e.g., anti-CD20 directed therapy, anti-IL6 directed therapy, or T cell directed therapy, including biosimilar equivalents) Being prescribed any condition or medication that precludes the use of, or is contraindicated with, MTX or folic acid, as determined by the topical prescription label or the investigator. Prior treatment with tofacitinib or other Janus kinase (JAK) inhibitors Prior to randomization, all biologic therapy must be discontinued, as follows: ≥ 2 weeks for etanercept and etanercept biosimilars, and ≥ 28 days for all other biologic agents (including biosimilars and investigational biosimilars). Prior exposure to any investigational drug (not including investigational biosimilars to approved treatments) within 12 weeks or 5 half-lives of the investigational drug, whichever is longer, prior to randomization Prior treatment with IV gamma globulin or a Prosorba Column within 6 months of randomization Prior treatment with alkylating agents such as cyclophosphamide or chlorambucil or total lymph node irradiation Prohibited concomitant medications (abatacept, adalimumab (ADA) (prohibited for Cohort 2), anakinra, anti-TNF inhibitors (e.g., infliximab, etanercept, golimumab, certolizumab, or biosimilar equivalents), azathioprine, chlorambucil, chloroquine, cyclophosphamide, cyclosporine, gold, hydroxychloroquine, immunoadsorption column, IV, intramuscular, or intra-articular steroids, leflunomide, mycophenolate mofetil, mycophenolate sodium Oral anticoagulants, including but not limited to warfarin, dabigatran, rivaroxaban, and apixaban; antiplatelet agents, such as clopidogrel (Note: NSAIDs and low-dose aspirin may be tolerated); heparin, low-molecular-weight heparin (LMWH); penicillamine; rituximab (or biosimilar equivalent); sirolimus; sulfasalazine; tacrolimus; tocilizumab and other anti-IL6R or anti-IL6 agents; tofacitinib and other JAK inhibitors; and all biosimilars. Current treatment with corticosteroids at doses >10 mg / day prednisone (or equivalent) or intra-articular or parenteral corticosteroids within 4 weeks prior to and during screening History of administration of live attenuated vaccines within 6 weeks prior to randomization or need to receive these vaccinations at any time during study drug treatment. Seasonal influenza and H1N1 vaccination is permitted if inactivated vaccine preparations are administered. Evidence of uncontrolled severe concomitant cardiac, neurological, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), metabolic, or GI disease that, in the opinion of the investigator, would prevent the patient from participating. Patients who meet the New York Heart Association Class III and Class IV criteria for congestive heart failure: Class III: Patients with severely limited activity; Class IV are comfortable only at rest. Patients who should be confined to a bed or chair and require complete rest; any physical activity causes discomfort and symptoms occur at rest. Screening by 12-lead ECG showing clinically relevant abnormalities that may affect patient safety or interpretation of study results. This screening includes a QT interval corrected using the Fridericia formula (QTcF) of >440 ms as demonstrated by at least two ECGs >30 minutes apart. History of or risk factors for ventricular arrhythmias, such as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome), structural heart disease (e.g., severe left ventricular systolic dysfunction, severe left ventricular hypertrophy), coronary heart disease (CHD; symptomatic or documented by diagnostic testing, previous coronary artery bypass graft surgery, or coronary artery lesion stenosis >70% in diameter that has not been revascularized or cannot be revascularized), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden death of unknown cause or cardiac ion channel mutations (e.g., congenital long QT syndrome) Currently receiving treatment with a drug known to prolong the QT interval at a dose that has a clinically meaningful effect on QT, as determined by the investigator. The investigator may contact the sponsor for confirmation, if necessary. The erythema is an uncontrolled disease state, such as asthma, psoriasis, or inflammatory bowel disease, that is commonly treated with oral or parenteral corticosteroids. -A history of vasculitis - Clinically significant ongoing liver disease in the opinion of the investigator Evidence of chronic and / or active hepatitis B or C, positive hepatitis B surface antigen (HBsAg) or positive hepatitis C serology (regardless of treatment status), or positive hepatitis B core antibody (HBcAb) Abnormalities in liver synthetic function tests (e.g., prothrombin, INR, PTT, albumin) that are deemed clinically significant by the investigator -Have a history of alcohol, drug, or chemical abuse within 12 months prior to screening, as determined by the investigator - A history of non-gallstone-associated pancreatitis or chronic pancreatitis (e.g., unexplained upper abdominal pain or malabsorptive diarrhea) that is clinically significant in the opinion of the investigator - have any known active infection (except fungal nail infection or oral herpes) History of recurrent bacterial, viral, mycobacterial, or fungal infections (defined as more than two similar episodes requiring antimicrobial treatment within the past 12 months), excluding recurrent oral or genital herpes (HSV1 / HSV2) · A history of opportunistic infection that, in the opinion of the investigator or sponsor, raises safety concerns regarding the patient's participation in the study Any major episode of infection requiring hospitalization or treatment with IV (intravenous) antimicrobials within 8 weeks before and during screening, or treatment with oral antimicrobials (antimicrobials include antifungals, antibacterials, and antivirals) within 2 weeks before and during screening ·Have a history or ongoing history of primary or secondary immunodeficiency, including a known history of HIV infection History of cancer, including hematologic malignancies and solid tumors, within 10 years prior to screening; basal cell or squamous cell carcinoma of the skin that has been excised and is considered cured, and intraepithelial carcinoma of the cervix that has been apparently treated successfully with curative therapy more than 1 year prior to screening, but not exclusively. Women who are pregnant, breastfeeding, or intending to become pregnant during the study or within 60 days of the end of the study For women of childbearing potential (including those who have had a tubal ligation): A positive serum pregnancy test result at screening or on Day 1; a serum pregnancy test is required on Day 1 only if the urine pregnancy test is positive (see Appendix 8 for definition of "childbearing potential"). Neuropathy or other painful conditions that, in the opinion of the investigator, may interfere with pain assessment. Patients requiring systemic anticoagulation with warfarin, other oral or injectable anticoagulants, or antiplatelet agents other than NSAIDs, aspirin, and other salicylates. Aspirin at doses up to 162 mg QD is permitted. - History of hospitalization for GI bleeding or blood transfusion - History of CV accident (CVA) within the past 10 years, history of hemorrhagic CVA, history of spontaneous intracranial hemorrhage, or history of traumatic intracranial hemorrhage within the past 10 years -Known bleeding tendency Any condition that may affect oral drug absorption (e.g., gastrectomy, clinically significant diabetic dyspepsia, or certain types of bariatric surgery such as gastric bypass); procedures such as gastric banding that simply divide the stomach into separate chambers are not exclusive · The presence of uncontrolled, clinically significant abnormal laboratory findings that may affect safety, interpretation of study data, or patient participation in the study. The following exclusion criteria are based on the screening laboratory tests. Unless otherwise specified, laboratory tests may be repeated once during the screening period (see section 4.5.1.1): Creatinine > 1.5 times the ULN (upper limit of normal) (may be repeated if 1.5-2 times the ULN) ALT or AST > 1.5 times ULN (may be repeated if 1.5-3 times ULN) Total bilirubin exceeds ULN (may be repeated if 1-3 times ULN) Hemoglobin level must be less than 8.5g / dL (may be repeated if hemoglobin level is between 7 and 8.4g / dL) ANC is less than 1.5×109 / L (if 1.2-1.5×109 / L, it may be repeated) - Platelet count is less than 100×109 / L (may be repeated if platelet count is between 80 and 100×109 / L) IgG <500 mg / dL (should not be repeated), prior treatment with non-TNFα inhibitor biologics for RA, including anti-IL6 directed therapy (e.g., tocilizumab, sarilumab, sirumab), anti-IL1 directed therapy (e.g., anakinra), or T cell directed therapy (e.g., abatacept), including biosimilar equivalents Prior treatment with any TNF inhibitor (e.g., infliximab, etanercept, ADA, golimumab, or certolizumab), including biosimilar equivalents and investigational biosimilars to approved agents Presence of any condition that contraindicates treatment by the ADA in accordance with approved local labeling ·A history of anaphylaxis or other severe allergic reaction to ADA. Clinical evaluation

[0525] Efficacy assessments included self-administered questionnaires prior to the administration of non-PRO assessments and prior to administration of study treatment. With the exception of the Day 28 visit, the order of efficacy assessments was standardized as follows:

[0526] PRO assessments: Patient Assessment of Arthritis Pain, Patient Global Assessment of Arthritis, HAQ-DI (Health Assessment Questionnaire-Disability Index), SF-36v2 (Short Form 36 Version 2 Health Survey) and FACIT-Fatigue.

[0527] Laboratory samples for safety, efficacy, biomarkers, and pharmacokinetics should be collected after the patient self-assessment is completed (unless specified).

[0528] Biomarkers were assessed in serum or plasma samples at baseline and at weeks 1, 4, and 12 for patients with available samples (Cohort 1: n=438; Cohort 2: n=86). Biomarkers assessed in this study were chemokine [CC motif] ligand 4 (CCL4), IL-6, and TNF-like cytokine 1A (TL1A). Total IgM, IgG, rheumatoid factor IgM autoantibody (RF), CCL4, TL1A, IL-6, and anti-CCP autoantibody (ACPA IgG) levels were analyzed by immunoassay. CD19 + B cells and CD3 + T cells were measured by flow cytometry. The proportion of patients achieving an ACR50 response at week 12 and the change in DAS28 score by week 12 were assessed compared with baseline levels of seropositivity (RF and / or ACPA positivity at baseline) or RF in both cohorts. To select which biomarkers to evaluate in this study, peripheral blood CD14 counts stimulated with immune complexes in the presence or absence of BTK inhibitors were used. + Monocytes were used to identify BTK-dependent myeloid biomarkers. Briefly, gene expression levels in human monocytes were assayed under unstimulated conditions; with human serum albumin immune complex stimulation; with stimulation and a low concentration of a BTK inhibitor with similar characteristics to fenebrutinib; or with stimulation and a high concentration of a BTK inhibitor. Genes were assayed for upregulation by at least 2-fold immune complex stimulation followed by at least 1.5-fold IC of the BTK inhibitor. 90 The subsequent decrease with concentration was used for selection. Genes annotated with cytokine activity were selected. A heat map reflecting gene expression is shown in Figure 32. The color bar represents normalized gene expression.

[0529] Investigator assessments: joint counts and visual arthritis scale (VAS), safety physician global assessment of arthritis (review of adverse events, vital signs, concomitant medications, and laboratory data). Cohort 1 only: SC comparator injection; Cohorts 1 and 2: oral study drug.

[0530] Disease Activity Score 28. DAS28-4(CRP) and DAS28-4(ESR) are calculated as follows: (i) the square-root-transformed 28-joint tender count (TJC28); (ii) the square-root-transformed 28-joint swollen count (SJC28); (iii) acute-phase reactants (erythrocyte sedimentation rate [ESR mm / hr] or high-sensitivity C-reactive protein [hsCRP mg / L]), log-transformed; and (iv) the patient's global assessment of disease activity on a visual rating scale (0–100 mm).

[0531] DAS28 is calculated according to the following formula: DAS 28(4)-ESR=0.56×SQRT(TJC28)+0.28SQRT(SJC28)+0.70×ln(ESR)+0.014×PtGA DAS 28(4)-CRP=0.56×SQRT(TJC28)+0.28SQRT(SJC28)+0.36×ln(CRP+1) +0.014×PtGA+0.96 Total score: range, 0.49-9.07 Disease remission ≤ 2.6 Disease activity: low ≤ 3.2; moderate > 3.2 and ≤ 5.1; high > 5.1 (PtGA = Patient Global Assessment of Disease Activity; ln = natural logarithm; SQRT = square root)

[0532] ACR assessment. The definition of ACR for calculating improvement in RA (ACR20) is calculated as a 20% improvement in tender and swollen joint counts, and a 20% improvement in three of the remaining five ACR core set measures: patient and physician global assessment, pain, disability, and acute phase reactants. Similarly, ACR50 and ACR70 are calculated as the respective percentage improvements. The sponsor will calculate the ACR score based on the components.

[0533] The specific components of the ACR assessment used in this study were: tender / painful joint count (68), swollen joint count (66), patient assessment of arthritis pain, patient global assessment of arthritis, physician global assessment of arthritis, CRP, and HAQ-DI.

[0534] Number of swollen and tender / painful joints: 66 joints were assessed for swelling and 68 joints for tenderness. Joints were assessed and classified as swollen / not swollen and tender / not tender by pressure and joint manipulation during physical examination. Artificial, arthrodesis, or fused joints are not considered for swelling or tenderness. The response of each joint to pressure / movement is assessed using the following scale: Yes, No, Not Done. The 68 joints assessed for tenderness / pain are as follows: Upper body: jaw joint, sternoclavicular bone, shoulder clavicle Upper limbs: shoulder, elbow, wrist (including the radiocarpal, carpal, and carpometacarpal joints considered as one unit), metacarpophalangeal joints (MCP I, II, III, IV, V), thumb interphalangeal joints, proximal interphalangeal joints (PIP II, III, IV, V), distal interphalangeal joints (DIP II, III, IV, V) Lower limbs: hip, knee, ankle, tarsus (including the subtalar, transverse and midtarsal joints considered as one unit), metatarsophalanges (MTP I, II, III, IV, V), interphalangeal joints, PIP (PIP II, III, IV, V)

[0535] The 66 joints were evaluated for swelling, the same as those listed above for tenderness / pain, except that the left and right hip joints were not included in the swollen joint count. Artificial joints were not evaluated.

[0536] Patient-reported and clinician-reported outcomes PRO (Patient's Assessment of Arthritis Pain, Patient's Global Assessment of Arthritis, HAQ-DI, SF-36v2, and FACIT-Fatigue scales, and ClinRO (Clinician's Global Assessment of Arthritis) data were collected by questionnaire and completed at designated time points in the study (i.e., weeks 1, 2, 6, 4, 8, 10, and 12).

[0537] The demographics and baseline characteristics of patients in both cohorts are shown in Figures 30A-30B. result

[0538] The test results are shown in Tables 1 and 2 below: JPEG2026041743000002.jpg54170

[0539] Table 1 shows that the trial met its primary ACR50 endpoint in both the 150 mg once-daily and 200 mg twice-daily arms of Cohort 1, and the results were statistically and clinically significant. The maximum difference in ACR50 response rate was 2.0% (150 mg once-daily). TIFF2026041743000003.tif72170

[0540] Table 2 shows that the trial met its primary ACR50 endpoint in Cohort 2, and the results were statistically and clinically significant. The maximum difference in ACR50 response rate was 2.0% (150 mg qd).

[0541] The secondary efficacy endpoint of ACR50 over time in Cohort 1 showed a dose-response relationship at Weeks 8 and 12. See Figure 1. The ACR50 response rate in Cohort 2 appeared to plateau beginning at Week 8, with endpoints met at Weeks 2, 8, and 12. See Figure 2. Figure 3 plots the proportion of patients achieving ACR20 / 50 / 70 responses versus non-responders by treatment visit. ACR20 and 70 responses are also summarized in Figures 24A and 24B. Clinically significant improvements with fenebrutinib versus placebo were observed for other secondary outcomes in both cohorts, including DAS28-ESR, CDAI, SDAI, and DAS low disease activity at Week 12. The primary and secondary efficacy endpoint responses at Week 12 are summarized in Figures 31A-31B. Results of comparisons of fenebrutinib with placebo and adalimumab for other secondary and exploratory outcomes showed comparable benefit for fenebrutinib 200 mg twice daily and adalimumab by week 12. These outcomes included ACR20, ACR70, DAS28-ESR, Boolean remission, quality of life assessment, and individual components of the ACR response rate. See Figures 24A-26C.

[0542] Results from each cohort, as measured by the ACR core parameters HAQ-DI, total tender joint count (TJC), total swollen joint count (SJC), patient global assessment (GA), physician global assessment (GA), and patient pain, all shown over time, are shown in Figures 4-15, as well as Figures 21C, 25A, and 25B.

[0543] Statistically significant improvements in DAS28 versus placebo were observed in each of the 150 mg once-daily and 200 mg twice-daily fenebrutinib groups in Cohort 1, as measured by the DAS28-3-CRP scores shown in Table 3. The 150 mg once-daily and 200 mg twice-daily fenebrutinib groups demonstrated significant differences versus placebo beginning at week 4. See Figure 16. Table 3 TIFF2026041743000004.tif47170

[0544] A statistically significant improvement in DAS28 versus placebo was observed in the 200 mg twice-daily fenebrutinib group in Cohort 2, as measured by DAS28-3-CRP score, as shown in Table 4. The fenebrutinib group showed a significant difference from placebo starting at week 2. See Figure 17. Table 4 TIFF2026041743000005.tif61170

[0545] A clinically and statistically significant reduction in CRP versus baseline was observed by week 8 in the 200 mg twice daily fenebrutinib group in Cohort 1 (59% of BL CRP at weeks 8 and 12). Cohort 2 also demonstrated decreased CRP levels at weeks 8 and 12 in the fenebrutinib group. See Figure 18 and Figure 25D.

[0546] A clinically and statistically significant decrease in ESR relative to baseline was observed by week 12 in the 200 mg twice-daily fenebrutinib group of Cohort 1 (63% of BL ESR at week 12). Cohort 1 also demonstrated decreased ESR levels in the fenebrutinib group at weeks 2, 4, and 8. Cohort 2 demonstrated decreased ESR levels in the fenebrutinib group at weeks 8 and 12. See Figure 19 and Figure 25C.

[0547] As shown in Table 5, the bone marrow-enriched biomarker CCL4 decreased in all fenebrutinib-treated groups in Cohort 1 compared to placebo starting at week 2. Similar results were observed in Cohort 2. TIFF2026041743000006.tif52170* indicates statistically significant results.

[0548] All doses of fenebrutinib reduced CCL4 levels by week 1 compared to placebo in cohorts 1 (Figure 23A) and 2 (Figure 28A). The greatest reduction compared to placebo in cohort 1 was observed in the fenebrutinib 200 mg twice daily group (-28%). In cohort 1, treatment with adalimumab reduced CCL4 levels by -36% compared to placebo. Reductions in CCL4 with adalimumab were compared to fenebrutinib treatment at weeks 4 and 12.

[0549] In Cohort 2, fenebrutinib at 200 mg twice daily reduced IL-6 levels (-50%) compared to placebo by week 12 (Figure 28B). This reduction was not observed in Cohort 1 (Figure 23B). TL1A was undetectable in patient samples tested (n=33).

[0550] As shown in Table 6, total IgM decreased from week 4 in all fenebrutinib-treated groups in Cohort 1 compared with placebo and ADA treatment. TIFF2026041743000007.tif46170* indicates statistically significant results.

[0551] As shown in Table 7, total IgG decreased in the medium- to high-dose fenebrutinib treatment groups in Cohort 1, starting at week 4, compared with placebo and ADA treatment. TIFF2026041743000008.tif52170

[0552] Rheumatoid factor (RF) IgM autoantibody levels were significantly reduced by fenebrutinib treatment by week 12 (66% in the 150 mg once-daily group; 64% in the 200 mg twice-daily group; 92% in the placebo group). The greatest reductions in total IgM, IgG, and RF IgM were observed with fenebrutinib 200 mg twice-daily in cohorts 1 and 2. In cohort 1, treatment with fenebrutinib 200 mg twice-daily resulted in a median reduction of -29% in RF IgM compared with placebo by week 12. Absolute reductions in immunoglobulin levels compared with placebo by week 12 in cohort 1 were -22 mg / dL for total IgM and -115 mg / dL for IgG with fenebrutinib 200 mg twice-daily treatment. By week 12, patients in Cohort 2 treated with fenebrutinib 200 mg twice daily experienced similar decreases in total IgM and IgG (-17 and -101 mg / dL, respectively, compared to placebo). Total IgM, IgG, and RF IgM are also summarized in Figures 22A-22B and 27. Adalimumab treatment (Cohort 1) reduced RF IgM levels by -20% compared to placebo by week 12 (Figure 22B, left), but did not reduce total IgM or IgG levels (Figure 22A). ACPA IgG levels showed a trend toward a decrease with fenebrutinib treatment but were not significantly changed compared to placebo in Cohort 1 (Figure 22B, right). In contrast, by week 12, ACPA IgG levels had decreased by −24% with fenebrutinib 200 mg twice daily compared with +15% in the placebo group in cohort 2 (FIG. 27).

[0553] As shown in Table 8, the B cell chemokine CXCL13 was reduced in all fenebrutinib-treated groups in Cohort 1 compared to placebo starting at week 4. Similar results were observed in Cohort 2. TIFF2026041743000009.tif45170

[0554] CD19 compared to baseline + B cells and CD3 + The percent changes in T cells are shown in Figures 23C and 23D for Cohort 1, respectively, and Figures 28C and 28D for Cohort 2, respectively (significance vs. placebo is indicated by * in all figures). By week 1, peripheral CD19 + A transient increase in B cells occurred in the fenebrutinib-treated groups (45-79% vs. placebo) in Cohort 1 and Cohort 2, with levels returning to the pretreatment range by week 12 (-4-13% vs. placebo). + T cells were more numerous (+10-15%) at week 1 after fenebrutinib treatment compared with placebo in cohorts 1 and 2.

[0555] Regarding screening for seropositivity status, in both cohorts, higher baseline levels of RF were associated with increased rates of ACR50 responders in the fenebrutinib 200 mg twice daily group. See Figures 29A-28B.

[0556] The overall safety profile of fenebrutinib in this study was comparable to that of placebo and ADA, although there were numerically more grade 3 LFT elevations in the fenebrutinib group. Results suggest that liver function monitoring may be warranted in patients receiving fenebrutinib.

[0557] Dose simulations based on the patient population in this study indicated that the potential optimal fenebrutinib dose range was 200–400 mg once daily or 100–200 mg twice daily. In addition to the doses examined in this study, doses of 200 mg once daily or 100 mg twice daily may be desirable.

[0558] Overall, this study demonstrated that treatment with fenebrutinib helped patients with moderate to severe RA compared with placebo. There was a significant improvement in clinical response, as reflected by ACR50 scores at week 12, in methotrexate-refractory patients who received fenebrutinib compared with patients who received placebo. Treatment with fenebrutinib results in better treatment outcomes compared with placebo in patients who have previously failed TNF inhibitor therapy.

[0559] Treatment with fenebrutinib altered levels of both B cell and bone marrow biomarkers. Fenebrutinib reduced ESR, CRP, and IL-6 levels compared with placebo; this effect was evident after 8–12 weeks of treatment, which may be due to the delayed effect of BTK inhibition on systemic inflammation.

[0560] Fenebrutinib has been shown to affect autoreactive B cells through a reduction in autoantibodies. However, this effect on autoreactive B cells was not accompanied by a reduction in B cells. The initial effect of fenebrutinib on peripheral B cells resulted in a transient increase in peripheral B cell numbers, followed by an inhibitory effect on B cells, as supported by a subsequent decrease in autoantibody levels.

[0561] Without wishing to be bound by theory, the efficacy results from this study may reflect a direct effect of BTK inhibition on the development and proliferation of autoreactive B cells, a reduction in the underlying inflammatory pathology in rheumatoid arthritis mediated through the effect of BTK inhibition on myeloid cells, or a combination of both mechanisms. Example 2 A phase II, multicenter, randomized, double-blind, placebo-controlled pilot and dose-finding study with fenebrutinib in patients with refractory chronic spontaneous urticaria (CSU)

[0562] This study was designed to evaluate the efficacy and safety of fenebrutinib compared with placebo as add-on therapy for the treatment of adult patients aged 18 to 75 years who have been diagnosed with CSU and remain symptomatic despite treatment with H1 antihistamines. The specific objectives and corresponding endpoints of this study are outlined below. Test objectives

[0563] The study consisted of two cohorts. The primary objective of Cohort 1 of the study was to evaluate the efficacy of orally administered fenebrutinib 200 mg twice daily compared with placebo as add-on treatment for patients with CSU who remained symptomatic despite treatment with H1 antihistamines.

[0564] The primary efficacy objective of Cohort 2 of this study was to evaluate the efficacy of fenebrutinib at three dose levels compared with placebo as add-on therapy for patients with CSU who remained symptomatic despite treatment with an H1 antihistamine. The primary clinical endpoint was the UAS7 score at week 8.

[0565] The secondary efficacy objectives of this study were: To assess the proportion of patients with good control (UAS7≦6) at 57 days. To assess the change in baseline UAS7 at Day 29 (Week 4).

[0566] The secondary efficacy objectives of this study were: Change from baseline in weekly itch scores at day 29 Change from baseline in weekly itch scores at day 57 Change from baseline in weekly urticaria scores at day 57 Proportion of patients with good control (UAS7≦6) at 29 days Percentage of patients who achieved complete response (UAS7=0) at 29 days Percentage of patients who achieved complete response (UAS7=0) at day 57 Proportion of patients achieving MID (≥11-point reduction from baseline) on UAS7 at Day 57 The proportion of patients who achieved the MID (≥ 5-point reduction from baseline) in weekly itch scores at Day 57 Time to achieve MID on UAS7 (≥11-point reduction from baseline) Time to achieve MID in weekly itch scores (≥ 5-point reduction from baseline) Number of angioedema cases Rescue medication use Change from baseline in UCT score at day 57

[0567] The safety objective of this study was to evaluate the safety of fenebrutinib compared with placebo in patients with CSU refractory to antihistamines.

[0568] The pharmacokinetic objective of this study was to characterize the pharmacokinetics of fenebrutinib in patients by measuring plasma concentrations at specific time points. PK exploratory objectives included the relationship between drug exposure and the pharmacological action, efficacy, and safety of fenebrutinib; the effects of selected covariates on measures of exposure and / or response to fenebrutinib; and the effects of genetic polymorphisms on measures of fenebrutinib exposure.

[0569] The biomarker discovery objectives for this study were to evaluate the effect of fenebrutinib on biomarkers to help define its pharmacological activity or efficacy, and to evaluate the relationship between changes in biomarkers and efficacy (including but not limited to serum total tryptase, urinary PGD2, and whole blood histamine). Study design

[0570] This pilot and dose-finding study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy and safety study of fenebrutinib as add-on therapy for the treatment of adult patients aged 18 to 75 years who were diagnosed with chronic urinary syndrome (CSU) and remained symptomatic despite treatment with H1 antihistamines (including doses up to four times the approved dose according to local treatment guidelines). The study consisted of two cohorts. Cohort 1 enrolled 41 patients across multiple centers. After screening, eligible patients were randomly assigned in an approximately 2:1 ratio to receive fenebrutinib 200 mg orally (PO) twice daily (BID) (n=28) or matching placebo (n=13) for 8 weeks, maintaining a stable dose of standard-of-care H1 antihistamine therapy throughout the study. Cohort 2, the dose-finding cohort, enrolled approximately 120 patients randomly assigned in a 1:1:1:1 ratio to receive GDC-0853 at doses of 50 mg PO daily (once daily), 150 mg PO once daily, or 200 mg PO twice daily, or placebo for 8 weeks, respectively, while maintaining a stable dose of standard-of-care H1 antihistamine therapy throughout the study.

[0571] Both cohorts consisted of three study periods spanning 14 weeks: (i) screening period (Day 14 to Day 1), (ii) treatment period [Day 1 to Day 57 (Week 0 to Week 8)], and (iii) follow-up period [Day 57 to Day 85 (Week 8 to Week 12)].

[0572] Patients in both cohorts will have an approximately 2-week screening period to establish eligibility for the study and baseline symptom scores. During the screening period, patients must maintain a stable dose of pre-screening concomitant therapy with standard-of-care H1 antihistamine (i.e., up to 4x the approved dose per local treatment guidelines). The screening period consists of visits on Days 14 and 7. Patients must meet all of the following criteria to enter the screening period: Demonstration of treatment with a standard of care H1 antihistamine-containing regimen for CSU on Day 14 and at least 3 consecutive days immediately preceding Day 14 An electronic symptom diary (Urticaria Patient Daily eDiary) may be completed twice daily throughout the screening period to establish the patient's Urticaria Activity Score (UAS7) score over 7 days.

[0573] To be eligible for randomization in both cohorts, patients had to have completed the Urticaria Patient Diary for 7 consecutive days prior to randomization and had a UAS7 score ≥16 (range: 0–42).

[0574] The primary efficacy endpoint was measured at Week 8 (Day 57). Patients must have maintained a stable dose of their pre-randomization H1 antihistamine therapy throughout the treatment period. After completion of the 8-week treatment period, all patients in both cohorts enter a 4-week safety follow-up period during which they do not receive fenebrutinib treatment as patients maintain a stable dose of their pre-randomization H1 antihistamine therapy.

[0575] During the study, patients were allowed to use a single dose of loratadine (up to 10 mg) or cetirizine (up to 10 mg) within 24 hours as rescue medication if symptoms worsened. If rescue therapy was required, it should not exceed four times the approved dose according to local treatment guidelines. Patients receiving four times the approved dose for background therapy should receive an alternative rescue medication. Patients were required to record the use of this medication in a daily diary. Selection Criteria

[0576] Patients must meet the following study entry criteria: · Willingness to provide written informed consent, adhere to the clinic visit schedule, adhere to the study drug regimen, and meet other study requirements. 18 to 75 years old Diagnosed with CSU refractory to H1 antihistamines at the time of randomization, as defined by all of the following: Presence of pruritus and urticaria for >6 consecutive weeks at any time prior to enrollment despite current use of an H1 antihistamine consistent with standard of care (i.e., up to 4 times the approved dose per topical treatment guidelines) during this period UAS7 score ≥ 16 for the 7 days prior to randomization (Day 1) Patients must be taking a stable daily dose of an H1 antihistamine consistent with standard of care for CSU, starting immediately before the screening visit and for at least 3 consecutive days through Day 1, and current use must be documented at all visits. CSU diagnosis ≥ 6 months - Willingness and ability to complete a daily urticaria patient diary for the duration of the study. Complete 7 days of daily eDiary entries for patients with urticaria during the 7 days prior to randomization No evidence of active, latent, or inadequately treated infection with tuberculosis (TB) as defined by: Negative QuantiFERON-TB-Gold® (QFT) test performed at the screening visit or within 3 months prior to screening (German site only: QFT is the preferred test) If QFT is not available, a Mantoux purified protein derivative (PPD) skin test, as defined by the Centers for Disease Control and Prevention guidelines, can be performed at the screening visit or within 3 months prior to screening and must be negative; and Patients who have received the Bacille Calmette-Guérin (BCG) vaccine should be screened using the QFT test only. Indeterminate QFT tests should be repeated. Two consecutive positive or indeterminate QFT test 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. · For women of childbearing potential (including women who have had a tubal ligation): Agree to maintain abstinence (abstain from heterosexual intercourse) or use a method of contraception that results in a failure rate of <1% per year, in accordance with the ADA local prescription label, for the duration of treatment and for at least 4 weeks after the last dose of study drug. For men: Agree to maintain abstinence (abstain from heterosexual intercourse) or use contraception and refrain from donating sperm. Exclusion criteria

[0577] Patients who meet any of the following criteria will be excluded from study enrollment: Treatment with omalizumab or other monoclonal antibody therapy used to treat CSU or primary non-response to omalizumab within 4 months prior to screening Use of a non-biologic investigational drug or participation in a clinical trial using a non-biologic agent must occur within 30 days (or within 5 half-lives of the investigational drug, whichever is longer) prior to administration of the study drug on Day 1. Use of an investigational biologic therapy or participation in an investigational clinical trial involving a biologic therapy within 90 days or 5 half-lives, whichever is longer, prior to Day 1 study drug administration Prior treatment with fenebrutinib or other BTK inhibitors - Patients whose urticaria is caused only by physical urticaria - Other diseases that are accompanied by symptoms of urticaria or angioedema, including urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, or leukemia - Having other skin conditions associated with itching, such as atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, or psoriasis Routine use (daily or every other day for at least 5 consecutive days) of the following medications within 30 days prior to screening: systemic or cutaneous (topical) corticosteroids (prescription or over-the-counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide · Pre-administration of intravenous steroids for the treatment of laryngeal angioedema IVIG or plasma exchange within 30 days prior to screening History of anaphylactic shock without a clearly identifiable, avoidable antigen (e.g., due to a food allergy) Hypersensitivity to fenebrutinib or any component of the formulation Major surgery within 8 weeks prior to screening or surgery planned before the end of the study (12 weeks after randomization) Patients requiring prohibited concomitant medications: Routine use (daily or every other day for 5 or more consecutive days) of systemic or topical corticosteroids (prescription or over-the-counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide within 30 days prior to screening Doxepin within 30 days prior to screening Omalizumab or other monoclonal antibody therapy used to treat CSU within 4 months prior to screening IVIG within 30 days prior to screening Plasma exchange within 30 days prior to screening LTRA within 1 day before screening Astemizole, terfenadine, and ebastine within 1 day prior to screening History of live attenuated vaccines within 6 weeks prior to randomization or the need to receive these vaccinations at any time during study drug treatment Seasonal influenza and H1N1 vaccination is acceptable if an inactivated vaccine formulation is administered. Evidence of clinically significant cardiac, neurological, psychiatric, pulmonary, renal, hepatic, endocrine (including uncontrolled diabetes mellitus), metabolic, or GI disease that, in the opinion of the investigator, compromises patient safety, interferes with interpretation of study results, or prevents patient participation Any items that cause uncertainty should be reviewed by the Medical Monitor. Uncontrolled disease states such as asthma, psoriasis, or inflammatory bowel disease, where erythema is commonly treated with oral or parenteral corticosteroids History of vasculitis Active liver disease Any known active infection (except fungal nail infection or oral herpes) History of recurrent bacterial, viral, mycobacterial, or fungal infections (defined as >2 similar episodes requiring antimicrobial treatment within the past 12 months), excluding recurrent oral or genital herpes (herpes simplex virus type 1 / herpes simplex virus type 2), or uncomplicated urinary tract infection in women. · A history of opportunistic infection that, in the opinion of the investigator or sponsor, raises safety concerns regarding the patient's participation in the study Any major episode of infection requiring hospitalization or treatment with IV (intravenous) antimicrobials within 8 weeks before and during screening, or treatment with oral antibiotics within 2 weeks before and during screening Antimicrobial agents include antifungal, antibacterial and antiviral agents. ·Have a history or ongoing history of primary or secondary immunodeficiency, including a known history of HIV infection Evidence of chronic and / or active hepatitis B or C Hepatitis B surface antigen (HBsAg) positive or hepatitis C serology (regardless of treatment status) positive, hepatitis B core antibody (HBcAb) positive -Hepatitis B core antibody (HBcAb) positive - History of cancer, including hematologic malignancies and solid tumors, within 10 years prior to screening Basal cell or squamous cell carcinoma of the skin that has been excised and is considered cured, and carcinoma in situ of the cervix that has been apparently treated successfully with curative therapy >1 year before screening are not exclusive. Women who are pregnant, breastfeeding, or planning to become pregnant during the study or within 4 weeks of completing the study For women of childbearing potential (including those who have had a tubal ligation): A positive serum pregnancy test result at screening or on Day 1 - A history of alcohol, drug (e.g., tetrahydrocannabinol, marijuana), or chemical abuse within 12 months prior to screening, as determined by the investigator or patients requiring systemic anticoagulation with NSAIDs, aspirin, and other antiplatelet agents other than salicylates. -A history of non-gallstone-related pancreatitis or chronic pancreatitis - History of hospitalization for GI bleeding or blood transfusion - History of cerebrovascular accident (CVA) or hemorrhagic CVA within the past 10 years - History of spontaneous intracranial hemorrhage or traumatic intracranial hemorrhage within the past 10 years Known bleeding tendency Screening with a 12-lead ECG for clinically relevant abnormalities that may affect patient safety or the interpretation of study results. This screening includes: Corrected QT interval (QTcF) using the Fridericia formula >440 ms as demonstrated by at least two ECGs >30 min apart was included. History of or risk factors for ventricular arrhythmias, such as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome), structural heart disease (e.g., severe left ventricular systolic dysfunction, severe left ventricular hypertrophy), coronary heart disease (symptomatic or documented by diagnostic tests, previous coronary artery bypass graft surgery, or coronary artery lesion stenosis >70% in diameter that has not been revascularized or cannot be revascularized), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden death of unknown cause or cardiac ion channel mutations (e.g., congenital long QT syndrome). Current treatment with medications well known to prolong the QT interval at doses that have a clinically meaningful effect on QT, as determined by the investigator (see https: / / crediblemeds.org / index.php / login / dlcheck). The investigator may contact the sponsor for confirmation if necessary. Any condition that may affect oral drug absorption (e.g., gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass). · Procedures such as gastric banding, which simply separates the stomach into separate chambers, are not exclusive. The occurrence of uncontrolled, clinically significant abnormal laboratory findings that may affect safety, interpretation of laboratory data, or patient participation in the study. The following exclusion criteria are based on the screening laboratory tests. Unless otherwise stated, laboratory tests may be repeated once during the screening period: Creatinine >1.5x the upper limit of normal (may be repeated if 1.5-2x the ULN) Creatinine clearance estimated by the Cockcroft-Gault formula <70 mL / min / 1.73 m 2 Less than 60-69 mL / min / 1.73 m 2 (May be repeated if ALT or AST > 1.5 times ULN (may be repeated if 1.5-3 times ULN) Total bilirubin >ULN (may be repeated if 1-3x ULN) Hemoglobin <11g / dL (may be repeated if 10-10.9g / dL) ANC <1.5×10 9 / L (1.2-1.5 × 10 9 (May be repeated if / L) Platelet count <100×10 9 / L (80-100 × 10 9 (May be repeated if / L) IgG<500mg / dL (should not be repeated) Abnormalities in liver synthetic function tests (e.g., PT, INR, PTT, albumin) determined by the investigator to be clinically significant Clinical evaluation

[0578] The primary efficacy endpoint was the change from baseline in UAS7 at week 8 (day 57). The change in UAS7 (Table 9) is a daily average (morning / afternoon) diary of the UAS (range: 0-6) composite score, which assesses the severity of two domains: itch intensity and number of wheals / hives, on a scale of 0-3 (0 = none to 3 = strong / severe). The UAS is recorded twice daily (morning and evening) by patients in their Urticaria Patient Daily eDiary. TIFF2026041743000010.tif41170

[0579] Continuous longitudinal efficacy endpoints will be analyzed using mixed models for repeated measures (MMRM) and descriptive statistics as appropriate. Additional model covariates include baseline UAS7 and its interaction with visit. Missing data will be handled by the model under non-random assumptions without the need for imputation.

[0580] Secondary efficacy measures are as described above in the "Study Objectives" section of this Example 2, and include UAS7 score and weekly itch score measurements. Weekly itch scores will be assessed as part of the study patient's urticaria diary.

[0581] TIFF2026041743000011.tif255170TIFF2026041743000012.tif255170TIFF2026041743000013.tif180170 result

[0582] Cohort 1: Fenebrutinib treatment resulted in initial activity (200 mg bid) starting at week 1, which was maintained through week 8. See Figure 20. At week 4, the secondary endpoint of UAS7 was met. The primary endpoint of UAS7 at week 8 was not met due to a surprisingly high placebo response. See Table 10 and Figure 20.

[0583] 64% of fenebrutinib-treated patients were well controlled at week 4 (% treatment difference vs. placebo: 48.6%, P=0.005). 65% of fenebrutinib-treated patients were well controlled at week 8 (% treatment difference vs. placebo: 31.9%, P=0.093).

[0584] The patient experienced improvement in weekly itch severity and weekly urticaria scores at weeks 4 and 8. See Tables 11 and 12. JPEG2026041743000014.jpg63170JPEG2026041743000015.jpg70170JPEG2026041743000016.jpg75170

[0585] As shown by Figure 33, which summarizes UAS7 scores over time in CU Index-positive and -negative patients, the greatest efficacy in Cohort 1 was observed in patients receiving fenebrutinib, who also tested positive for the CU Index (sample sizes based on week 8 are summarized in the graph below). Results for Cohort 2, as shown in Figure 34, were consistent with this observation. Each treatment group in Cohort 2 demonstrated greater efficacy (as assessed by UAS7 score) in CU Index-positive patients compared with CU Index-negative patients (UAS7 MID = 9.5-10.5; sample sizes based on week 4 are summarized in the graph below). Figure 35 summarizes the weekly itch scores at week 8 (as LS mean treatment difference) for each treatment group in Cohort 1 and Cohort 2, both stratified between CU Index-positive and CU Index-negative patients. Administration of fenebrutinib reduced weekly itch scores in each group, as shown by data from all participants, but was particularly effective at all doses in patients who tested positive on the CU Index. The 50 mg group showed the greatest difference in efficacy between CU Index-positive and CU Index-negative patients at week 8. UAS7 data for each treatment group in both cohorts at week 8 are summarized in Figure 36, again for all participants, the CU Index-negative (<10) and CU Index-positive (> / =10) groups (mean treatment effect in LS, 90% CI).

[0586] We also specifically evaluated some patient samples for IgG anti-FcERI autoantibodies. Figure 37 shows the levels of these autoantibodies over time in fenebrutinib-treated patients compared with placebo-treated patients. Serum samples were collected at weeks 0 and 8 from patients receiving fenebrutinib (left) and placebo (right). Sample sizes for each group are indicated. Prior to direct FcERI immunoassay, samples were aliquoted and preincubated with equimolar concentrations of rhFcERI or an unrelated control protein. Reactivity levels were measured relative to a mouse monoclonal antibody standard. IgG anti-FcERI was defined as the difference in reactivity between aliquoted samples and is expressed in relative units (RU). The bold line without a marker represents the mean for patients who were anti-FcERI positive at baseline. The dotted line represents the mean + 3 standard deviations for healthy volunteer samples. Some sample lines from patients with negative IgG anti-FcERI overlap at the low end of the assay range. Administration of fenebrutinib significantly reduced IgG anti-FcERI autoantibodies. Without wishing to be bound by any theory, it is believed that anti-FcERI may be a driver of positive CU index test results and is associated with refractory CSU. As shown in Figure 38, patients who tested positive for anti-FcERI autoantibodies generally showed a greater decrease in UAS7 over time when administered fenebrutinib at any dose in Cohort 2 compared to patients who tested negative for anti-FcERI autoantibodies. Example 3: A phase II, randomized, double-blind, placebo-controlled study of the safety and efficacy of fenebrutinib in patients with moderately to severely active systemic lupus erythematosus

[0587] This study was designed to evaluate the efficacy and safety of fenebrutinib in combination with standard of care (SOC) therapy compared with placebo in patients with moderately to severely active SLE. The study enrolled 260 patients from 44 centers in 12 countries. The specific objectives and corresponding endpoints of the study are outlined below. Test objectives

[0588] The primary efficacy objective of this study was to evaluate the efficacy of fenebrutinib at three dose levels compared with placebo used in combination with SOC in patients with moderately to severely active SLE, as measured by SRI-4 response at 48 weeks.

[0589] The secondary efficacy objectives of this study were: To assess the clinical efficacy of fenebrutinib over time using SRI-4 as a standardized disease activity measure: · SRI-4 response at week 48 with sustained reduction in oral corticosteroid (OCS) dose to <10 mg / day and ≤ daily dose from week 36 to week 48 · SRI-4 response at week 24 with sustained reduction in OCS dose to <10 mg / day and ≤ daily dose from week 12 to week 24 SRI-4 response at 24 weeks To evaluate whether patients with high plasmablast signature levels have an enhanced clinical response to fenebrutinib compared with patients with low levels: SRI-4 response at 48 weeks · SRI-4 response at week 48 with sustained reduction in OCS dose to <10 mg / day and ≤ daily dose from week 36 to week 48 To assess the clinical efficacy of fenebrutinib over time using the BILAG-based Composite Lupus Assessment (BICLA) and SRI-6 as standardized disease activity measures: SRI-6 response at 24 and 48 weeks BICLA response at 24 and 48 weeks

[0590] The exploratory efficacy objectives of this study were to evaluate the clinical efficacy of fenebrutinib over time using multiple standardized disease activity measures: SRI-5, 7 and 8 responses at 48 weeks - SRI-5 to 8 response at week 48 with sustained reduction in OCS dose to <10 mg / day and ≤ daily dose from week 36 to week 48 SRI-5, 7 and 8 response at 24 weeks. · SRI-5~8 response at week 24 with sustained reduction of OCS dose to <10 mg / day and ≤ daily dose from week 12 to week 24

[0591] The secondary efficacy objectives of this study were: To evaluate the ability of fenebrutinib to extend the time to first SLE relapse To assess the ability of fenebrutinib to reduce the number of total SLE relapses To assess the clinical efficacy of fenebrutinib over time based on the individual components of SLE To assess whether patients with high plasmablast signature levels have an improved clinical response to fenebrutinib compared with patients with low levels To evaluate the ability of fenebrutinib to improve the skin manifestations of SLE To evaluate the ability of fenebrutinib to prevent systemic damage To evaluate the ability of fenebrutinib to improve arthritis To assess the ability of fenebrutinib to improve fatigue To assess the ability of fenebrutinib to improve patient global assessment To assess whether fenebrutinib can be steroid-sparing.

[0592] The safety objective of this study was to evaluate the safety of fenebrutinib administered in combination with SOC in patients with moderately to severely active SLE.

[0593] The pharmacokinetic objective for this study was to characterize the pharmacokinetics of fenebrutinib in patients. Exploratory PK objectives included the relationship between drug exposure and the pharmacological action, efficacy, and safety of fenebrutinib; the effects of selected covariates on measures of exposure and / or response to fenebrutinib; and the effects of genetic polymorphisms on measures of fenebrutinib exposure.

[0594] The biomarker exploration objectives of this study are as follows: To evaluate the effect of fenebrutinib-induced changes in biomarkers and efficacy. To evaluate whether baseline biomarkers, including plasmablasts, autoantibodies, and other inflammatory biomarkers, can identify patients with an enhanced clinical response to fenebrutinib. To assess whether the levels of the above biomarkers are associated with disease progression. Study design

[0595] This was a multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to evaluate the safety and efficacy of fenebrutinib in combination with SOC therapy in patients with moderately to severely active SLE. Moderate-to-severe SLE was defined as serologic evidence of SLE at screening and baseline (i.e., day 1) accompanied by clinical disease activity and active oral treatment for SLE.

[0596] The study consisted of a screening period (up to 35 days) and a 48-week treatment period, followed by either an 8-week safety follow-up visit or the possibility of enrollment in an open-label extension (OLE) study at week 56. Approximately 240 patients who met all eligibility criteria were randomized in a 1:1:1 ratio to one of the following three groups: ·Group A: GDC-0853 200mg twice a day (BID) ·Group B: GDC-0853 150mg once a day (QD) Group C: placebo

[0597] All three groups received blinded study medication in combination with background SOC therapy. Randomization was stratified by disease activity at screening, initial oral corticosteroid (OCS) dose, and geographic region. All patients received blinded study medication (fenebrutinib, placebo, or both to maintain blinding) twice daily from baseline through week 48 and were evaluated at clinic visits every 4 weeks during treatment (including a start-up phone call at week 1).

[0598] Background SOC therapy could consist of OCS (which must be stable for 2 weeks prior to screening and doses not exceeding 40 mg / day of prednisone or equivalent) and / or specific oral immunosuppressive regimens (which must be stable for 2 months prior to screening). All immunosuppressants and antimalarials remained stable throughout the study unless dose reduction was required due to toxicity. All patients receiving immunosuppressive treatment were also encouraged to receive supportive care (e.g., folic acid, calcium, vitamin D). For patients taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) at study enrollment, the dose of the ACE inhibitor or ARB should be kept stable for at least 10 days prior to randomization and, if possible, throughout the entire study.

[0599] For patients receiving OCS at baseline, there are two 12-week OCS tapering strategies available to achieve a pre-specified OCS taper of <10 mg / day prednisone or equivalent, followed by holding the last dose of each OCS stability strategy (i.e., the 12-week period immediately following the 12-week OCS tapering strategy) stable for an additional 12 weeks.

[0600] In the event of increased SLE disease activity, there may be two temporary increases in corticosteroid dose, called "bursts," that may be administered as needed. Bursts may be administered only during the burst regimen (defined as the first 10 weeks of each OCS tapering regimen) and only once per regimen. Bursts are defined as a temporary increase in the corticosteroid dose (up to 40 mg / d of prednisone or equivalent for Burst Regimens 1 and up to 20 mg / d of prednisone or equivalent for Burst Regimens 2), followed by a gradual decrease to the dose immediately preceding the burst, all within 2 weeks.

[0601] If active SLE requires further treatment beyond the permitted burst therapy, as identified by the investigator, patients may receive escape therapy. However, such patients will be considered trial-defined non-responders for the purposes of the primary analysis. During taper, burst, and escape therapy, patients will continue to receive trial treatment at the assigned dose. Beginning with the screening period, all patients must record their actual OCS use weekly as directed by study staff.

[0602] An open-label IMC and scientific monitoring committee will be used to monitor multiple safety assessments. Additionally, to conduct a preliminary evaluation of the benefit-risk profile of fenebrutinib and potentially stop it early for futility and / or safety issues, an interim analysis will be conducted after 50-80 patients in each treatment group have completed 24 weeks of treatment and been evaluated for SLE Responder Index (SRI)-4 response.

[0603] Patient inclusion and exclusion criteria are described below. Patients must meet the following study entry criteria: Signed informed consent form, aged 18-75 years, inclusive, and able to comply with the study protocol Achievement of SLE classification criteria according to either the current American College of Rheumatology (ACR) or Systemic Lupus International Clinical Collaboration (SLICC) criteria at any time before or at the time of screening At least one serological marker of SLE on screening: positive antinuclear antibodies with an immunofluorescence assay (ANA) titer of ≥ 1:80; positive anti-double-stranded DNA (anti-dsDNA) antibodies; or positive anti-Smith antibodies Moderately to severely active SLE, defined as all of the following at both screening and Day 1, unless otherwise indicated: i.SLEDAI-2K score ≥ 8 (at screening only) and clinical SLEDAI-2K score ≥ 4.0 (both at screening and day 1); ii. Physician global rating ≥ 1.0 (out of 3); and iii. Currently receiving at least one standard oral treatment for SLE (e.g., corticosteroids, antimalarials, and / or immunosuppressants) within the dose ranges as specified below. For OCS, the dose must be ≤40 mg / day prednisone (or equivalent) and must be stable for at least 2 weeks before and during screening. If receiving antimalarial or immunosuppressive therapy, you may only be receiving medications from the following list within the specified dose range. The dose and route of administration must be stable for 8 weeks before and during screening: Azathioprine: 1 to 2.5 mg / kg / day Methotrexate: 7.5-25 mg / week Mycophenolate mofetil: 500-3000mg / day Mycophenolate sodium: 360-2160 mg / day Hydroxychloroquine: 200-400mg / day Chloroquine: 100-250 mg / day Quinacrine: 100-200mg / day For women of childbearing potential: Agree to maintain abstinence (abstain from heterosexual intercourse) or use a method of contraception that results in a failure rate of <1% per year during study treatment and for a minimum of 60 days after the last dose of study drug or for any longer period required by local standard of care requirements. Women using estrogen-containing hormonal contraceptives as a method of contraception must also use a barrier. For men: Agreement to abstain (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm.

[0604] Patients who meet any of the following criteria will be excluded from study enrollment: Proteinuria exceeding 3.5g / 24 hours in the first morning void, or equivalent proteinuria detected by urinary protein / creatinine ratio (uPCR) Active proliferative lupus nephritis (as assessed by the examiner) or histologic evidence of active Class III or Class IV lupus nephritis on a renal biopsy performed within 6 months prior to screening (or during the screening period) A history of needing hemodialysis or high-dose corticosteroids (>100 mg / d prednisone or equivalent) for management of lupus kidney disease within the 90 days following Day 1 - Development of neuropsychiatric or central nervous system lupus symptoms, including but not limited to, seizures, psychosis, or acute confusional state within 52 weeks of screening Serum creatinine > 2.5 mg / dL or estimated glomerular filtration rate (based on the 4-parameter modification of diet in renal disease formula) > 30 mL / min or receiving chronic renal replacement therapy - History of solid organ transplant Newly diagnosed transverse myelitis (within the past 24 weeks) History of antiphospholipid syndrome (APLS) with or without associated consumptive coagulopathy; presence of antiphospholipid antibodies or history of fetal loss but no current history of thromboembolic disease or need for anticoagulation therapy is not exclusive. Evidence of active, latent, or inadequately treated infection with Mycobacterium tuberculosis (TB) as follows: A positive QuantiFERON TB-Gold® QFT test performed at the screening visit. If QFT is not available, a Mantoux purified protein derivative (PPD) skin test as defined by Centers for Disease Control and Prevention (CDC) guidelines, performed at the screening visit or within 12 weeks prior to screening, read topically Women who are pregnant or lactating (breastfeeding; within the past 12 weeks), or who intend to become pregnant, donate eggs or breast milk, or participate in in vitro fertilization during the study Significant, uncontrolled medical disease within 12 weeks prior to screening in any organ system unrelated to SLE (e.g., cardiac, neurological, pulmonary, renal, hepatic, endocrine [including uncontrolled diabetes mellitus], metabolic, GI, or psychiatric disease [including suicidal ideation]) that, in the opinion of the investigator or sponsor, would prevent the patient from participating In addition to SLE, have a concomitant chronic condition (e.g., asthma, Crohn's disease) that required oral, intravenous (IV), or intramuscular (IM) steroids or immunosuppressant use in the 24 weeks prior to screening or is likely to require such use during the course of the study. - A history of non-gallstone-associated pancreatitis or chronic pancreatitis (e.g., with upper abdominal pain or malabsorptive diarrhea) that was clinically significant in the opinion of the investigator Evidence of autoimmune myositis History of cancer, including hematologic malignancies and solid tumors, within 10 years of screening; basal cell carcinoma or squamous cell carcinoma of the skin that has been excised and considered cured. Neoplasia in situ of the cervix that has been adequately treated with curative therapy more than 1 year prior to screening is not exclusive. - A history of alcohol, drug, or chemical abuse within one year prior to screening, as determined by the investigator - Having undergone major surgery requiring hospitalization within 4 weeks of screening - History of cerebrovascular accident (CVA) or hemorrhagic CVA within the past 10 years, or history of spontaneous or traumatic intracranial hemorrhage within the past 10 years -A history of clinically uncontrolled cardiac arrhythmia Screening with a 12-lead ECG for clinically relevant abnormalities that may affect patient safety or the interpretation of study results. This screening includes: Corrected QT interval (QTcF) using the Fridericia formula of 450 msec for female patients and 430 msec for male patients as demonstrated by at least two ECGs separated by 30 minutes was included. ·A history of clinically significant ventricular arrhythmias or risk factors for ventricular arrhythmias, such as long QT syndrome or other genetic risk factors, heart disease, or a family history of sudden unexplained death or cardiac ion channel mutations Currently being treated with a drug (excluding antimalarials) known to prolong the QT interval at a dose that has a clinically meaningful effect on QT, as determined by the investigator Any condition that may affect oral drug absorption (e.g., gastrectomy, clinically significant diabetic dyspepsia, or certain types of bariatric surgery such as gastric bypass); procedures such as gastric banding that simply divide the stomach into separate chambers are not exclusive. The need for systemic anticoagulation with warfarin or other oral or injectable anticoagulants (other than NSAIDs, aspirin (≤325 mg / day), or other salicylates) -Known bleeding tendency Any history of hospitalization for GI bleeding or blood transfusion · History or ongoing history of primary or secondary immunodeficiency, including known history of HIV infection, or IgG <500 mg / dL - Any known active infection (excluding fungal nail infection or oral herpes) at the time of enrollment and during screening, including enrollment Have a history of treated recurrent bacterial, viral, mycobacterial, or fungal infections, defined as two similar episodes requiring antimicrobial treatment within the past 52 weeks, except for the following: Oral or genital herpes (herpes simplex virus type 1 / herpes simplex virus type 2) Uncomplicated cystitis or asymptomatic bacteriuria Uncomplicated viral, bacterial or culture-negative bronchitis without pneumonia Bacterial or viral sinusitis Bacterial or fungal (yeast) vaginal infections · A history of opportunistic infection that, in the opinion of the investigator or sponsor, raises safety concerns regarding the patient's participation in the study -Having a major episode of infection requiring hospitalization or treatment with IV or IM antibiotics within 4 weeks before or during screening, or treatment with oral antibiotics within 2 weeks before and during screening (excluding Pneumocystis jiroveci pneumonia prophylaxis) History of severe and / or disseminated viral infections, particularly herpesviruses, e.g., HSV1, HSV2, varicella-zoster virus (VZV), and cytomegalovirus; uncomplicated influenza during influenza season, cold sores, and genital herpes are not exclusive Evidence of chronic and / or active hepatitis B or C · Have received any of the following medications and / or procedures within the indicated time period: - Having received plasma exchange or IV Ig in the last 12 weeks before screening - Receipt of B-cell depleting therapy (e.g., anti-CD20 or anti-CD19) within 24 weeks prior to screening Receipt of belimumab, blissibimod, tabalumab (or other anti-B-cell activating factor [BAFF] agents), atacicept (or other anti-transmembrane activator and calcium modulator and cyclophilin ligand [CAML] interactor [TACI] agents), epratuzumab (or other anti-CD22 agents), or denosumab within 5 half-lives or 12 weeks (whichever is longer) prior to screening -Receipt of cyclophosphamide or other alkylating agents within 12 weeks prior to screening -Receipt of oral cyclosporine, tacrolimus, topical calcineurin inhibitors, anakinra (IL-1 inhibitor), sirolimus (IL-2 inhibitor), or other calcineurin inhibitors within 4 weeks prior to screening -Receipt of thalidomide or thalidomide derivatives within 24 weeks prior to screening Receipt of tumor necrosis factor (TNF) antagonists, tocilizumab, or other biologics not mentioned above within 12 weeks prior to screening -Received any investigational drug within 4 weeks or 5 half-lives of screening, whichever is longer. - Any parenteral (IV), IM, or intra-articular steroids received within 4 weeks prior to screening -Receipt of any other immunosuppressant medication for SLE not listed in the inclusion criteria within 12 weeks or 5 half-lives, whichever is longer, prior to screening, unless approved by the medical monitor Live vaccines within 6 weeks prior to randomization; seasonal influenza and H1N1 vaccination are permitted if an inactivated vaccine preparation is administered. Use of the following categories of medications, herbal supplements, or foods should be avoided within 1 week or 5 half-lives, whichever is longer, prior to randomization based on potential drug interactions (CYP3A inhibitors / inducers): If the initial result is out of range during screening, the test may be repeated once for any of the following laboratory results: AST or ALT > 1.5 × ULN Total bilirubin >1.2ULN Amylase or lipase >2×ULN Hemoglobin <7g / dL Absolute neutrophil count (ANC) < 1.5 × 10 9 / L Absolute lymphocyte count (ALC) <0.5×10 9 / L ·Platelet count<50,000 / μL

[0605] Interim Analysis: An interim analysis was performed after approximately 50 patients in each treatment group completed the 24-week SRI-4 response assessment. The purpose of the interim analysis was to perform a preliminary benefit-risk assessment of the fenebrutinib treatment group compared with the placebo treatment group to allow for potential stopping due to futility and / or safety concerns, or to potentially inform the clinical development plan for fenebrutinib.

[0606] Patients were considered SRI-4 responders if they experienced the following: (i) a reduction in SLEDAI-2K from baseline of at least 4 points, (ii) no worsening of BILAG (no new A domains and fewer than two new B domains), and (iii) no worsening of Patient Physician Global Assessment (PGA).

[0607] Interim results: 57% of patients (28 patients) in the fenebrutinib 200 mg twice-daily group were SRI-4 responders at week 24. 49% of patients (25 patients) in the fenebrutinib 150 mg once-daily group were SRI-4 responders at week 24. 46% of placebo patients (23 patients) were also SRI-4 responders at week 24. These results demonstrated the efficacy of fenebrutinib in treating SLE in this study.

[0608] Fenebrutinib was safe and well tolerated at each dose level in the interim analysis. Some patients in the 200 mg twice-daily group experienced signs of elevated ALT and AST.

[0609] C. Study End The end of the study is defined as the last patient, the last safety follow-up visit in this protocol, the last patient to discontinue the study, or the last patient enrolled in the OLE, if one has been initiated, whichever occurs later. The maximum duration of a patient's study is 61 weeks, which includes up to 35 days of screening, 48 weeks of treatment, and an 8-week safety follow-up period (unless enrolled in an OLE study). Biomarkers

[0610] According to the biomarker objectives provided in the above test objectives, the following biomarkers were investigated. In Table 13, biomarkers are measured at baseline and subsequent time points during and after treatment. One set of biomarkers evaluated is the plasmablast signature. Plasmablasts are rapidly dividing, short-lived antibody-secreting cells. Although they represent a small proportion of B cells in the blood, they are responsible for the majority of antibody transcripts found in whole blood mRNA. The plasmablast signature includes the biomarkers IgJ, Mzbl, and Txndc5. The gene expression of IgJ, Mzbl, and Txndc5 can be measured by, for example, evaluating the mRNA level of the gene in the patient's blood relative to a reference level. TIFF2026041743000017.tif94170

[0611] Results: Efficacy and results at week 48 are summarized in Table 14. At week 48, the SRI-4 response rates for the 150 mg once-daily and 200 mg twice-daily groups were 51% (95% CI: -8.5, 21.2) and 52% (95% CI: -7.3, 22.4), respectively, compared with 44% for placebo. The BICLA response rates at week 48 for fenebrutinib 150 mg once-daily and fenebrutinib 200 mg twice-daily were 53% (95% CI: -3.4, 26.8) and 42% (95% CI: -14.2, 16.1), respectively, compared with 41% for placebo. TIFF2026041743000018.tif233170

[0612] Biomarker results are summarized in Table 15. Treatment with both doses of fenebrutinib significantly increased CD19 expression in plasmablasts by week 48 compared to placebo. + B cells expressed significantly reduced levels of anti-dsDNA autoantibodies, IgG, and BTK-dependent RNA signatures. C4 levels were somewhat improved by fenebrutinib compared with placebo. These results demonstrate that oral administration of fenebrutinib successfully inhibited BTK targets and pathways. TIFF2026041743000019.tif214170

[0613] The present disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, but the descriptions and examples should not be construed as limiting the scope of the disclosure. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. 1. A method of treating a human patient with moderate to severe active rheumatoid arthritis, wherein the patient has not had an adequate response to prior treatment with one or more conventional non-biologic DMARDs, the method comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 to about 400 mg daily.

2. 10. The method of claim 1, wherein the conventional non-biologic DMARD in the prior treatment is methotrexate.

3. 3. The method of claim 1 or 2, wherein the fenebrutinib or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents.

4. 1. A method of treating a human patient with moderate to severe active rheumatoid arthritis, wherein the patient has had an inadequate response to or intolerance to prior treatment with one or more biologic rheumatoid arthritis drugs, the method comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 to about 400 mg daily.

5. 5. The method of claim 4, wherein the biologic rheumatoid arthritis drug is selected from the group consisting of a TNF-alpha inhibitor, abatacept, tocilizumab, sarilumab, sirumab, anakinra, and any biosimilar equivalents thereof.

6. The method of any one of claims 1 to 5, wherein the patient exhibits relief of one or more symptoms of rheumatoid arthritis after treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

7. 7. The method of claim 6, wherein the reduction in the patient's symptoms is measured by at least a 50% reduction in the patient's American College of Rheumatology score (ACR50).

8. 7. The method of claim 6, wherein the reduction in the patient's symptoms is a decrease in the patient's DAS28 score.

9. 9. The method of any one of claims 6 to 8, wherein the relief of one or more symptoms of rheumatoid arthritis occurs within or at 4 weeks of treatment.

10. 9. The method of any one of claims 6 to 8, wherein the relief of one or more symptoms of rheumatoid arthritis occurs within or at 8 weeks of treatment.

11. 9. The method of any one of claims 6 to 8, wherein the relief of one or more symptoms of rheumatoid arthritis occurs within or at 12 weeks of treatment.

12. 12. The method of any one of claims 1 to 11, wherein the method further comprises measuring a clinical or laboratory endpoint for the patient to assess the effectiveness of the treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

13. 13. The method of claim 12, wherein the clinical endpoint is selected from the group consisting of the patient's ACR50 score, ACR70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-Fatigue score, CRP relative to baseline, and ESR relative to baseline.

14. 14. The method of claim 13, wherein the clinical or laboratory endpoint is measured after 4 weeks of treatment.

15. 14. The method of claim 13, wherein the clinical or laboratory endpoint is measured after 8 weeks of treatment.

16. 14. The method of claim 13, wherein the clinical or laboratory endpoint is measured after 12 weeks of treatment.

17. The method of any one of claims 1 to 16, wherein the method first comprises a step of determining the presence of the autoantibody in a blood sample from a patient having the autoantibody prior to treatment of the patient with fenebrutinib or a pharmaceutically acceptable salt thereof.

18. 18. The method of claim 17, wherein the autoantibodies determined in the sample are selected from the group consisting of rheumatoid factor antibodies and anti-citrullinated peptide antibodies.

19. 1. A compound for use in a method for treating moderately to severely active rheumatoid arthritis in a human patient, said patient having an inadequate response to prior treatment with one or more conventional non-biologic DMARDs, said compound being fenebrutinib or a pharmaceutically acceptable salt thereof, said treatment being fenebrutinib at a dose of about 150 to about 400 mg daily.

20. 1. A compound for use in a method for treating moderately to severely active rheumatoid arthritis in a human patient, wherein said patient has had an inadequate response to, or intolerance to, prior treatment with one or more biologic rheumatoid arthritis drugs, said compound being fenebrutinib or a pharmaceutically acceptable salt thereof, and said treatment being fenebrutinib at a dose of about 150 to about 400 mg daily.

21. A compound according to claim 19 or 20 for use in a method according to any one of claims 1 to 18.

22. 1. A method of treating a human patient with chronic spontaneous urticaria, wherein the patient exhibits symptoms of the disease despite previous treatment with an H1 antihistamine, the method comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 50 mg to about 400 mg daily.

23. 23. The method of claim 22, wherein after treatment, the patient has a mean reduction in weekly itch severity score from baseline.

24. 23. The method of claim 22, wherein after treatment, the patient has a decrease in Urticaria Activity Score (UAS7) from baseline after treatment.

25. 25. The method of claim 23 or 24, wherein the change from baseline occurs within or at 4 weeks of treatment.

26. 25. The method of claim 23 or 24, wherein the change from baseline occurs within or at 8 weeks of treatment.

27. 25. The method of claim 23 or 24, wherein the change from baseline occurs within or at 12 weeks of treatment.

28. 28. The method of any one of claims 22 to 27, wherein the patient is concurrently administered an H1 antihistamine.

29. 29. The method of any one of claims 22 to 28, comprising first determining the presence of said autoantibodies in a blood sample from said patient prior to administering fenebrutinib or a pharmaceutically acceptable salt thereof to said patient having said autoantibodies.

30. 1. A compound for use in a method of treating chronic spontaneous urticaria in a patient, wherein said patient exhibits symptoms of disease despite previous treatment with an H1 antihistamine, said compound being fenebrutinib or a pharmaceutically acceptable salt thereof, and said treatment being fenebrutinib at a dose of about 50 to about 400 mg per day.

31. A compound according to claim 30 for use in a method according to any one of claims 23 to 29.

32. 1. A method of treating a human patient with moderate to severe active systemic lupus erythematosus, wherein the patient exhibits symptoms of the disease despite previous standard oral SLE treatment, the method comprising administering fenebrutinib or a pharmaceutically acceptable salt thereof at a dose of about 150 mg to about 400 mg daily.

33. 33. The method of claim 32, wherein the standard oral SLE treatment is selected from the group consisting of oral corticosteroids, antimalarials, and immunosuppressants.

34. 34. The method of claim 32 or 33, wherein the administration is administered in combination with an oral corticosteroid.

35. 35. The method of any one of claims 32 to 34, wherein after treatment, the patient exhibits a reduction in one or more clinical symptoms of SLE.

36. 36. The method of any one of claims 32-35, wherein the reduction in clinical symptoms of the patient is measured by the patient's SLE Responder Index (SRI-4) score.

37. 36. The method of claim 35, wherein the alleviation of one or more clinical symptoms of SLE occurs within or at 24 weeks of treatment.

38. 36. The method of claim 35, wherein the alleviation of one or more clinical symptoms of SLE occurs within or at 48 weeks of treatment.

39. 1. A compound for use in a method of treating a human patient with moderate to severe active systemic lupus erythematosus, wherein said patient is exhibiting symptoms of the disease despite previous standard oral SLE treatment, said compound being fenebrutinib or a pharmaceutically acceptable salt thereof, and said treatment being fenebrutinib at a dose of about 150 to about 400 mg per day.

40. A compound according to claim 39 for use in a method according to any one of claims 32 to 38.

41. 1. A composition for use in a method of treating a human patient with moderate to severe active systemic lupus erythematosus, wherein the patient exhibits symptoms of the disease despite previous standard oral SLE treatment, the composition comprising fenebrutinib or a pharmaceutically acceptable salt thereof, and the treatment is fenebrutinib at a dose of about 150 to about 400 mg per day.

42. A composition according to claim 41 for use in a method according to any one of claims 32 to 38.

43. 39. The method of any one of claims 1-18, 22-29, or 32-38, wherein fenebrutinib or a pharmaceutically acceptable salt thereof is administered orally in the form of one or more tablets or capsules.

44. 44. The method of claim 43, wherein the fenebrutinib is administered orally as the free base in the form of one or more tablets or capsules.

45. 45. The method of claim 43 or 44, wherein the fenebrutinib is administered orally as the free base in the form of one or more tablets.

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