METHODS FOR TREATING RHEUMATOID ARTHRITIS, CHRONIC SPONTANEOUS URTICARIA AND DISSEMINATED LUPUS ERYTHEMATOSUS BY USING A BRUTON TYROSINE KINASE INHIBITOR

Abstract

This disclosure relates to methods for treating rheumatoid arthritis, chronic spontaneous urticaria, and systemic lupus erythematosus by using fenebrutinib, a Bruton's tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

Description

METHODS FOR TREATING RHEUMATOID ARTHRITIS, CHRONIC SPONTANEOUS URTICARIA, AND DISSEMINATED LUPUS ERYTHEMATOSUS THROUGH THE USE OF A BRUTON'S TYROSINE KINASE INHIBITOR CROSS REFERENCE TO RELATED REQUESTS

[0001] This application claims the benefit of US Provisional Application No. 62 / 795,477, filed on January 22, 2019, and US Provisional Application No. 62 / 913,270, filed on October 10, 2019, the disclosures of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION

[0002] The present disclosure relates to methods of treating rheumatoid arthritis, chronic spontaneous urticaria and disseminated lupus erythematosus through the use of a Bruton's tyrosine kinase (BTK) inhibitor. BACKGROUND OF THE INVENTION

[0003] Bruton's Tyrosine Kinase (BTK): The discovery of genetic bases for primary immunodeficiencies has been the source of new therapeutic targets in immunomodulatory treatments. In humans, mutations in the gene for Bruton's tyrosine kinase (BTK), which is located on the X chromosome, can lead to the development of an immunodeficiency state characterized by the significant absence of circulating B lymphocytes (Bruton OC. Pediatrics 1952, 9:722-8; Conley ME, etal, Immunol Rev 2005, 203:216-34), and very low immunoglobulin levels due to a defect in the differentiation of B lymphocytes at the pro- to pre-lymphocyte stage. B that prevents the assembly of the B cell receptor (BCR) complex and the expression of the immunoglobulin gene (Reth M, Nielsen P, Adv Immunol 2014, 122:129-75. doi: 10.1016 / B978-0-12-800267 -4.00004-3). Affected male patients have a primary immune insufficiency, X-linked agammaglobulinemia (XLA), and are susceptible to recurrent infections that begin shortly after birth. Patients with XLA can live relatively normal lives with standard intravenous (IV) immunoglobulin treatment, suggesting that BTK can be safely inhibited, especially in people with established immune systems. IV immunoglobulin replacement therapy decreases the rate of infection, reduces hospitalization rates for patients with XLA, and has greatly 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 at tyrosine Y551 by the Src family kinase Lyn. Autophosphorylation and activation also occur at tyrosine Y223 in a BTK-specific manner. Once activated, BTK induces PLCy2+ and Ca2-dependent signaling, which generates the activation of NF-kB and NFAT-dependent pathways that produce cell differentiation and activation (Niiro H, Clark EA., Nat Rev Immunol 2002, 2: 945-56). Furthermore, BTK is important in FcsRI signaling in both basophils and mast cells, key cell types in the pathogenesis of CSU. BTK null mice have prevented QRQonn / i ζηζ / Ε / γ FceRI signaling, resulting in a decrease in histamine and inflammatory cytokine release (lyer AS, etal., J BioChem 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 that can lead to a significant reduction in the quality of life, unemployment and premature death. Hypotheses on the pathogenesis of RA have focused on the production of autoantibodies, the formation of immune complex in the synovial membrane, the production of proinflammatory cytokine, in particular interlucin-6 (IL-6) and tumor necrosis factor-alpha (TNF). -α), and the function of B lymphocytes and myeloid cells in inflamed synovium (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 medications 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 disease that produce complete remission.

[0006] Treatments targeting B lymphocytes have become a focus of development as immunomodulators in autoimmune disorders. BTK is a key kinase in signaling cascades followed by activation of the B cell antigen receptor in B cells, in binding to the Fe receptor of immune complexes in myeloid cells, and in some toll-like receptor signaling events in B cells. , myeloid cells and dendritic cells (Satterthwaite AB, Witte ON, Immunol. Rev. 2000, 175:120-7; Sochorová et al., Blood 2007, 109;2553-6.). Autoimmune disorders marked by prominent B cell and immune complex mediated activities, such as RA and disseminated lupus erythematosus, may benefit from targeted antagonism of BTK signaling.

[0007] Chronic spontaneous urticaria (CSU): CSU, also called chronic idiopathic urticaria (CIU), is defined by the presence of wheals (wheals), angioedema, or both for at least 6 weeks without an obvious cause (Greaves M., Curr Opin Allergy Clin Immunol 2003, 3:363-8). Previous estimates regarding the prevalence of CSU were approximately 0.1%, which persists in 20% of patients with CSU 2 decades after diagnosis (Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000, 105:664-72; Saín !SS. Chronic spontaneous urticaria: etiology and pathogensis. Immunol Allergy Clin North. Am 2014, 34:33-52. doi: 10.1016 / j.iac.2013.09.012). The most recent evidence indicates that the point prevalence of disease is approximately 1% (Maurer M, et al., Arch Dermatol 2006, 142:1337-42). Affected patients experience pruritic wheals with associated erythema and / or episodes of angioedema. CSU is reported to be associated with angioedema in approximately 50% of cases (McGirt LY, et al., Allergy 2011, 66:317-30). The description of classic urticaria is a wheal and rash with a pale raised lesion and surrounding erythema, ranging in size from a few millimeters to a few centimeters in length, generally occurring in groups and often coalescing to form confluent lesions. long. QRQonn / i ζηζ / Ε / γ

[0008] The etiology of CSU is not clear. There are several theories, including one that proposes an infectious origin and another 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 30-60% 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 of a specific IgE antibody directed to an endogenous antigen. A study of more than 450 CSU patients indicates that more than 50% of CSU patients had IgE antibodies directed against thyroperoxidase (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. In patients with CSU, increased numbers of mast cells can be found 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 lower thresholds for activation, and respond more robustly by releasing more histamine and other inflammatory mediators. Similarly, increased numbers of basophils have been observed in the skin with and without lesions of CSU patients (Ying S, et al., J Allergy Clin Immunol 2002,109:694-700).

[0010] About half of CSU patients achieve symptomatic control with treatment with H1-antihistamines at approved doses. In some cases, the antihistamine dose is increased (up to 4 times the approved dose according to local treatment indications) and additional treatments, such as leukotriene receptor antagonists (LTRAs), are used, despite increased doses. Antihistamines and LTRAs are not approved for the treatment of CSU. These agents have variable success and may be associated with serious adverse effects. Patients may remain symptomatic despite continued treatment with H1-antihistamines (up to 4 times the approved dose for local treatment indications, Powell RJ, et al. Clin Exp Allergy 2015, 45:547-65. doi: 10.1111 / cea . 12494), and treatments such as immunosuppressants (for example, cyclosporine, corticosteroids, intravenous immunoglobulin G, and methotrexate) and plasmapheresis (Kozel MA, Sabroe RA., Chronic urticaria, aetiology, management and curren!) have been used for this group of patients. and future treatment options. Drugs 2004, 64:2515-36). These agents have variable success and may be associated with serious adverse effects. More recently, omalizumab was approved for the treatment of refractory CSU / CIU. CSU can be a debilitating condition due to the lack of clinical response as well as the unpredictable course of the disease, which can have a profound negative influence on the patient's quality of life.

[0011] Disseminated Lupus Erythematosus (SLE): SLE is an autoimmune rheumatic disease that occurs primarily in women of childbearing age. It is characterized by multiorgan involvement and immunologic abnormalities, and much of the tissue damage is thought to occur through autoantibody formation and immune complex deposition. The disease is heterogeneous in its clinical presentation, course and prognosis. However, most patients present with joint involvement, rashes QRQonn / i cutaneous ζηζ / Ε / γ, mouth ulcers, Raynaud's phenomenon and / or severe fatigue. Inflammation of pleural and pericardial tissues may also occur. The most serious manifestations include renal and central nervous system involvement, which are associated with poor outcomes including temporary or permanent disability or death. In general, the disease follows a relapsing-remitting course with intermittent periods of disease activity (flare-up) interspersed with periods of relative inactivity.

[0012] Medications for the successful treatment of SLE as measured by long-term remission are limited, and only one medication has been tested for treatment of SLE in 50 years (Burness CB, McCormack P.L., Drugs 2011, 71 :2435-44). Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) provide partial symptomatic relief. Antimalarial drugs are generally well tolerated in patients with SLE and appear to have a beneficial effect in preventing lupus flares, increasing long-term survival and possibly mitigating certain types of organ damage (Ruiz-lrastorza G, Olivares N , Ruiz-Arruza I, et al., Arthritis Res. Ther. 2009, 11 :R109). However, these agents are often considered to have insufficient efficacy for moderate to severe manifestations of SLE.

[0013] As a measure of unmet need, the risk of mortality remains elevated for patients with lupus. In the modern era, based on a multi-site international cohort of 9500 lupus patients, the standardized mortality ratio was 2.4, with particularly high mortality observed with kidney disease (Fors Nieves CE, Izmirly PM., Curr. Rheumatol. Rep. 2016,18:21). The development of new treatments for patients with SLE with increased efficacy and decreased toxicity remains a necessary and important area of ​​research.

[0014] All references cited herein, including patent applications and patent publications, are incorporated herein by reference in their entirety, as if each individual reference is specifically and individually stated to be incorporated by reference. BRIEF DESCRIPTION OF THE INVENTION

[0015] Provided herein are methods and uses of a BTK inhibitor, fenebrutinib, or a pharmaceutically acceptable salt thereof, for treating rheumatoid arthritis, chronic spontaneous urticaria, and disseminated lupus erythematosus. In particular, the methods and uses provided herein include the administration of fenebrutinib to patients who have (i) moderately to severely active RA with inadequate response to previous treatment, (i) symptomatic CSU despite previous H1 antihistamine treatment ; or (iii) moderately to severely active SLE with inadequate response to previous treatment.

[0016] Fenebrutinib is a compound of formula: QRQQnn / l 7Π7 / Β / Υ and is also known by the following names: GDC-0853; (62S)-23-(hydroxymethyl)-17,17,31,62-tetramethyl-13,14,17,18-tetrahydro-4-aza-1 (2)-cyclopenta[4,5]pyrrolo[1 ,2-a]pyrazina6(1,4)-p¡peraz¡na-2(2,4),3(3,5),5(2,5)-tr¡pyrádina-7(3 )-oxetanaheptaphan-11(16H),36(31 / - / )-dione; and (S)-2-(3'-(hydroxy¡methyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-¡l)p¡ peraz¡n-1-¡l)p¡r¡d¡n-2-¡l)am¡no)-6-oxo-1,6-d¡hydro-[3,4'b¡p¡r¡ d¡n]-2'-¡l)-7,7-dimethyl-2,3,4,6,7,8-hexahídro-1 H-cyclopenta[4,5]pyrrolo[1,2 -a]pyrazin-1-one. The R enantiomer of the compound is: (R)-2-(3'-(hydroxy¡methyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3 -¡l)piperaz¡n-1-¡l)p¡r¡d¡n-2-¡l)am¡no)-6-oxo-1,6d¡hydro-[3,4'-b ¡p¡r¡d¡n]-2'-¡l)-7,7-dimet¡l-2,3,4,6,7,8-hexah¡dro-1 H-cyclopenta[4, 5]pyrrolo[1,2-a]pyrazin-1-one.

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

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

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

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

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

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

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

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

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

[0026] E7: The method according to E1, wherein the dose of fenebrutinib is about 200 mg to about 300 mg daily. QRQonn / i ζηζ / Ε / γ

[0027] Ε9: The method according to E1, wherein the dose of fenebrutinib is about 200 mg to about 400 mg daily.

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

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

[0030] E12: The method according to E11, wherein if administered twice a day, each dose contains the same amount of fenebrutinib.

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

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

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

[0034] E16: The method according to E14, wherein the additional therapeutic agent is a kinase inhibitor Janus.

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

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

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

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

[0039] E21: The method according to any of E1-E20, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified by RA disease activity by inflammation markers. laboratory and joint counts. > 6 tender / painful joints on movement (68 joint counts) and > 6 swollen joints (66 joint counts).

[0040] E22: The method according to any of E1-E20, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified by hsCRP greater than or equal to 0.400 mg / dL.

[0041] E23: The method according to any of E1-E20, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified with a test QRQQnn / l 7Π7 / Β / Υ positive for anti-cyclic citrullinated protein / peptide antibody (anti-CCP or ACPA), rheumatoid factor or both.

[0042] E24: The method according to any of E1-E20, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified as follows: • Has a diagnosis of RA with adult onset as defined according to the European League Against Rheumatism / 2010 ACR classification criteria. • RA disease activity using laboratory inflammation markers and joint counts: > 6 tender / painful joints on movement (68 joint counts) and > 6 swollen joints (66 joint counts). • hsCRP greater than or equal to 0.400 mg / dL; • Positive for anti-cyclic citrullinated peptide / protein antibody (anti-CCP or ACPA), rheumatoid factor or both; and • Has received one or more conventional non-biological DMARDs for at least 12 weeks at a stable dose prior to treatment with fenebrutinib.

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

[0044] E26: A method of treating a human patient who has moderately to severely active rheumatoid arthritis, wherein the patient has demonstrated an inadequate response or intolerance to previous treatment with one or more biological drugs for rheumatoid arthritis, wherein the The method comprises administering fenebrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 150 to about 400 mg daily.

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

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

[0047] E28: The method according to E26, wherein the dose of fenebrutinib is about 300 mg administered once a day.

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

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

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

[0051] E31: The method according to E26, wherein the dose of fenebrutinib is about 150 mg QRQQnn / l 7Π7 / Ε / Υ administered twice daily.

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

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

[0054] E33: The method according to any of E26-E32, wherein the biological drug for rheumatoid arthritis is selected from the group consisting of a TNF-alpha inhibitor, abatacept, tocilizumab, sarilumab, sirukumab, anakinra and any equivalent biosimilar of these.

[0055] E34: The method according to E33, wherein the biological drug for rheumatoid arthritis is a TNF-alpha inhibitor.

[0056] E35: The method according to E34, wherein the TNF-alpha inhibitor is selected from the group consisting of enadalimumab, infliximab, etanercept, golimumab, certolizumab, or a biosimilar equivalent thereof.

[0057] E36: ​​The method according to E35, wherein the TNF-alpha inhibitor is adalimumab.

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

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

[0060] E39: The method according to E37, wherein the additional therapeutic agent is a kinase inhibitor Janus.

[0061] E40: The method according to E39, wherein the Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, peficitinib 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 according to any of E39-E41, wherein both therapeutic agents are administered orally in a single tablet or capsule.

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

[0065] E44: The method according to any of E26-E43, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified by insufficient efficacy or loss of efficacy at a dose and duration that, according to local clinical practice, is considered acceptable to adequately evaluate the clinical response to previous treatment with at least one and no more than two biologic drugs for rheumatoid arthritis.

[0066] E45: The method according to any of E26-E43, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified from the QRQonn / i ζηζ / Ε / γ as follows: • Positive for anti-cyclic citrullinated peptide / protein antibody (anti-CCP or ACPA), rheumatoid factor or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0067] E46: The method according to any of E26-E43, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: • hsCRP greater than or equal to 0.650 mg / dL; • Positive for anti-cyclic citrullinated peptide / protein antibody (anti-CCP or ACPA), rheumatoid factor or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0068] E47: The method according to any of E26-E43, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: • RA disease activity by laboratory markers of inflammation and joint counts: > 6 tender / moving joints (68 joint counts) and > 6 swollen joints (66 joint counts). • hsCRP greater than or equal to 0.650 mg / dL; • Positive for anti-cyclic citrullinated peptide / protein antibody (anti-CCP or ACPA), rheumatoid factor or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0069] E48: The method according to any of E26-E43, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: • Has a diagnosis of RA with adult onset as defined according to the European League Against Rheumatism / 2010 ACR classification criteria. • RA disease activity using laboratory inflammation markers and joint counts: > 6 tender / painful joints on movement (68 joint counts) and > 6 QRQQnn / l 7Π7 / Β / Υ swollen joints (66 joint counts). • hsCRP greater than or equal to 0.650 mg / dL; • Positive for anti-cyclic citrullinated protein / peptide antibody (anti-CCP or ACPA), rheumatoid factor, or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis. [ 0070] E49: The method according to any of E1-E48, wherein the patient has a reduction in one or more symptoms of rheumatoid arthritis after treatment with fenebrutinib, or a pharmaceutically acceptable salt thereof.

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

[0072] E51: The method according to 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 according to E49, wherein the reduction in patient symptoms is measured by a 20% reduction in the patient's American College of Rheumatology (ACR20) score.

[0074] E53: The method according to 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 reduction in the patient's symptoms is a reduction in the patient's DAS28-3-CRP score.

[0077] E56: The method according to E49, wherein the reduction in patient symptoms is a reduction in CRP compared to the patient's baseline value.

[0078] E57: The method according to E49, wherein the reduction in patient symptoms is a reduction in ESR compared to the patient's baseline value.

[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 according to E49, wherein the reduction in the patient's symptoms is a reduction in the patient's FACIT-Fatigue score.

[0081] E60: The method according to E49, wherein the reduction in patient symptoms is a reduction in two or more of the measurements described in E50-E59.

[0082] E61: The method according to any of E50-E52, wherein the reduction in the patient's symptoms is also measured by a reduction in one or more of the measurements described in E54-E59. QRQonn / i ζηζ / Ε / γ

[0083] Ε62: The method according to any of E49-E61, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within or at 2 weeks of treatment.

[0084] E63: The method according to any of E49-E61, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within or at 4 weeks of treatment.

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

[0086] E65: The method according to any of E49-E61, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within or at 12 weeks of treatment. QRQQnn / l 7Π7 / Β / Υ

[0087] E66: The method according to any of E1-E65, wherein the method further comprises the step of measuring one or more clinical or laboratory endpoints for the patient to evaluate the efficacy of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0088] E67: The method according to E66, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of the following patient criteria: ACR50 score, ACR 70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-fatigue score, CRP compared with baseline, and ESR compared with baseline.

[0089] E67a: The method according to E56 or E67, wherein the initial CRP value is the level of CRP in a sample from the patient before initiating administration of fenebrutinib, or a pharmaceutically acceptable salt of this.

[0090] E67b: The method according to E57, E67 or E67a, wherein the initial ESR value is the level of ESR in a sample from the patient before initiating administration of fenebrutinib, or an acceptable salt from the point of view pharmacist of this.

[0091] E68: The method according to E66 or E67, measures after 2 weeks of treatment.

[0092] E69: The method according to E66 or E67, measures after 4 weeks of treatment.

[0093] E70: The method according to E66 or E67, measures after 8 weeks of treatment.

[0094] E71: The method according to E66 or E67, measures after 12 weeks of treatment. where the clinical or laboratory endpoint is where the clinical or laboratory endpoint is where the clinical or laboratory endpoint is

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

[0096] E73: The method according to any of E1-E71, wherein the method comprises a first step of identifying in a blood sample of the patient: (i) the presence of autoantibodies and (i) elevated ESR levels relative to baseline, before administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient who tests positive for said autoantibodies and elevated ESR.

[0097] E74: The method according to any of E1-E71, wherein the method comprises a first step of identifying in a blood sample of the patient: (i) the presence of autoantibodies and (i) elevated levels of CRP relative to the baseline value, in a blood sample from the patient before administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient who tests positive for said autoantibodies and elevated CRP.

[0098] E75: The method according to any of E1-E71, wherein the method comprises a first step of identifying in a blood sample of the patient: (i) the presence of autoantibodies, (i) elevated levels of CRP relative to baseline and (II) elevated ESR levels relative to baseline, before administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient who tests positive for said autoantibodies and elevated CRP.

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

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

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

[0102] E77: The method according to any of E72-E76, wherein the autoantibodies include IgM antibodies.

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

[0104] E79: A method of administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to treat a human patient with moderately to severely active rheumatoid arthritis, wherein the patient exhibits an abnormality in one or more biomarkers of liver function after administration of fenebrutinib, wherein the method comprises (a) administering to said patient fenebrutinib, or a pharmaceutically acceptable salt thereof, at a dose of less than about 150 to about 400 mg per day for a period of time, followed by (b) administering to said patient fenebrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 150 to about 400 mg per day.

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

[0106] E81: The method according to E79, wherein the dose in step (a) is equal to or less than about 150 mg per day.

[0107] E82: The method according to any of E79-E81, wherein the dose in step (b) is the same dose QRQQnn / l 7Π7 / Β / Υ in step (a).

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

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

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

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

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

[0113] E88: The method according to any of E79-E87, wherein prior to step (a), administration of fenebrutinib, or a pharmaceutically acceptable salt thereof, is withheld until biomarkers of liver function are within normal limits.

[0114] E89: The method according to any of E79-E87, wherein the time period of step (a) is continued until liver function biomarkers are within normal limits.

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

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

[0117] E92: The method of identifying a human patient who has moderately to severely active rheumatoid arthritis, where the patient is most likely to exhibit benefit from treatment comprising fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the method comprises determining the levels of one or more biomarkers selected from the group consisting of rheumatoid factor IgM, total IgM, total IgG, CXCL13, and CCL4 in a patient sample, wherein elevated levels of one or more More biomarkers in the sample indicate that the patient is more likely to exhibit benefit from treatment with fenebrutinib.

[0118] E93: The method according to E92, wherein the patient has demonstrated an inadequate response to prior treatment with one or more conventional nonbiologic DMARDs.

[0119] E94: The method according to E92, wherein the patient has demonstrated an inadequate response or intolerance to prior treatment with one or more biologic drugs for rheumatoid arthritis.

[0120] E95: The method according to any of E91-E94, wherein the sample has been found to have QRQQnn / l 7Α7 / Ε / ΥΙΛΙ elevated levels of two of the biomarkers.

[0121] E96: The method according to any of E91-E94, wherein the sample is found to have elevated levels of three of the biomarkers.

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

[0123] E98: The method according to any of E91-E94, wherein the sample has been found to have elevated levels of each of the IgM biomarkers of rheumatoid factor, total IgM, total IgG, CXCL13 and CCL4.

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

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

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

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

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

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

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

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

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

[0134] E106: The compound for use in the method according to E103, wherein the dose of fenebrutinib is about 100 mg administered twice a day. QRQQnn / l 7Π7 / Β / Υ

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

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

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

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

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

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

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

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

[0143] E114: The compound for use in the method according to any of E103-E113, wherein the conventional non-biological DMARD in the above treatment is methotrexate.

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

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

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

[0147] E118: The compound for use in the method according to E117, wherein the Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, peficitinib and upadacitinib, and acceptable salts from the point of pharmaceutical view of these.

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

[0149] E120: The compound for use in the method according to any of Ε115-E120, wherein both therapeutic agents are administered orally in a single tablet or capsule.

[0150] E121: The compound for use in the method according to any of Ε115-E121, wherein methotrexate is also administered. QRQQnn / l 7Π7 / Β / Υ

[0151] Ε122: The compound for use in the method according to any of E103-E121, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified by disease activity of RA by laboratory inflammation markers and joint counts where inadequate response by joint counts refers to > 6 tender / painful joints on movement (68 joint counts) and > 6 swollen joints (66 joint counts).

[0152] E123: The compound for use in the method according to any of E103-E121, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified by hsCRP greater than or equal at 0.400 mg / dL.

[0153] E124: The compound for use in the method according to any of E103-E121, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified with a positive antibody test anti-cyclic citrullinated protein / peptide (anti-CCP or ACPA), rheumatoid factor, or both.

[0154] E125: The compound for use in the method according to any of E103-E121, wherein the patient who has an inadequate response to previous treatment with one or more conventional non-biological DMARDs is identified as follows: • Has a diagnosis of RA with adult onset as defined according to the European League Against Rheumatism / 2010 ACR classification criteria. • RA disease activity using laboratory inflammation markers and joint counts: > 6 tender / painful joints on movement (68 joint counts) and > 6 swollen joints (66 joint counts). • hsCRP greater than or equal to 0.400 mg / dL; • Positive for anti-cyclic citrullinated protein / peptide antibody (anti-CCP or ACPA), rheumatoid factor, or both; and • Has received one or more conventional non-biological DMARDs for at least 12 weeks at a stable dose prior to treatment with fenebrutinib.

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

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

[0157] E128: The compound for use in the method according to E127, wherein the dose of fenebrutinib is QRQQnn / l 7Π7 / Β / Υ of about 200 mg administered twice daily.

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

[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: The compound for use in the method according to E127, wherein the dose of fenebrutinib is about 100 mg administered twice a day.

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

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

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

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

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

[0166] E134: The compound for use in the method according to any of E127-E133, wherein the biological drug for rheumatoid arthritis is selected from the group consisting of a TNF-alpha inhibitor, abatacept, tocilizumab, sarilumab, sirukumab, anakinra and any biosimilar equivalent of these.

[0167] E135: The compound for use in the method according to E134, wherein the biological drug for rheumatoid arthritis is a TNF-alpha inhibitor.

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

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

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

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

[0172] E140: The compound for use in the method according to E138, wherein the additional therapeutic agent is a Janus kinase inhibitor. QRQQnn / l 7Π7 / Β / Υ

[0173] Ε141: The compound for use in the method according to E140, wherein the Janus kinase inhibitor is selected from the group consisting of tofacitinib, baricitinib, filgotinib, peficitinib and upadacitinib, and salts acceptable from the point of pharmaceutical view of these.

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

[0175] E143: The compound for use in the method according to any of Ε140-E142, wherein both therapeutic agents are administered orally in a single tablet or capsule.

[0176] E144: The compound for use in the method according to any of Ε140-E143, wherein methotrexate is also administered.

[0177] E145: The compound for use in the method according to any of E127-E144, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified by insufficient efficacy or loss of efficacy at a dose and duration that, according to local clinical practice, is considered acceptable to adequately evaluate the clinical response to previous treatment with at least one and no more than two biologic drugs for rheumatoid arthritis.

[0178] E146: The compound for use in the method according to any of E127-E144, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: • Positive for anti-cyclic citrullinated peptide / protein antibody (anti-CCP or ACPA), rheumatoid factor or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0179] E147: The compound for use in the method according to any of E127-E144, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: • hsCRP greater than or equal to 0.650 mg / dL; • Positive for anti-cyclic citrullinated peptide / protein antibody (anti-CCP or ACPA), rheumatoid factor or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0180] E148: The compound for use in the method according to any of E127-E144, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: QRQQnn / l 7Π7 / Β / Υ • RA disease activity using laboratory inflammation markers and joint counts: > 6 tender / painful joints on movement (68 joint counts) and > 6 swollen joints (66 joint counts) joints). • hsCRP greater than or equal to 0.650 mg / dL; • Positive for anti-cyclic citrullinated protein / peptide antibody (anti-CCP or ACPA), rheumatoid factor, or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0181] E149: The compound for use in the method according to any of E127-E144, wherein the patient who has an inadequate response to previous treatment with one or more biological drugs for rheumatoid arthritis is identified as follows: • Has a diagnosis of RA with adult onset as defined according to the European League Against Rheumatism / 2010 ACR classification criteria. • RA disease activity using laboratory inflammation markers and joint counts: > 6 tender / painful joints on movement (68 joint counts) and > 6 swollen joints (66 joint counts). • hsCRP greater than or equal to 0.650 mg / dL; • Positive for anti-cyclic citrullinated protein / peptide antibody (anti-CCP or ACPA), rheumatoid factor, or both; and • Experienced intolerance to, or insufficient efficacy or loss of efficacy at, a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response to prior treatment with at least one and no more of two biological drugs for rheumatoid arthritis.

[0182] E150: The compound for use in the method according to any of E127-E149, wherein the patient has a reduction in one or more symptoms of rheumatoid arthritis after treatment with fenebrutinib, or a salt acceptable from the point from a pharmaceutical point of view of this.

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

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

[0185] E153: The compound for use in the method according to E150, wherein the reduction in patient symptoms is measured by a 20% reduction in the patient's score according to the American College of QRQQnn / l 7Π7 / Β / Υ Rheumatology (ACR20).

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

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

[0188] E156: The compound for use in the method according to E150, wherein the reduction in symptoms of the patient is a reduction in the DAS28-3-CRP score of the patient.

[0189] E157: The compound for use in the method according to E150, wherein the reduction in patient symptoms is a reduction in CRP compared to the patient's baseline value.

[0190] E158: The compound for use in the method according to E150, wherein the reduction in patient symptoms is a reduction in ESR compared to the patient's baseline value.

[0191] E159: The compound for use in the method according to E150, wherein the reduction in the patient's symptoms is a reduction in the patient's SF-36 score.

[0192] E160: The 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: The compound for use in the method according to E150, wherein the reduction in patient symptoms is a reduction in two or more of the measurements described in E151 -E160.

[0194] E162: The compound for use in the method according to any of E151-E153, wherein the reduction in patient symptoms is also measured by a reduction in one or more of the measurements described in E155-E160.

[0195] E163: The compound for use in the method according to any of E150-E162, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within or at 2 weeks of treatment.

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

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

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

[0199] E167: The compound for use in the method according to any of E103-E166, wherein the method further comprises the step of measuring one or more clinical or laboratory endpoints for the patient in order to evaluate the effectiveness of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

[0200] E168: The compound for use in the method according to E167, wherein the one or more clinical or laboratory endpoints are selected from the group consisting of the following patient criteria: QRQonn / i ζηζ / Ε / γ ACR50 score, ACR 70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-fatigue score, CRP compared to baseline and ESR compared with initial value. QRQQnn / l 7Π7 / Β / Υ

[0201] E168a: The compound for use in the method according to E157 or E168, wherein the initial CRP value is the level of CRP in a sample from the patient before initiating administration of fenebrutinib or an acceptable salt from the pharmaceutical point of view of this.

[0202] E168b: The compound for use in the method according to E158, E168 or E168a, wherein the initial ESR value is the level of ESR in a patient sample before initiating administration of fenebrutinib or an acceptable salt from the pharmaceutical point of view of this.

[0203] E169: The compound for use in the method according to E167 clinical or laboratory assessment is measured after 2 weeks of treatment.

[0204] E170: The compound for use in the method according to E167 clinical or laboratory assessment is measured after 4 weeks of treatment.

[0205] E171: The compound for use in the method according to E167 clinical or laboratory assessment is measured after 8 weeks of treatment.

[0206] E172: The compound for use in the method according to E167 clinical or laboratory assessment is measured after 12 weeks of treatment. E168, E168, E168, E168, in in in where the where the where the where the criterion of criterion of criterion of criterion of

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

[0208] E174: The compound for use in the method according to any of E103-E172, wherein the method comprises a first step of identifying in a patient's blood sample: (i) the presence of autoantibodies and ( i) elevated ESR levels compared to baseline, before administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient who tests positive for said autoantibodies and elevated ESR.

[0209] E175: The compound for use in the method according to any of E103-E172, wherein the method comprises a first step of identifying in a patient's blood sample: (i) the presence of autoantibodies and ( i) elevated levels of CRP compared to baseline, in a blood sample from the patient before administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient who tests positive for said autoantibodies and elevated CRP.

[0210] E176: The compound for use in the method according to any of E103-E172, wherein the method comprises a first step of identifying in a patient's blood sample: (i) the presence of autoantibodies, ( i) elevated CRP levels relative to baseline and (II) elevated ESR levels relative to baseline, before administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient who tests positive for said autoantibodies and elevated CRP.

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

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

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

[0214] E178: The compound for use in the method according to any of E173-E176, wherein the autoantibodies include IgM antibodies.

[0215] E179: The compound for use in the method according to any of E103-E172, wherein the method first comprises the step of confirming that the patient is seropositive before treatment with fenebrutinib, or a salt acceptable from the point from a pharmaceutical point of view of this.

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

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

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

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

[0220] E184: A method of treating a human patient having chronic spontaneous urticaria, wherein the patient presents symptoms of the disease despite previous H1 antihistamine treatment, wherein the method comprises the administration of fenebrutinib, or a salt acceptable from the pharmaceutical point of view of this, at a dose of about 50 mg to about 400 mg daily.

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

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

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

[0224] E187: The method according to E184, wherein the dose of fenebrutinib is about 150 mg administered once a day. QRQonn / i ζηζ / Ε / γ

[0225] Ε188: The method according to E184, wherein the dose of fenebrutinib is about 100 mg administered once a day.

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

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

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

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

[0230] E191 a: The method according to E184, wherein the daily dose of fenebrutinib is about 100 mg, administered as about 50 mg twice a day.

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

[0232] E193: The method according to E192, wherein the mean reduction is at least a 3-point mean reduction in change from the initial value.

[0233] E194: The method according to E192, wherein the average reduction is at least a 5-point average reduction in change from the initial value.

[0234] E195: The method according to any of Ε184-E194, wherein the patient has a reduction in urticaria activity score (UAS7) from a baseline value after treatment.

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

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

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

[0238] E199: The method according to any of Ε184-E198, wherein the patient has a reduction in weekly wheal count from a baseline value after treatment.

[0239] E200: The method according to E199, wherein the weekly wheal count reduction is a reduction of at least 6 points from the baseline value.

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

[0241] E202: The method according to any of Ε192-E200, wherein the reduction from the baseline value occurs within or at 8 weeks of treatment. QRQQnn / l 7Π7 / Ε / Υ

[0242] Ε203: The method according to any of Ε192-E200, wherein the reduction from the baseline value occurs within or at 12 weeks of treatment.

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

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

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

[0247] E207: The method according to any of E184-E206, wherein the method first comprises the step of identifying the presence of autoantibodies in a blood sample of the patient before administering fenebrutinib, or a salt acceptable from the point from this pharmaceutical point of view, to the patient who has said autoantibodies.

[0248] E208: The method according to E207, wherein the autoantibodies are capable of activating mast cells and / or basophils.

[0249] E209: The method according to E207, wherein the autoantibodies identified in the sample are selected from the group consisting of TPO-binding IgE antibodies, IL24-binding IgE antibodies, IgE-binding IgG antibodies and IgG antibodies that bind to FcERI.

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

[0251] E210-Í: The method according to any of E207-E210, wherein the identified autoantibodies comprise IgG antibodies that bind to FcERI.

[0252] E210-Í: The method according to E210-Í, wherein the level of FcERI-binding IgG antibodies in the sample is elevated relative to the level in a healthy subject without chronic spontaneous urticaria.

[0253] E211: A method for treating a human patient with chronic spontaneous urticaria, wherein the patient presents symptoms of the disease despite previous H1 antihistamine treatment, wherein the method comprises: (i) determining that the patient sample comprises elevated levels of one or more biomarkers selected from the group consisting of TPO-binding IgE antibodies, IL24-binding IgE antibodies, IgE-binding IgG antibodies, and IgE-binding IgG antibodies. bind FcERI; and (ii) administering to the patient from about 50 mg to about 400 mg daily of fenebrutinib, or a salt QRQQnn / l 7A7 / R / Y pharmaceutically acceptable for this.

[0254] E212: The method of identifying a human patient who has chronic spontaneous urticaria, wherein the patient exhibits symptoms of the disease despite prior H1 antihistamine treatment, wherein the patient is more likely to exhibit benefits from the treatment comprising fenebrutinib, or a pharmaceutically acceptable salt thereof, by determining the levels of one or more biomarkers selected from the group consisting of TPO-binding IgE antibodies, IL24-binding IgE antibodies, IgG that bind IgE and IgG antibodies that bind FcERI; in a sample from the patient, where elevated levels of the one or more biomarkers in the sample indicate that the patient is more likely to exhibit benefit from treatment with fenebrutinib.

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

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

[0257] E213: A method of administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to treat a human patient with chronic spontaneous urticaria, wherein the patient exhibits symptoms of the disease despite antihistamine treatment H1 above, and wherein the patient exhibits an abnormality in one or more biomarkers of liver function after administration of fenebrutinib, wherein the method comprises (a) administering to said patient fenebrutinib, or a salt acceptable from the point of view pharmacist thereof, at a lower dose of about 150 to about 400 mg per day for a period of time, followed by (b) administering to said 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 dose in step (a) is equal to or less than about 200 mg per day.

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

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

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

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

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

[0264] E220: The method according to any of E213-E219, wherein the one or more biomarkers of the QRQonn / i ζηζ / Ε / γ liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin and alkaline phosphatase.

[0265] E221: The method according to any of E213-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 of E213-E221, wherein before step (a), the administration of fenebrutinib, or a pharmaceutically acceptable salt thereof, is interrupted until the biomarkers of liver function are within normal limits.

[0267] E223: The method according to any of E213-E222, wherein the time period of step (a) continues until the liver function biomarkers are within normal limits.

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

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

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

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

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

[0273] E229: A compound for use in a method of treating a human patient having chronic spontaneous urticaria, wherein the patient presents symptoms of the disease despite previous H1 antihistamine treatment, wherein the compound is fenebrutinib or a pharmaceutically acceptable salt thereof, and wherein the treatment is performed at a dose of fenebrutinib of about 50 mg to about 400 mg daily.

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

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

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

[0277] E232: The 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 QRQQnn / l 7Π7 / Β / Υ of about 100 mg administered once a day.

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

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

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

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

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

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

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

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

[0287] E240: The compound for use in the method according to any of E229-E239, wherein the patient has a reduction in urticaria activity score (UAS7) from a baseline value after treatment.

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

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

[0290] E243: The compound for use in the method according to E240, wherein the patient has a UAS7 reduction of at least 11 points after treatment.

[0291] E244: The compound for use in the method according to any of E229-E243, wherein the patient has a reduction in weekly wheal count from baseline after treatment.

[0292] E245: The compound for use in the method according to E244, wherein the reduction in weekly wheal count is a reduction of at least 6 points from baseline.

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

[0294] E247: The compound for use in the method according to any of E237-E245, wherein the QRQQnn / l 7Π7 / Β / Υ reduction from baseline occurs within or at 8 weeks of treatment.

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

[0296] E248a: The compound for use in the method according to any of E237-E248, wherein the baseline is the value determined in the patient prior to initiation of fenebrutinib administration, or an acceptable salt from the point of origin. pharmaceutical view of this.

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

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

[0300] E252: The compound for use in the method according to any of E229-E251, wherein the method first comprises the step of identifying the presence of autoantibodies in a blood sample of the patient before administering fenebrutinib, or a salt acceptable from the pharmaceutical point of view of this, to the patient who has said autoantibodies.

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

[0302] E254: The compound for use in the method according to E252, wherein the autoantibodies identified in the sample are selected from the group consisting of IgE antibodies that bind to TPO, IgE antibodies that bind to IL24, antibodies IgG that bind to IgE and IgG antibodies that bind to FcERI.

[0303] E254-I: The compound for use in the method according to E252-E254, wherein the autoantibodies identified in the sample comprise IgG antibodies that bind to FcERI.

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

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

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

[0307] E258: The compound for use in the method according to any of E229-E257, wherein fenebrutinib, or a pharmaceutically acceptable salt thereof, is administered orally in the form of one or more tablets. QRQQnn / l 7Π7 / Β / Υ

[0308] Ε259: The compound for use in the method according to any of E229-E258, wherein the compound is the free base of fenebrutinib.

[0309] E260: A method of treating a human patient having moderately to severely active disseminated lupus erythematosus, wherein the patient presents with symptoms of the disease despite previous standard oral SLE treatment, wherein the method comprises administration of fenebrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 150 mg to about 400 mg daily.

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

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

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

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

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

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

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

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

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

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

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

[0321] E270: The method according to any of E260-E269, wherein the treatment for standard oral SLE is selected from the group consisting of an oral corticosteroid, an antimalarial and an immunosuppressant.

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

[0323] E272: The method according to any of E260-E271, wherein the administration is in combination QRQQnn / l 7Π7 / Β / Υ with an oral corticosteroid.

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

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

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

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

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

[0329] E278: The method according to any of E260-E277, further comprising the step of measuring one or more clinical endpoints for the patient to assess the efficacy of treatment with fenebrutinib or an acceptable salt from the pharmaceutical point of view of this.

[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 of E278-E280, wherein the clinical endpoint is measured after 24 weeks of treatment.

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

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

[0335] E284: The method according to any of E260-E282, wherein the method first comprises the step of identifying the presence of one or more biomarkers in a blood sample of the patient before treatment with fenebrutinib, or a salt acceptable from the pharmaceutical point of view of this, where the biomarkers comprise IgJ, MZB1 and TXNDC5.

[0336] E284a: The method according to any of E260-E282, wherein the method first comprises the step of identifying the presence of one or more biomarkers selected from the group consisting of IgJ, MZB1 and TXNDC5 in a blood sample of the patient before treatment with fenebrutinib, or an acceptable salt QRQonn / i ζηζ / Ε / γ from its pharmaceutical point of view.

[0337] E285: A method of treating a human patient with moderately to severely active disseminated lupus erythematosus, wherein the patient presents with symptoms of the disease despite previous standard oral SLE treatment, comprising administering about 150 mg to about 400 mg daily of fenebrutinib, or a pharmaceutically acceptable salt thereof, to a patient where the patient's sample has been found to have elevated levels of one or more biomarkers selected from the group consisting of CCL3 , CCL4, CCL20, CXCL13and autoantibodies.

[0338] E286: A method for treating a human patient with moderately to severely active disseminated lupus erythematosus, wherein the patient presents with symptoms of the disease despite previous standard oral SLE treatment, wherein the method comprises: (i) determining that the patient sample comprises elevated levels of one or more biomarkers selected from the group consisting of CCL3, CCL4, CCL20, CXCL13, and autoantibodies; and (i) administering to the patient about 150 to about 400 mg daily of fenebrutinib, or a pharmaceutically acceptable salt thereof.

[0339] E287: The method of identifying a patient with SLE who is most likely to exhibit benefit from treatment comprising fenebrutinib, or a pharmaceutically acceptable salt thereof, by determining levels of one or more biomarkers selected from the group consisting of CCL3, CCL4, CCL20, CXCL13 and autoantibodies in a sample of the patient, wherein elevated levels of the one or more biomarkers in the sample indicate that the patient is more likely to exhibit benefit from treatment with fenebrutinib .

[0340] E288: A compound for use in a method of treating a human patient who has moderately to severely active disseminated lupus erythematosus, wherein the patient presents symptoms of the disease despite previous standard oral SLE treatment, in 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: The compound for use in the method according to E288, wherein the dose of fenebrutinib is about 200 mg administered twice a day.

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

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

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

[0345] E291a: The compound for use in the method according to E288, wherein the daily dose of QRQonn / i ζηζ / Ε / γ fenebrutinib is about 200 mg, given as about 100 mg twice a day.

[0346] E292: The 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 daily.

[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 daily.

[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 daily.

[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 daily.

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

[0352] E298: The compound for use in the method according to any of E288-E297, wherein the standard oral SLE treatment is selected from the group consisting of an oral corticosteroid, an antimalarial and an immunosuppressant.

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

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

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

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

[0357] E303: The compound for use in the method according to E302 or E303, wherein the reduction in the patient's clinical symptoms is measured by the composite lupus assessment score based on the Lupus Assessment Group of the British Isles (BICLA) of the patient.

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

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

[0360] E306: The compound for use in the method according to any of E288-E305, further comprising the step of measuring one or more clinical endpoints for the patient in order to evaluate the QRQQnn / l 7Π7 / Β / Υ efficacy of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

[0366] E312: The compound for use in the method according to any of E288-E310, wherein the method first comprises the step of identifying the presence of one or more biomarkers in a blood sample of the patient before treatment with fenebrutinib, or a pharmaceutically acceptable salt thereof, wherein the biomarkers comprise IgJ, MZB1 and TXNDC5.

[0367] E313: Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in the treatment of a human patient with moderately to severely active rheumatoid arthritis, wherein the patient has exhibited an abnormality in one or further biomarkers of liver function after administration of fenebrutinib, wherein the method comprises (a) administering to said patient fenebrutinib, or a pharmaceutically acceptable salt thereof, at a lower dose of about 150 mg to about 400 mg per day for a period of time, followed by (b) administering to said patient fenebrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 150 mg to about 400 mg per day. day.

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

[0369] E315: Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in the QRQQnn / l 7Π7 / Β / Υ treatment of a human patient with moderately to severely active disseminated lupus erythematosus, where the patient has exhibited an abnormality in one or more biomarkers of liver function after administration of fenebrutinib, where the The method comprises (a) administering to said patient fenebrutinib, or a pharmaceutically acceptable salt thereof, at a lower dose of about 150 mg to about 400 mg per day for a period of time, followed by (b ) administering to said 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 as described in any of E313-E315, wherein the dose in step (a) is equal to or less than about 200 mg per day.

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

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

[0373] E319: Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use as described in any of E313-E317, wherein the dose in step (b) is a dose less than the dose in stage (a).

[0374] E320: Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use as described in any of E313-E319, wherein the abnormality in one or more biomarkers of liver function is an abnormality of Grade 2.

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

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

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

[0378] Also provided herein is a compound for use in the manufacture of a medicament for any of the treatment methods described in the above embodiments, wherein the compound is fenebrutinib or a technically acceptable salt. pharmacist of this.

[0379] In addition to the specific embodiments described above, any QRQQnn / l 7Π7 / Β / Υ of the embodiments of this invention.

[0380] It should be understood that one, some or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will be apparent to a mid-level skilled person. These and other embodiments of the invention are described in more detail in the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0381] The patent or application file contains at least one color drawing. The Office will provide copies of this patent or patent application publication with color drawings upon request and payment of the necessary fee.

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

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

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

[0385] Figure 4 shows the ACR HAQ-DI score parameters for Cohort 1 of the fenebrutinib RA study of Example 1.

[0386] Figure 5 shows the patient global assessment (patient GA) scores over time for cohort 1 of the fenebrutinib RA study of Example 1.

[0387] Figure 6 shows the physician global assessment (physician GA) scores over time for Cohort 1 of the fenebrutinib RA study of Example 1.

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

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

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

[0391] Figure 10 shows total HAQ-DI for clinical study cohort 1 of the fenebrutinib RA study of Example 1.

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

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

[0394] Figure 13 shows patient GA over time in cohort 2 of the RA study with QRQQnn / l 7Π7 / Β / Υ fenebrutinib from Example 1.

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

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

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

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

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

[0400] Figure 19 shows the reductions in ESR over time in cohort 1 of the fenebrutinib RA study of Example 1.

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

[0402] Figures 21A-21C show the response of ACR50 (Figure 21 A), the mean change in baseline value of DAS28-4-CRP (Figure 21B) and the mean change in baseline value of HAQ-DI (Figure 210) per visit for cohorts 1 and 2 of the fenebrutinib RA study of Example 1. The legend for all graphs is shown in Figure 21C.

[0403] Figures 22A-22B show the absolute change from baseline in total IgM and IgG (Figure 22A) and the percentage change from baseline in rheumatoid factor (RF) and ACPA levels (Figure 22B) in week 12 for cohort 1 in the fenebrutinib RA study of Example 1. Significance compared to placebo is indicated by *. X-axis on each graph from left to right: PBO, 50 mg QD, 150 mg QD, 200 mg BID, ADA.

[0404] Figures 23A-23D show the percentage change from baseline to week 12 in CCL4 (Figure 23A), IL-6 (Figure 23B), CD19+ B cells (Figure 23C), and CD3+ T cells (Figure 23D ) for cohort 1 in the fenebrutinib RA study of Example 1. Significance compared to placebo is indicated by *.

[0405] Figures 24A-24B show the response of ACR20 (Figure 24A) and ACR70 (Figure 24B) from week 1 to week 12 for cohorts 1 and 2 of the RAcon fenebrutinib study of Example 1.

[0406] Figures 25A-25D show the change in ACR components of SJC (Figure 25A), TJC (Figure 25B), ESR (Figure 25C) and CRP (Figure 25D) from baseline to week 12 for the Cohorts 1 and 2 of the fenebrutinib RA study of Example 1.

[0407] Figures 26A-26C show the change in the ACR components of the physician's global assessment score (Figure 26A), the patient's global assessment score (Figure 26B), and the patient's global assessment score (Figure 26B). QRQQnn / l 7Π7 / Β / Υ patient pain assessment (Figure 26C) from baseline to week 12 for cohorts 1 and 2 of the fenebrutinib RA study of Example 1.

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

[0409] Figures 28A-28D show the percentage change from baseline to week 12 of CCL4 (Figure 28A), IL-6 (Figure 28B), CD19+ B cells (Figure 28C), and CD3+ T cells (Figure 28D ) from cohort 2 of the fenebrutinib RA study of Example 1. Significance compared to placebo is indicated by *.

[0410] Figures 29A-29B show the ACR50 response rate at week 12 as a function of baseline rheumatoid factor (RF) level, by quartile, for cohort 1 (Figure 29A) and cohort 2 (Figure 29B ) from the RA study with fenebrutinib of Example 1.

[0411] Figures 30A-30B-2 are tables summarizing the demographic and baseline characteristics of patients in the fenebrutinib RA study of Example 1.

[0412] Figures 31A-1 to -31B-2 are tables summarizing the primary and secondary efficacy endpoints at week 12 of the fenebrutinib RA study of Example 1.

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

[0414] Figure 33 shows graphs of UAS7 scores over time for subjects in Cohort 1 of the CSU study of Example 2, separated into those who tested positive on the CU index (CUI) or negative on the CUI.

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

[0416] Figure 35 is a graph of weekly itch at week 8 for both cohorts from the CSU study of Example 2. The treatment difference in LS means for all participants in both cohorts is shown, as well as disaggregated by the CUI negative group and the CUI positive group.

[0417] Figure 36 is a summary of the UAS7 scores at week 8 of both cohorts from the CSU study of Example 2, as values ​​for all participants in both cohorts, as well as broken down by CUI negative group (<10 ) and the CUI positive group (> / = 10).

[0418] Figure 37 is a graph of the level of anti-FcERi IgG autoantibodies in subjects from cohort 1 and 2 of the CSU study of! Example 2, separated by those who received fenebrutinib (left) and those who received placebo (right), from week 0 to week 8.

[0419] Figure 38 shows plots of UAS7 scores from week 0 to week 8 in individuals from Cohort 2 of the CSU study of Example 2, broken down by those who tested positive for QRQQnn / l 7Π7 / Β / Υ anti-FcERI autoantibodies (right) and those who tested negative for anti-FcERI autoantibodies (left). MiD from UAS7- 9.5-10.5. DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0420] Before describing the invention in detail, it should be understood that this invention is not limited to particular biological compositions or systems, which, of course, may vary. It should also be understood that the terminology used herein is intended solely to describe particular embodiments and is not intended to be limiting.

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

[0422] As used herein, the expression about refers to the usual error range for the respective value known to the mid-level skilled person in this technical field. Reference to a value or parameter herein includes (and describes) embodiments that refer to that value or parameter. In some embodiments, the expression about refers to a range of plus or minus 10% for the respective value. In some embodiments, the expression about refers to a range of plus or minus 5% for the respective value. In some embodiments, the expression about refers to a range of plus or minus 2% for the respective value. In some embodiments, the expression about refers to a range of plus or minus 1% for the respective value.

[0423] The aspects and embodiments of the invention described herein are understood to include aspects and embodiments of the type comprising, consisting of, and essentially consisting of.

[0424] The term pharmaceutical formulation refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective, and that does not contain additional components that are unacceptably toxic to a subject to whom the formulation would be administered. In some embodiments, such formulations are sterile. Pharmaceutically acceptable excipients (vehicles, additives) are those that can reasonably be administered to a mammalian subject to provide an effective dose of the active ingredient used.

[0425] As used herein, the term treatment refers to clinical intervention designed for the purpose of altering the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include slowing the rate of disease progression, improving or palliating the disease state, and remission or improving the 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 thereof decrease; the disease becomes more tolerable for the QRQonn / i ζηζ / Ε / γ patient; the rate of degeneration or deterioration, or the rate of development of the disease or disorder slows or stops; the progression of the disease or disorder is slowed or stopped; or the end point of degeneration is less debilitating. For example, an individual is successfully treated if one or more symptoms associated with cancer are mitigated or eliminated, including, but not limited to, reducing the proliferation of (or destroying) cancer cells, decreasing symptoms resulting from the disease, increasing the quality of life of those who suffer from the disease, reduce the dose of other medications necessary to treat the disease and / or prolong the survival of the individuals. Treatment of certain diseases or disorders may in some embodiments include, but is not limited to, specific clinical or other endpoints, such as those described in the examples provided herein.

[0426] An effective amount is at least the minimum amount required to effect average improvement or prevention of a particular disorder. An effective amount herein may vary according to factors such as the disease state, age, sex and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or harmful effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, decreasing the severity or delaying the onset of the disease, including the biochemical, histological and / or behavioral symptoms of the disease. , its complications and the intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, beneficial or desired results include clinical results such as a decrease in one or more symptoms resulting from the disease, an increase in the quality of life of those suffering from the disease, a decrease in the dosage of other medications necessary to treat the disease, improving the effect of other drugs such as through targeting, delaying disease progression and / or prolonging survival. An effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective dose of a drug, compound or pharmaceutical composition is an amount sufficient to achieve prophylactic or therapeutic treatment, either directly or indirectly. As is known in the clinical setting, an effective amount of a drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition. Therefore, an effective amount may be considered in the context of the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, together with one or more other agents, it can be administered. achieve or a desirable result is achieved.

[0427] The dose ranges provided herein refer to the free form of fenebrutinib. It will be apparent to a person of mid-level skill how to calculate a corresponding amount of a pharmaceutical salt form of fenebrutinib, taking into account the difference in molecular weight between the free form of fenebrutinib and a salt form. For example, in some embodiments provided herein, a patient is administered about 200 mg daily of fenebrutinib, or an acceptable salt. QRQQnn / l 7Π7 / Β / Υ pharmacist of this. If a pharmaceutically acceptable salt form is administered in such embodiments, because the salt form has a higher molecular weight than the free form of fenebrutinib, the total weight of the acceptable fenebrutinib salt from The pharmaceutically administered dose is greater than 200 mg, but corresponds to around 200 mg of the free form of fenebrutinib.

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

[0429] As used herein, treatment intolerance refers to a patient's lack of ability to continue receiving a drug or treatment due to one or more adverse reactions or sensitivity to the drug or treatment. Intolerance may require cessation of treatment for a period of time or indefinitely. Intolerance may be caused, for example, by a side effect of a drug treatment in a particular patient or group of patients.

[0430] As used herein, symptomatic disease refers to the appearance of symptoms or signs of a disease in a patient. Such symptoms or signs of the disease may be observable by a physician or other care provider, or by the patient themselves, or by one or more laboratory tests. A patient has symptomatic disease when he or she presents such signs. In some embodiments, a patient is considered to have symptomatic disease in accordance with the specific patient inclusion criteria set forth in the examples provided herein.

[0431] As used herein, together with or in combination with refers to the administration of one treatment modality (for example, a pharmacological treatment) in addition to another treatment modality. As such, these terms refer 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 synonymously with moderately to severely active rheumatoid arthritis, refers to active RA as measured by accepted standards in the field of rheumatology (e.g. (e.g. DAS28, ACR50, SDAI, joint counts). In some embodiments, a patient who has 6 or more tender joints and 6 or more swollen joints has moderately to severely active RA. In other embodiments, a patient QRQQnn / l 7Π7 / Β / Υ who has (i) 6 or more tender joints and 6 or more swollen joints, and (i) an elevated level of a laboratory measure of inflammation, has 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 disseminated lupus erythematosus, which may be used synonymously with moderately to severely active disseminated lupus erythematosus, refers to active SLE as measured by standards accepted in the field (e.g. , SLEDAI-2K score and / or physician global assessment). In some embodiments, a patient who has a SLEDAI-2K score > 8 (at screening only) with a clinical SLEDAI-2K score > 4.0 (at both screening and day 1) and a physician global assessment > 1.0 (out of 3) is considered to have moderately to severely active SLE. In some embodiments, the patient who has moderately to severely active SLE has the above symptoms and is currently receiving at least one standard oral treatment (e.g., corticosteroids, antimalarials, and / or immunosuppressants) for SLE.

[0435] As used herein, the term DMARD refers to a disease-modifying antirheumatic drug. As used herein, DMARDs include conventional nonbiologic DMARDs (eg, methotrexate, azathioprine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, sulfasalazine, hydroxychloroquine, and minocycline) and targeted nonbiologic DMARDs such as Janus kinase inhibitors. (JAK inhibitors), SYK inhibitors, IRAK1 inhibitors, IRAK4 inhibitors, RIP1K inhibitors, and apremilast. Exemplary conventional non-biologic DMARDs include, but are not limited to, methotrexate, azathioprine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, sulfasalazine, hydroxychloroquine, and minocycline. Exemplary targeted non-biologic DMARDs include apremilast, tofacitinib, baricitinib, filgotinib, peficitinib, and upadacitinib, including pharmaceutically acceptable salts thereof. In some embodiments, the hydroxychloroquine is in the form of a sulfate salt (ie, hydroxychloroquine sulfate). Exemplary Janus kinase inhibitors include, but are not limited to, tofacitinib, baricitinib, filgotinib, peficitinib, and upadacitinib, and pharmaceutically acceptable salts thereof.

[0436] As used herein, a biologic drug for rheumatoid arthritis refers to a biologic molecule, such as a protein, that interferes with or modulates the activity of a cellular receptor associated with an inflammatory and / or autoimmune response associated with rheumatoid arthritis. rheumatoid arthritis, particularly TNF-alpha, B-cell receptors, T-cell receptors, cytokines (eg, IL-1, IL-6, and IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Biologic drugs for rheumatoid arthritis 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 drugs for rheumatoid arthritis 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 drug for rheumatoid arthritis is QRQonn / i ζηζ / Ε / γ adalimumab, tocilizumab or sarilumab.

[0437] In some embodiments, the biologic drug for rheumatoid arthritis is a non-TNFo inhibitory biologic, eg, abatacept, tocilizumab, sarilumab, sirukumab, anakinra, or any biosimilar biologic or equivalent with the same mode of action as listed agents, including investigational biosimilar agents.

[0438] As used herein, a biologic inhibitor of TNF-alpha refers to a biologic agent (i.e., an antibody) that inhibits, to some extent, a biologic function of tumor necrosis factor alpha (TNF-alpha). ), for example, by binding to TNF-alpha and neutralizing or reducing its activity. Examples of biologic 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-lymphocyte antagonist is a molecule that, upon binding to a B-lymphocyte surface marker, destroys or depletes B-lymphocytes in a mammal and / or interferes with one or more functions of B cells. Exemplary B cell antagonists include, but are not limited to, antibodies to CD20, antibodies to CD22, antibodies to BR3, and BR3-Fc immunoadhesin. 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, interferes with one or more functions of T cells, 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, an IL-6 receptor antagonist refers to an agent that inhibits, to a certain extent, a biological function of interleukin-6 (IL-6), for example, by binding to the IL-6 receptor and neutralize or reduce its activity. In some embodiments, the IL-6 receptor antagonist is tocilizumab, sarilumab, and any biosimilar equivalent thereof.

[0442] As used herein, an IL-1 receptor antagonist refers to an agent that inhibits, to a certain extent, a biological function of interleukin-6 (IL-1), for example, by binding to the IL-1 receptor and neutralize or reduce its activity. In some embodiments, the IL-1 receptor antagonist is anakinra.

[0443] As used herein, ACR and ACR score refer to the American College of Rheumatology standard score for measuring rheumatoid arthritis activity in a patient. ACR20 refers to a 20% improvement on a scale of 28 intervals. ACR50 refers to a 50% improvement. ACR70 refers to a 70% improvement. See Rocha, K. www.rheumatoidarthritis.org / treatment / acr-score (last visited August 7, 2018); Aletaha, D. etal. 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 rheumatoid arthritis functional disability and severity. QRQonn / i ζηζ / Ε / γ general. See B. Bruce, J.F. Fríes, 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 as measured, in part, by reference to 28 joints of a patient who has rheumatoid arthritis. See National Rheumatoid Arthritis Society (www.nras.org.uk / the-das28-score, last visited 7 August 2018); J. Fransen, P.L.C.M. van Riel., Clin Exp Rheumatol 2005;23 (Supi.39): S93-S99. As used herein, DAS283-CRP refers to a DAS28 score as 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 Health Questionnaire 36, which is used as a tool to monitor health care outcomes in patients. See Tarlov A.R., et al., JAMA 1989, 262(7): 925-30; Linde, L, etal., J Rheumatol, 35 (2008), pp. 1528-1537.

[0447] As used herein, FACIT-Fatigue or the FACIT-Fatigue Scale refers to the Functional Assessment Scale for the Treatment of Chronic Illnesses-Fatigue (FACIT-Fatigue), which is a standard measure of fatigue. patient through patient survey, in, for example, patients with rheumatoid arthritis. See Celia, D, etal., JRheumatol. 2005, 32(5):811-9.

[0448] As used herein, CRP refers to C-reactive protein, or the blood test to determine inflammation in the body that measures C-reactive protein in the blood. CRP, a protein produced in the liver, will increase in concentration in the blood in response to inflammation. CRP can be measured using an hsCRP test, which measures highly sensitive CRP. In some embodiments, a positive elevated CRP result is, as measured by hsCRP testing, >0.400 mg / dL hsCRP. In other embodiments, a positive elevated CRP result is, as measured by an hsCRP test, > 0.650 mg / dL hsCRP. CRP testing is widely available through a variety of providers (LabCorp, Quest Diagnostics, Life Line Screening, etc.).

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

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

[0451] As used herein, autoantibody positive or autoantibody positive refers to a QRQQnn / l 7A7 / R / Y patient who has elevated levels of autoantibodies. Such patients will test positive for one or both of these autoantibodies. In some embodiments, autoantibody positive includes seropositive patients. Test kits or assays to measure autoantibodies in a patient sample are commercially available (e.g. Anti-CCP Cobas e601 through Covance, Diastat through Axis-Shield, Immunoscan-CCP Plus through Eurodiagnostica, ELIA-CCP through Phadia and Quanta Lite through 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 will test positive for one or both of RF and ACPA. In some embodiments, a positive RF diagnosis means that a blood sample from the patient shows more than 20 units / mL of RF, and a positive ACPA diagnosis means that a blood sample from the patient shows more than 5 units / mL. of ACPA. See Isaacs, J.D., ef 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 a blood sample from the patient shows 15 lU / mL or more of RF IgM, and a positive ACPA diagnosis means that a blood sample from the patient shows 17 U / mL. or more of ACPA IgG. Test kits or assays are commercially available (Anti-CCP Cobas e601, Diastat, ImmunoscanCCP Plus, ELIA-CCP and Quanta Lite).

[0453] As used herein, seronegative refers to a patient who does not show elevated levels of both RF and ACPA (i.e., the patient tests negative on both measures).

[0454] As used herein, UAS7 refers to the 7-day summed urticaria activity score, which, among other things, evaluates wheal count and itch severity in patients with CSU. UAS7 is further described in the clinical study of example 2.

[0455] As used herein, FU antihistamine refers to drugs that are antagonists of histamine H1 receptors, and are commonly prescribed for allergies, hives, and other allergic or hypersensitivity reactions or conditions. The 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, dexbrompheniramine, triprolidine, dimetindene, 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, UC index or chronic urticaria index refers to a commercially available in vitro basophil histamine release assay in which the patient's serum is mixed with QRQonn / i ζηζ / Ε / γ donor basophils and the levels of histamine released are measured by a quantitative enzyme immunoassay. A UC index value greater than or equal to 10 indicates that the patient has either an autoimmune basis for his or her urticaria (e.g., antibodies to IgE, FceRI, or anti-FcERII) or an alternative histamine-releasing factor. See Biagtan, M.J., et al, J Allergy Clin Immunoi. 2011, 127(6): 1626-27. A commercially available CU index test is CU índex® through Víracor (www.v¡racor-eurofíns.com / 2103-cu-¡ndex, last visited August 23, 2018).

[0457] As used herein, standard oral SLE treatment refers to oral drugs commonly prescribed to patients with SLE. In some embodiments, a standard oral SLE treatment is selected from corticosteroids, antimalarials, and immunosuppressants. In some embodiments, standard oral SLE treatments are selected from: an oral corticosteroid, azathioprine, methotrexate, mycophenolate mofetil, mycophenolic sodium, hydroxychloroquine, chloroquine, and quinacrine.

[0458] As used herein, SRI-4 refers to the SLE response index response. The SRI-4 response criterion is commonly used in SLE studies, is accepted by health authorities to measure reduction in SLE disease activity, and is a composite measure that includes the SLE disease activity index ( SLEDAI-2K), the British Isles Lupus Assessment Group (BILAG) 2004 and the GP Global Assessment. See Luijten K.M., Autoimmun. Rev. 2012,11(5): 326-9.

[0459] As used herein, BICLA refers to the BILAG-based composite lupus assessment. BILCA response is a common secondary metric to SRI-4 as a meaningful measure of SLE disease activity. See Luijten K.M., Autoimmun. Rev. 2012,11(5): 326-9.

[0460] An oral corticosteroid or OCS as defined herein, refers to glucocorticoids, steroids and / or cortisol-like drugs suitable for oral administration for the treatment of the diseases provided herein, and includes, but is not limited to, prednisone, cortisone, cortisone acetate, hydrocortisone, dexamethasone, prednisolone and methylprednisolone.

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

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

[0463] As used herein, the term biomarker refers to an indicator, for example, predictive, diagnostic and / or prognostic, that can be detected in a sample. The biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer) characterized by certain molecular, pathological, histological and / or clinical features. In some embodiments, a biomarker is a gene. The QRQQnn / l 7Π7 / Β / Υ biomarkers include, but are not limited to, polynucleotides (e.g., DNA and / or RNA), polypeptides, modifications of polypeptides and polynucleotides (e.g., post-translational modifications), carbohydrates and / or molecular markers based on glycolipids. The amount or level of a biomarker associated with greater clinical benefit for an individual is a detectable level in a biological sample. These can be measured by methods known to those in the mid-level trade and also disclosed herein. The expression level or amount of biomarker assessed may, in some embodiments, be used to determine response to treatment. In certain embodiments, the expression level or amount of one or more biomarkers is associated with a certain response to treatment.

[0464] The term sample, as used herein, refers to a composition that is obtained or derived from a subject and / or individual of interest that contains a cellular and / or molecular entity that is to be characterized and / or identify, for example, based on physical, biochemical, chemical and / or physiological characteristics. For example, the phrase disease sample and variations thereof refer to any sample obtained from a subject of interest that would be expected or known to contain the cellular and / or molecular entity to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell waste, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, blood, cells derived from blood, urine, cerebrospinal fluid, saliva, sputum, tears, perspiration, mucus, used from tumors and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cell extracts and combinations of these.

[0465] By tissue sample or cell sample is meant a collection of similar cells obtained from a tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue from a fresh, frozen and / or preserved organ, biopsy and / or aspirate; blood or any blood component such as plasma; body fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time during the subject's gestation or development. The tissue or cell sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a diseased tissue / organ. The tissue or cell sample may contain compounds that do not naturally intermix with the tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics or the like.

[0466] A reference sample, reference cell, reference tissue, control sample, control cell or control tissue, as used herein, refers to a sample, cell, tissue, standard or level that is used for comparative purposes. In one embodiment, a reference sample, a reference cell, a reference tissue, a control sample, a control cell or a control tissue is obtained from a healthy and / or non-diseased part of the body (e.g. example, tissue or cells) from the same subject or individual. For example, healthy and / or non-diseased cells or tissue adjacent to diseased cells or tissue. In another embodiment, a reference sample is obtained from an untreated tissue and / or cell from the body of the same subject or QRQonn / i ζηζ / Ε / γ individual. In yet another embodiment, a reference sample, a reference cell, a reference tissue, a control sample, a control cell or a control tissue is obtained from a healthy and / or non-diseased part of the body ( for example, tissues or cells) of an individual who is not the subject or individual. In yet another embodiment, a reference sample, a reference cell, a reference tissue, a control sample, a control cell or a control tissue is obtained from an untreated tissue and / or cell 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 particular type of disease. Diagnosis may also refer to the classification of a particular subtype of disease, for example, by histopathological criteria, or by molecular characteristics (for example, a subtype characterized by the expression of one or a combination of biomarkers (for example, particular genes or proteins). encoded by said genes)).

[0468] An effective response of a patient or the degree of response of a patient to treatment with a medication and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for or suffering from a disease or disorder, such as cancer . In one embodiment, such benefit includes any one or more of: extending survival (including overall survival and progression-free survival); result in an objective answer (including a complete answer or a partial answer); or improve 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 the degree of response of a patient to treatment for a particular disorder or disease may be evaluated, for example, by one or more standardized assessments, such as the standardized assessments described herein.

[0469] A patient who does not have an effective response to treatment refers to a patient who does not have any of the following: extension of survival (including overall survival and progression-free survival); objective answer (including a complete answer or a partial answer); or amelioration of signs or symptoms of cancer. In some embodiments, a patient who does not have an effective response to treatment refers to a patient who does not have improvement in one or more signs or symptoms of a disorder or disease, such as SLE, CSU, or RA. / / . 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 treatment methods 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. WO 2017 / 148837, which is incorporated herein by reference in its entirety, discloses formulations and dosage forms comprising fenebrutinib and technically acceptable salts. QRQQnn / l 7Π7 / Β / Υ pharmacist of this. In some embodiments, a formulation described in WO 2017 / 148837 is used to administer 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, intrapulmonary and intranasal administration and, if desired for local treatment, intralesional administration. In preferred embodiments, oral administration is preferred.

[0472] Pharmaceutically acceptable salts of fenebrutinib may be used in the methods herein. As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of the active compounds that are prepared with relatively non-toxic bases or acids, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acid functionalities, basic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat 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, zinc and the like salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, natural amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine. , diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, netylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine , triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds 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, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphorous acids and the like, as well as well as the salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, italic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acid (see, for example, Berge, S. M., et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66 , 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted to either basic addition salts or acid addition salts.

[0473] In some of the embodiments provided herein, oral doses of fenebrutinib, or QRQQnn / l 7Π7 / Β / Υ a pharmaceutically acceptable salt of this, preferably in the form of tablets or capsules, containing 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 wherein the dosage form comprises a pharmaceutically acceptable salt of fenebrutinib, the oral dosage form comprises 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 the free form of fenebrutinib.

[0474] In some embodiments, daily doses of fenebrutinib, or a pharmaceutically acceptable salt thereof, include about 50-400 mg daily; about 150-400 mg daily; about 200-400 mg daily; about 250-400 mg daily; about 300-400 mg daily; about 50-300 mg daily; about 100-300 mg daily; about 150-300 mg daily; about 250-300 mg daily; about 50-200 mg daily; about 100-200 mg daily; about 150-200 mg daily; and around 200-300 mg daily. In some embodiments, the oral dose is 50 mg QD, 100 mg QD, 150 mg QD, 200 mg QD, 250 mg QD, 300 mg QD, 100 mg BID, 150 mg BID, or 200 mg BID. In some embodiments where a pharmaceutically acceptable salt form of fenebrutinib is administered, the daily dose is an amount equivalent to a dose or dose range of the free form of fenebrutinib as described herein ( for example, equivalent to about 50-400 mg daily; about 150-400 mg daily; about 200-400 mg daily; etc. of the free form of fenebrutinib).

[0475] In some embodiments, a composition and formulation herein may also contain more than one active ingredient as necessary for the particular indication being treated (e.g., RA, CSU and / or SLE), preferably those with complementary activities that do not negatively affect each other. Such active ingredients are suitably present in combination in amounts that are 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, peficitinib and upadacitinib. In some embodiments, the tablet or capsule contains fenebrutinib, or a pharmaceutically acceptable salt thereof, and tofacitinib. / / / . Treatment methods

[0476] Provided herein are methods of treating RA, CSU, or SLE in specific patient populations described herein by administering fenebrutinib or a pharmaceutically acceptable salt or salt thereof. In one aspect, methods are provided herein for treating a human patient who has moderately to severely active RA, wherein the patient has demonstrated an inadequate response to prior treatment with one or more conventional non-biological DMARDs. In another aspect, the patient has demonstrated an inadequate response or intolerance to previous treatment with one or more biological drugs for rheumatoid arthritis. The more specific aspects of these treatment methods are described in QRQonn / i ζηζ / Ε / γ the brief description of the invention (i.e. Ε1, E2, etc.). In the clinical trial results provided herein, fenebrutinib was found to be safe and effective in the treatment of RA in the patient populations described above.

[0477] In another aspect, methods are provided herein for treating patients with CSU who remain with symptomatic disease despite prior treatment with H1 antihistamines. In the clinical trial results provided herein, fenebrutinib was found to be safe and effective in the treatment of CSU in this patient population. The more specific aspects of these treatment methods are described in the brief description of the invention.

[0478] In another aspect, methods are provided herein for treating patients who have moderately to severely active SLE, wherein the patient has symptomatic disease despite prior standard oral SLE treatment. In the clinical trial results provided herein, fenebrutinib was found to be safe and effective in the treatment of SLE in this patient population. The more specific aspects of these treatment methods are described in the brief description of the invention.

[0479] Also provided herein are methods of treating RA, CSU or SLE in the specific patient populations described herein by administering fenebrutinib or a pharmaceutically acceptable salt thereof, wherein the patient is monitor after treatment for elevated liver enzymes associated with hepatotoxicity. It was found that at certain doses of fenebrutinib, some patients experience an increase in liver enzymes associated with hepatotoxicity and therefore it would be advisable to monitor such cases during treatment and, in some cases, discontinue treatment for some time or reduce the dose of fenebrutinib if justified. In some embodiments, if the patient shows signs of elevated liver enzymes associated with hepatoxicity, administration of fenebrutinib is interrupted, stopped for a period of time and restarted, or continued at a lower dose. The more specific aspects of these treatment methods are described in the brief description of the invention.

[0480] Fenebrutinib, or a pharmaceutically acceptable salt or salt thereof, may be used either alone or in combination with other agents in a treatment method described herein. For example, the additional therapeutic agent may be an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, an apoptosis enhancer, a neurotropic factor, an agent for the treatment of cardiovascular diseases, an agent for the treatment of liver diseases, a antiviral agent, an agent for the treatment of blood disorders, an agent for the treatment of diabetes and an agent for the treatment of immunodeficiency disorders. The second therapeutic agent may be an NSAID anti-inflammatory agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to fenebrutinib or a pharmaceutically acceptable salt thereof so that they do not adversely affect each other. More specific aspects of these treatment methods using treatment combinations are described in the brief description of the QRQonn / i ζηζ / Ε / γ invention.

[0481] In some embodiments, the additional therapeutic agent is selected from the group consisting of: corticosteroids (e.g., prednisone, prednisolone, methylprednisolone and hydrocortisone); disease-modifying antirheumatic drugs (DMARDs, for example, immunosuppressive or anti-inflammatory agents); antimalarial agents (for example, hydroxychloroquine and chloroquine); immunosuppressive agents (eg, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate); anti-inflammatory agents (eg, aspirin, NSAIDs (eg, ibuprofen, naproxen, indomethacin, nabumetone, celecoxib)); antihypertensive agents (eg, calcium channel blockers (eg, amlodipine, nifedipine) and diuretics (eg, furosemide)); statins (for example, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin); anti-B lymphocyte agents (eg, anti-CD20 (eg, rituximab), anti-CD22); anti-B cell stimulatory agents (anti-BLyS, e.g. belimumab, blisibimod); type 1 interferon receptor antagonist (e.g., anifrolumab); T cell modulators (eg, rigerimod); abatacept; anticoagulants (eg, heparin, warfarin); and vitamin D supplements.

[0482] In other aspects, the patient to be treated in the methods provided herein has a disease that expresses (has been shown to express, for example, in a diagnostic test) one or more biomarkers. In some embodiments, the patient's disease expresses a lower level of the biomarker. In some embodiments, the patient's disease expresses a higher level of the biomarker. Specific biomarkers are described both in the brief description of the invention and in the examples below. In some embodiments of any of the methods, assays and / or kits provided herein, the one or more biomarkers are present in the sample when 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, for example, 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, for example, 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 other embodiments, for example, in certain embodiments where the disorder is CSU, the one or more biomarkers are selected from the group consisting of TPO-binding IgE antibodies, IL24-binding IgE antibodies, IgG antibodies that bind to IgE and IgG antibodies that bind to FcERI. In still other embodiments where the disorder is CSU, the one or more biomarkers include IgG antibodies that bind to FcERI (for example, it includes at least IgG antibodies that bind to FcERI, but may further comprise one or more of others biomarkers or no other biomarker). In still other embodiments, for example, in certain embodiments where the disorder is CSU, the one or more biomarkers are one or more autoantibodies assessed by the CU index method. In some ways QRQQnn / l 7Π7 / Β / Υ embodiment, a CU index value greater than or equal to 10 indicates an elevated level of one or more biomarkers (e.g., autoantibodies). In certain embodiments, an elevated level of one or more of these biomarkers (such as one or more biomarkers in a patient with SLE, or one or more biomarkers in a patient with CSU) indicates that the patient is more likely to benefit. of treatment with fenebrutinib, or a pharmaceutically acceptable salt thereof, than a subject who does not have an elevated level, for example, a subject who has the same disorder but without elevated levels of biomarkers, or a healthy subject without the disorder, or a subject whose levels are approximately at baseline levels determined by a mid-level professional (such as an average of a population or a subset thereof). In some embodiments, a patient who is more likely to benefit includes having a better response (for example, a greater reduction in one or more symptoms, or more symptoms are reduced) to treatment with fenebrutinib or a medically acceptable salt. of this compared to a subject with the same disorder, who is administered the same dose of fenebrutinib or a pharmaceutically acceptable salt thereof, but without elevated levels of one or more biomarkers.

[0483] In some embodiments of the methods provided herein, the patient has CSU and tests positive for UC index. In certain embodiments, such a UC index-positive patient is more likely to benefit (e.g., have a better response) from treatment with fenebrutinib or a pharmaceutically acceptable salt thereof compared to a patient with CSU that tests negative on the CU index. In certain embodiments, a CSU patient with a positive UC index is likely to have a greater reduction in one or more symptoms or symptom measures when treated with fenebrutinib or a pharmaceutically acceptable salt thereof, in comparison with a CSU patient with a negative UC index. In still other embodiments, a CSU patient with a positive UC index is likely to respond to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof (for example, through reduction of one or more symptoms or measures of symptoms) to a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof, compared to a UC index-negative patient. Therefore, in some embodiments, provided herein is a method of reducing the level of fenebrutinib or a pharmaceutically acceptable salt thereof administered to a patient in need thereof, wherein the patient has CSU, comprising determining whether the patient is a UC index positive patient and administering to said UC index positive patient a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof compared to a UC index patient negative. In certain embodiments, the greatest response, or the greatest reduction in one or more symptoms or symptom measures, is the reduction of UAS7, or the reduction of the weekly itch score, or both. In certain embodiments, a UC index positive patient has a greater reduction in UAS7, or a greater reduction in weekly itch score, or both, compared to a UC index negative patient who is administered the same dose of fenebrutinib or a salt acceptable from the point of view QRQQnn / l 7Π7 / Β / Υ pharmacist of this. In still other embodiments, a patient with positive UC index has about the same reduction in UAS7, or about the same reduction in weekly itch score, or both, compared to a patient with negative UC index at the same time. that you are given 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 evaluated over 4 weeks, or over 8 weeks, or over 12 weeks.

[0484] In some embodiments of the methods provided herein, the patient has CSU and tests positive for IgG antibodies that bind to FcERI (e.g., anti-FcERI IgG autoantibodies). In certain embodiments, a patient who tests positive for FcERI-binding IgG antibodies is more likely to benefit (e.g., have a better response) from treatment with fenebrutinib or a pharmaceutically acceptable salt thereof. compared to a CSU patient who tests negative for FcERI-binding IgG antibodies. In certain embodiments, a patient who tests positive for FcERI-binding IgG antibodies is likely to have a greater reduction in one or more symptoms or symptom measures when treated with fenebrutinib or a pharmaceutically acceptable salt. of this, compared to a patient with CSU who tests negative for these antibodies. In still other embodiments, a CSU patient who tests positive for FcERI-binding IgG antibodies is likely to respond to treatment with fenebrutinib or a pharmaceutically acceptable salt thereof (e.g., via the reduction of one or more symptoms or measures of symptoms) to a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof, compared to a CSU patient who tests negative for such antibodies. Therefore, in some embodiments, provided herein is a method of reducing the level of fenebrutinib or a pharmaceutically acceptable salt thereof administered to a patient in need thereof, wherein the patient has CSU, comprising determining whether the patient tests positive for FcERI-binding IgG antibodies and administering to said antibody-positive patient a lower dose of fenebrutinib or a pharmaceutically acceptable salt thereof compared to a patient who tests negative for FcERI. IgG antibodies that bind to FcERI. In certain embodiments, the greatest response, or the greatest reduction in one or more symptoms or symptom measures, is the reduction of UAS7, or the reduction of the weekly itch score, or both. In certain embodiments, a patient who tests positive for FcERI-binding IgG antibodies has a greater reduction in UAS7, or a greater reduction in weekly itch score, or both, compared to a patient who tests negative for said antibodies. antibodies to which the same dose of fenebrutinib or a pharmaceutically acceptable salt of it is administered. In still other embodiments, a patient who tests positive for FcERI-binding IgG antibodies has about the same reduction in UAS7, or about the same reduction in weekly itch score, or both, compared to a patient who tests negative for said antibodies and who is administered a higher dose of fenebrutinib or a pharmaceutically acceptable salt of it. In certain embodiments, the UAS7 score, or the QRQQnn / l 7Π7 / Β / Υ weekly itch score, or both, are assessed for 4 weeks, or for 8 weeks, or for 12 weeks.

[0485] In some embodiments, where a patient with a disorder has one or more elevated levels of biomarkers (e.g., elevated levels of one or more antibodies, such as IgG antibodies that bind FcERI; or tests positive for the UC index), the levels are high compared to a healthy subject without the disorder. In other embodiments, the levels are elevated relative to a baseline value, such as a baseline value determined by screening a population or subpopulation, or a baseline value provided by the manufacturer of a biomarker test, or the lower limit. of quantification. In some embodiments, the baseline value is the average of a group of patients with the disorder, or the average of a group of healthy subjects. In some embodiments, the baseline value is the average plus one standard deviation, the average plus two standard deviations, or the average 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 the assay methods and / or kits, the biomarker is detected in the sample by a method selected from the group consisting of FACS, Western blotting, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, stain blot, immunodetection methods, HPLC, surface plasmon resonance, optical spectroscopy, mass spectroscopy, HPLC, qPCR, RT-qPCR, multiplex qPCR or RT-qPCR, RNA sequencing, microarray analysis, SAGE, MassARRAY technique, and FISH, and combinations of these.

[0487] In some embodiments of any of the methods, assays and / or kits, the biomarker is detected in the sample through protein expression. In some embodiments, protein expression is determined by immunohistochemistry (IHC). In some embodiments, the biomarker is detected through the use of an antibody. In some embodiments, the biomarker is detected as weak staining intensity by IHC. In some embodiments, the biomarker is detected as moderate staining intensity by IHC. In some embodiments, the biomarker is detected as a strong staining intensity by IHC. In some embodiments, the staining is membrane staining, cytoplasmic staining, or combinations of these. IV. Biomarkers, detection and diagnosis 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 a patient treated with, or to be treated with, fenebrutinib. In some embodiments, the method comprises obtaining a sample from a patient treated with, or to be treated with, fenebrutinib. In the brief description of the invention above, additional embodiments of biomarkers, detection and diagnosis methods are provided.

[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 full contents of which are incorporated herein by reference. QRQQnn / l 7Π7 / Β / Υ

[0490] In some embodiments, the sample obtained from a patient to be treated, or currently being treated, is whole blood. In some embodiments, whole blood comprises 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 levels / amount of a biomarker can be determined qualitatively and / or quantitatively based on any suitable criteria known in the art, including, but not limited to, DNA, mRNA, cDNA, proteins, fragments of proteins and / or number of copies of the gene. In certain embodiments, the presence and / or expression levels / amount of a biomarker in a first sample is increased or elevated compared to the presence / absence and / or expression levels / amount in a second sample. In certain embodiments, the presence / absence and / or expression levels / amount of a biomarker in a first sample is decreased or reduced compared to the presence and / or expression levels / amount in a second sample. In certain embodiments, the second sample is a reference sample, a reference cell, a reference tissue, a control sample, a control cell, or a control tissue. Additional disclosures for determining the presence / absence and / or expression levels / amount of a gene are described herein.

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

[0493] In some embodiments of any of the methods, reduced expression refers to an overall reduction of about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% , 90%, 95%, 96%, 97%, 98%, 99% or more at the biomarker level (e.g., protein or nucleic acid (e.g., gene or mRNA)), detected by methods known in the art standards such as those described herein, in comparison with a reference sample, reference cell, reference tissue, control sample, cell QRQQnn / l 7Π7 / Β / Υ control or control fabric. In certain embodiments, reduced expression refers to the decrease in the level / amount of expression of a biomarker in the sample where the decrease is at least about any of 0.9X, 0.8X, 0.7X, 0.6X, 0.5 X, 0.4x, 0.3x, 0.2x, 0.1x, 0.05x, or 0.01x of the level / amount of expression of the respective biomarker in a 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 was taken from the patient before starting treatment. For example, in some embodiments of the methods provided herein, treatment of the patient results in reduced 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 as described herein) and the patient has an elevated expression of one or more biomarkers, compared to a subject who does not have the disorder or disease. In certain embodiments, the patient has a disorder or disease (such as a disorder or disease as described herein) and the patient has an elevated expression of one or more biomarkers, compared to another subject who also has the disorder. or illness.

[0495] The presence and / or level / amount of expression of various biomarkers in a sample can be analyzed using a number of methodologies, many of which are known in the art and understood by those in the mid-level trade, including , among others, immunohistochemistry (IHC), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting (FACS), MassARRAY, proteomics, blood-based quantitative assays (such as, e.g. , serum ELISA), biochemical enzyme activity assays, in situ hybridization, Southern analysis, Northern analysis, whole genome sequencing, polymerase chain reaction (PCR), including quantitative real-time PCR (qRT-PCR ) and other methods of detection of the type of amplification, such as, for example, branched DNA, SISBA, TMA and the like), RNA sequencing, FISH, microarray analysis, gene expression profiling and / or serial analysis of gene expression ( SAGE), as well as any of the wide variety of assays that can be performed using protein, gene, and / or tissue array analysis. Typical protocols for assessing the status of genes and gene products are found, for example, in Ausubel et al., eds., 1995, Current Protocols in Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 ( Immunoblotting) and 18 (PCR Analysis). Multiplexed immunoassays such as those available through Rules Based Medicine or Meso Scale Discovery (MSD) can also be used.

[0496] In some embodiments, the presence and / or level / amount of expression of a biomarker is QRQQnn / l 7Π7 / Β / Υ determined by a method comprising: (a) performing gene expression profiling, PCR (such as rtPCR or qRT-PCR), RNA sequencing, microarray analysis, SAGE, MassARRAY technique, or FISH in a sample; and b) determine the presence and / or the level / amount of expression of a biomarker in the sample. In some embodiments, the microarray method comprises the use of a microarray chip that has one or more nucleic acid molecules that can hybridize under stringent conditions with a nucleic acid molecule that encodes a gene mentioned above or that has one or more polypeptides (such as peptides or antibodies) that can bind to one or more of the proteins encoded by the genes mentioned above. 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 the evaluation of mRNA in cells are well known and include, for example, hybridization assays using complementary DNA probes (such as in situ hybridization using labeled riboprobes specific for the one or more genes, Northern blotting and related techniques) and various nucleic acid amplification assays (such as RT-PCR using complementary primers specific for one or more of the genes, and other methods of detection of the type of amplification, such as, for example, branched DNA, SISBA , TMA and similar).

[0498] Mammalian samples can conveniently be evaluated for mRNA by Northern analysis, blot blotting, or PCR. In addition, such methods may include one or more steps that allow the levels of target mRNA in a biological sample to be determined (for example, by simultaneously examining the levels of a comparative control mRNA sequence of a housekeeping gene, such as a member of the actin family). Optionally, the sequence of the amplified target cDNA can be determined.

[0499] Optional methods include protocols that examine or detect mRNA, such as target mRNA, in a tissue or cell sample using microarray technologies. 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 such that the sequence and position of each member of the array is known. For example, a selection of genes whose expression correlates with increased or reduced clinical benefit from antiangiogenic treatment can be provided on 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 level / amount of expression is measured by observing protein expression levels of a gene mentioned above. In certain embodiments, the method comprises contacting the biological sample with antibodies for a biomarker QRQQnn / l 7Π7 / Β / Υ described herein under conditions permissive for biomarker binding, and detect whether a complex is formed between the antibodies and the biomarker. Such a method may be an in vitro or in vivo method.

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

[0502] In certain embodiments, samples are normalized for both differences in the amount of the biomarker tested and variability in the quality of the samples used, and variability between test runs. Such normalization can be achieved by detecting and incorporating the expression of certain normalizing biomarkers, including known housekeeping genes. Alternatively, the normalization can be based on the mean or median of the signal of all the genes evaluated or of a large subset of these (global normalization approach). On a gene-by-gene basis, the measured normalized amount of a subject's mRNA or protein is compared to the amount found in a reference set. Normalized expression levels for each mRNA or protein for each sample tested per subject can be expressed as a percentage of the expression level measured in the reference set. The presence and / or level / amount of expression measured in a sample to be tested from a particular subject will fall within a certain percentile 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 detection of target genes or gene products in cancer samples can be applied to other samples of the organism. By screening such samples of the organism, a simple early diagnosis for these cancers can be achieved. In addition, the progress of treatment can be more easily monitored by testing samples of the organism for the target genes or gene products.

[0504] In certain embodiments, a reference sample, reference cell, reference tissue, control sample, control cell or control tissue is a single sample or multiple pooled samples from the same subject or individual that are obtained in one or more different time points than when the test sample is obtained. For example, a 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 pooled multiple sample from one or more healthy individuals other than the subject or individual. In certain embodiments, a reference sample, reference cell, reference tissue, control sample, control cell or control tissue is a pooled multiplex sample from one or more individuals with a disease or disorder other than the subject. or the individual. In certain embodiments, a QRQQnn / l 7Π7 / Β / Υ reference sample, reference cell, reference tissue, control sample, control cell or control tissue are pooled RNA samples from normal tissues or pooled serum or plasma samples from one or more individuals who are not the subject or the individual.

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

[0506] In another embodiment of the invention, an article of manufacture or kit is provided comprising fenebrutinib, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent. In some embodiments, the article of manufacture or kit further comprises a package insert comprising instructions for using fenebrutinib, or a pharmaceutically acceptable salt thereof, together with the second therapeutic agent for treating a disease provided herein. (e.g. RA, CSU and / or SLE).

[0507] In some embodiments, fenebrutinib, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent are in the same capsule or tablet, or in separate capsules or tablets with a kit. Suitable containers for kits include, for example, bottles or boxes. In some embodiments, the container contains the formulation, and the label on or associated with the container may indicate instructions for its use. The crafting item or kit may also include other commercially and user-desirable materials, including other package inserts with instructions for use.

[0508] The descriptive memory is considered sufficient to allow the practice of the invention by a person of the mid-level trade. Various modifications of the invention, in addition to those shown and described herein, will be apparent to persons of intermediate level craft from the foregoing description and will be included within the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety for all purposes. EXAMPLES QRQonn / i ζηζ / Ε / γ

[0509] The present disclosure will be understood more fully by reference to the following examples. However, these should not be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that persons in the mid-level trade will come up with various modifications or changes thereto, which are to be included within the spirit and scope of the present application and the scope of the attached claims. EXAMPLE 1 PARALLEL GROUP STUDY OF TWO COHORTS, RANDOMIZED, PHASE II, DOUBLE BLIND IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS, WHICH EVALUATES THE EFFICACY AND SAFETY OF FENEBRUTINIB IN COMPARISON WITH THE PLACEBO AND ADALIMUMAB IN PATIENTS WITH AN INADEQUATE RESPONSE TO TREATMENT WITH METHOTREXATE PREVIOUS (COHORT 1) AND COMPARED TO PLACEBO IN PATIENTS WITH AN INADEQUATE RESPONSE OR INTOLERANCE TO PREVIOUS TNF TREATMENT (COHORT 2)

[0510] This study was designed to evaluate the efficacy and safety of fenebrutinib compared to placebo (cohorts 1 and 2) and compared to adalimumab (ADA) (cohort 1), each in combination with methotrexate (MTX), in patients with moderately to severely active rheumatoid arthritis (RA). The specific objectives and corresponding endpoints of this study are described below. Study objectives

[0511] The primary efficacy objective of Cohort 1 of this study was to evaluate the efficacy of fenebrutinib at three dose levels compared to placebo used in combination with stable doses of MTX in patients with active RA who have had an inadequate response. to MTX and have not received prior TNF treatment.

[0512] The primary efficacy objective of Cohort 2 of this study was to evaluate the efficacy of fenebrutinib compared to placebo used in combination with stable doses of MTX in patients with active RA who have had an inadequate response or intolerance to 1 or 2 TNF inhibitors and may have been previously exposed to no more than one non-TNF biologic agent.

[0513] The secondary efficacy objectives of this study were as follows: • To evaluate the efficacy of fenebrutinib compared to ADA used in combination with stable doses of MTX in patients with active RA who have had an inadequate response to MTX and have not received prior TNF treatment. • Evaluate the efficacy of fenebrutinib over time with multiple standardized assessments (ACR20, ACR50, ACR70, DAS28, DAS28-3-CRP, etc.) and based on individual components of the ACR (tender joint count / painful joints, 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 rates at days 7, 14, 28 QRQQnn / l 7Π7 / Β / Υ and 56). • Assess DAS28 remission (< 2.6) and LDA status (< 3.2) on days 7, 14, 28, 56, and 84. • Assess ACR / EULAR remission according to Boolean-based definition (tender joint count < 1, swollen joint count < 1, CRP < 1, and patient global assessment < 1) on days 7,14, 28 , 56 and 84. • Assess SDAI-based remission (defined as 3.3 for ACR / EULAR remission) and CDAI-based remission (defined as < 2.8) on days 7,14, 28, 56, and 84. • To evaluate the effect of fenebrutinib compared to 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 measure 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 of this study is to characterize the pharmacokinetics of fenebrutinib in patients using a population PK approach. Exploratory PK endpoints included the relationship between drug exposure measurements and fenebrutinib pharmacodynamic effects, efficacy, and safety; the impact of selected covariates on measures of exposure and / or response to fenebrutinib; and the impact of genetic polymorphisms on fenebrutinib exposure measurements.

[0516] The exploratory biomarker targets of this study were as follows: • To assess the effect of fenebrutinib on biomarkers to help define MOA. • Evaluate the relationship between changes in biomarkers and efficacy. • To evaluate whether biomarkers, measured at baseline, identify a subset of patients with better clinical benefit from fenebrutinib. Study design

[0517] The study was a multicenter, phase II, randomized, double-blind, placebo-controlled, active comparator (cohort 1 only), parallel group, dose-ranging study to evaluate the efficacy and safety of fenebrutinib in patients with RA of moderately to severely active and an inadequate response to prior MTX treatment (cohort 1) or to MTX and TNF treatment who may also have been exposed to no more than one non-TNF-inhibiting biologic agent (cohort 2). Moderately to severe active RA was defined by > 6 tender / painful joints on movement (joint count 68) and > 6 swollen joints (joint count 66) at both screening and day 1 (randomization), as well as a high-sensitivity C-reactive protein (hsCRP) > 0.400 mg / dL for Cohort 1 and an hsCRP > 0.650 mg / dL for Cohort 2 at screening.

[0518] 578 patients were enrolled in the study. In Cohort 1, 480 MTX-IR patients were randomized to placebo (110 patients), ADA (111 patients), or one of three doses of fenebrutinib: 50 mg QD (40 patients), 150 QRQonn / i znz / R / YiAi mg QD (109 patients) or 200 mg BID (110 patients). In Cohort 2, 98 patients with TNF-IR were randomized to placebo or fenebrutinib 200 mg BID. After a screening period of up to 28 days, patients in both cohorts received blinded study drug (oral fenebrutinib or equivalent placebo) for 12 weeks, after which they had the option to enter 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 a subcutaneous (SC) comparator drug (ADA or placebo).

[0519] Cohort 1 Treatment Regimens. Cohort 1 patients will be randomly assigned in a 1:1:1:1:1 manner to 1 of 5 parallel treatment groups; Once enrollment in arm A is complete, patients will be randomized 1:1:1:1 into the remaining 4 treatment arms: • Group A: 50 mg QD fenebrutinib (tablets BID) + placebo injections SC every 2 weeks (Q2W) (n = 40) • Group B: 150 mg QD fenebrutinib (tablets BID) + placebo injections SC Q2W (n = 109) • Group C: 200 mg BID of fenebrutinib (tablets BID) + placebo injections SC Q2W (n = 110) • Group D: placebo (tablets BID) + placebo injections SC Q2W (n = 110) • Group E : placebo (BID tablets) + ADA SC Q2W 40 mg injections (n ​​= 111)

[0520] Cohort 2 Treatment Regimens. Patients in Cohort 2 will be randomly assigned in a 1:1 manner to 1 of 2 parallel treatment groups: • Arm A: fenebrutinib 200 mg QD (BID tablets, n=49) • Arm B: placebo (BID tablet, n=49)

[0521] Patients must enter and remain on stable treatment with MTX and a stable dose of folio acid during the study. For patients receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and / or corticosteroids, continued use of stable doses of oral NSAIDs (for at least 2 weeks before randomization) and / or stable doses of oral corticosteroids (for at least 6 weeks before randomization) (< 10 mg / day prednisone equivalent) and should be continued unchanged throughout the study, unless adjustment is necessary for safety reasons. Patients receiving proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) should be stabilized on a regimen beginning at least 2 weeks before randomization and continuing throughout the study. Inclusion criteria

[0522] All patients must meet the following criteria to enter the study: • Age from 18 to 75 years at screening. • Able and willing to give written informed consent and comply with protocol requirements. • Have a diagnosis of RA with adult onset as defined according to the European League Against Rheumatism / 2010 ACR classification criteria • RA disease activity using laboratory inflammatory markers and body count. QRQonn / i ζηζ / Ε / γ joints: > 6 tender / painful joints on movement (joint count 68) and > 6 swollen joints (joint count 66) BOTH at screening and day 1 (randomization). • At screening, you must have hsCRP as follows: Cohort 1: > 0.400 mg / dL (can be repeated once) Cohort 2: > 0.650 mg / dL (can be repeated once). • Positive for anti-cyclic citrullinated protein / peptide antibody (anti-CCP or ACPA), rheumatoid factor, or both (if based on historical data, documentation of previous positive laboratory value is required on the electronic case report form) . • Have received MTX for at least 12 weeks immediately before randomization, of which the last 8 weeks before randomization must have been at a stable dose between 7.5 and 25 mg / week (oral or parenteral). For patients entering the trial with MTX doses < 15 mg / week, there must be clear documentation in the medical record indicating that higher doses were not tolerated or that the MTX dose is the highest acceptable dose according to the guidelines. local clinical practice. • Be willing to withdraw all non-biological disease-modifying antirheumatic drugs (DMARDs), other than MTX and leflunomide, at least 4 weeks before randomization. Patients previously treated with leflunomide must either have discontinued treatment > 8 weeks before randomization or have discontinued with the following elimination procedure at least 28 days before randomization: Cholestyramine or activated charcoal must be taken at standard doses for a minimum of 6 days, but ideally for the standard 11 days (US Arava® package insert; summary of Arava® product characteristics). • Be willing to receive treatment at an adequate and stable dose of folic acid (not less than 5 mg total dose per week) during the study. • Only for patients currently receiving oral corticosteroids: Treatment must be at a stable dose of < 10 mg / d prednisone (or equivalent) for 6 weeks prior to randomization and with a plan to remain at a stable dose during randomization. study duration. • Only for patients currently receiving NSAIDs on a regular basis (e.g., not as needed): Treatment must be at a stable dose for the 2 weeks prior to randomization and with a plan to remain at a stable dose for the duration of the study. • Only for patients currently receiving PPI or H2RA: Treatment must be at a stable dose for the 2 weeks prior to randomization and with a plan to remain at a stable dose for the duration of the study. • There is no evidence of active, latent, or inadequately treated Mycobacterium tuberculosis (TB) infection. • For women of childbearing potential (including those with tubal ligation): Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception that results in QRQonn / i ζηζ / Ε / γ failure rate of < 1% per year during the treatment period and for at least 60 days after the last dose of study drug or longer if required by the local prescribing label for ADA. • For men: agreement to remain abstinent (refrain from heterosexual relations) or use contraceptive measures and agree to refrain from donating sperm.

[0523] To enroll in Cohort 2, patients must also meet the following criteria: • Experienced an inadequate response or intolerance to prior treatment with at least one and no more than 2 biologic TNFa inhibitors ((e.g., infliximab, etanercept, adalimumab, golimumab, or certolizumab, or biosimilar equivalent) and, in the opinion of the investigator, any of the following (which must be documented in the eCRF): o Experienced insufficient efficacy or loss of efficacy at a dose and duration that, in accordance with local clinical practice, is considered acceptable to adequately evaluate clinical response o Experienced intolerance to such treatment • May also have been exposed to no more than a non-TNFa inhibitory biologic agent (e.g., abatacept, tocilizumab, sarilumab, sirukumab, anakinra, or any biologic agent or biosimilar equivalent with the same mode of action as the listed agents, including investigational biosimilar agents) Exclusion criteria

[0524] Patients who met the following criteria were excluded from the study: • History or current inflammatory joint disease other than RA or other systemic autoimmune disorder • Systemic involvement secondary to RA leading to clinically significant organ dysfunction or increased risk of study participation, according to the investigator • Functional class IV, of according to revised criteria for global performance status in rheumatoid arthritis from ACR 1991 • Major surgery, including bone / joint surgery (e.g., joint fusion) within 8 weeks before screening or planned joint surgery within 12 weeks after randomization • Previous treatment with fenebrutinib or other BTK inhibitors • History of treatment with cell-depleting therapy, including B-cell-depleting therapy (e.g., anti-CD20 targeted therapy such as rituximab) • History of treatment with any non-TNF-inhibiting biologic DMARD (e.g., anti-CD20 targeted therapy, anti-IL6 targeted therapy, or T-cell targeted therapy, including biosimilar equivalents • Any condition or medication that precludes use or is contraindicated with MTX or acid leaflet, according to the local prescription label or the investigator QRQQnn / l 7Π7 / Β / Υ • History of treatment with tofacitinib or other Janus kinase (JAK) inhibitors • Prior to randomization, all biological treatments must have been discontinued as follows: Etanercept and etanercept biosimilar agents for > 2 weeks. All other biological agents (including biosimilars and investigational biosimilars of approved agents) for > 28 days • Prior exposure to any investigational agent (not including investigational biosimilars to approved treatments) within 12 weeks or 5 half-lives of the investigational agent, whichever is longer, before randomization • Previous treatment within 6 months of randomization with IV gamma globulin or the Prosorba column • History of treatment with alkylating agents such as cyclophosphamide or chlorambucil or with total lymphoid irradiation • Require any 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 · immunosorbent column · IV, intramuscular or intra-articular spheroids · leflunomide · mycophenolate mofetil · mycophenolic acid sodium · oral anticoagulants, including, but not limited to, warfarin, dabigatran, rivaroxaban, apixaban · antiplatelet agents, such as clopidogrel ( note: NSAIDs and low-dose aspirin are acceptable) · 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 · all biosimilar agents) • Current treatment with corticosteroids at doses > 10 mg / day prednisone (or equivalent) or intra-articular or parenteral corticosteroids within 4 weeks before and during screening • History of vaccination live attenuated within 6 weeks prior to randomization or requirement to receive these vaccines at any time during treatment with study drug. Seasonal influenza and H1N1 influenza vaccines are permitted if inactivated vaccine formulations are administered. • Evidence of serious concomitant uncontrolled cardiac, neurological, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including diabetes mellitus), metabolic, or gastrointestinal disease that, in the opinion of the investigator, would preclude patient participation • Patients who meet the New York Heart Association class III and class IV criteria for congestive heart failure: Class III: Patients with marked activity limitation; They are comfortable only when they rest. Class IV: Patients who must be at complete rest, confined to bed or a chair; any physical activity causes discomfort and symptoms appear when they rest • 12-lead ECG screening that demonstrates clinically relevant abnormalities that may affect patient safety or interpretation of study results, including corrected QT interval QRQonn / i ζηζ / Ε / γ using the Fridericia formula (QTcF) > 440 ms demonstrated by at least two ECGs > 30 minutes apart • History of ventricular arrhythmias or risk factors for ventricular arrhythmias, such as long QT syndrome and other generic risk factors (eg, Brugada syndrome), structural heart disease (eg, severe left ventricular systolic dysfunction, severe left ventricular hypertrophy), coronary heart disease (CHD; symptomatic, or with diagnostic test-confirmed ischemia, graft of anterior coronary artery bypass grafting or coronary lesions in > 70% diameter stenosis that cannot or have not been revascularized), clinically significant electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or cardiac ion channel mutations (eg, congenital long QT syndrome) • Current treatment with drugs known to prolong the QT interval at doses that have a clinically relevant effect on QT, as determined by the investigator. The researcher may contact the Sponsor to confirm if necessary. • Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flare-ups are usually treated with oral or parenteral corticosteroids • History of vasculitis • Current liver disease that is clinically significant according to the investigator • Evidence of surface antigen serology chronic and / or active hepatitis B or C positive hepatitis B (HBsAg) or hepatitis C (regardless of treatment status), positive hepatitis B core antibody (HBcAb) • Abnormalities in liver synthetic function tests (eg, prothrombin, INR, PTT, albumin) that are believed by the Investigator to be clinically significant • History of alcohol, drug, or chemical use within the 12 months prior to screening as determined by the Investigator • History of pancreatitis not related to gallstones or chronic pancreatitis considered clinically significant by the investigator (for example, unexplained upper abdominal pain or malabsorptive diarrhea) • Any known active infection (except fungal nail infections or oral herpes) • History of bacterial infections, recurrent viral, mycobacterial, or fungal infections (defined as >2 similar episodes requiring antimicrobial treatment within the previous 12 months), with the exception of recurrent oral or genital herpes (HSV1 / HSV2) • Any history of opportunistic infections deemed by the Investigator or Sponsor that raises safety concerns in terms of patient participation in the study • Any major episode of infection requiring hospitalization or IV antimicrobial treatment QRQQnn / l 7Π7 / Β / Υ within 8 weeks before and during screening or treatment with oral antimicrobials within 2 weeks before and during screening. Antimicrobials include antifungal, antibacterial, and antiviral agents. • History or active presence of primary or secondary immunodeficiency, including known history of HIV infection • History of cancer, including solid tumors and hematologic malignancies, within 10 years prior to screening; Basal or squamous cell carcinoma of the skin that was removed and considered cured and carcinoma in situ of the cervix treated with apparent success by curative treatment >1 year before screening are not exclusive. • Pregnant, lactating (breastfeeding), or planning to become pregnant during the study or within 60 days after the end of the study • For women of childbearing potential (including those with tubal ligation): Positive serum pregnancy test at screening or day 1; A serum pregnancy test is needed on day 1 ONLY if the urine pregnancy test is positive (see Annex 8 for definition of of childbearing potential). • Neuropathies or other pain conditions that may interfere with pain assessment at the discretion of the investigator · Need for systemic anticoagulation with warfarin, other oral or injectable anticoagulants, or antiplatelet agents other than NSAIDs, aspirin, or other salicylates. Aspirin is permitted at doses up to 162 mg QD. • History of hospitalization or transfusion for Gl hemorrhage • History of CV accident (CVA) within 10 years, any history of hemorrhagic stroke, history of spontaneous intracranial hemorrhage, or history of traumatic intracranial hemorrhage within 10 years • Known bleeding diathesis • Any condition that possibly affects the absorption of oral drugs (for example, gastrectomy, clinically significant diabetic gastroenteropathy, 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 excluded • Any uncontrolled clinically significant laboratory abnormality that would affect safety, interpretation of study data, or patient participation in the study • The following criteria Exclusion criteria are based on screening laboratory tests. Laboratory tests may be repeated once during the screening period unless otherwise indicated (see Section 4.5.1.1): o Creatinine >1.5 times ULN (can be repeated if 1.5-2 χ ULN) o ALT or AST >1.5 times ULN (can be repeated if 1.5-3 x ULN) o Total bilirubin >ULN (can be repeated if is 1 -3 x ULN) QRQonn / i ζηζ / Ε / γ o Hemoglobin <8.5 g / dL (can be repeated if 7-8.4 g / dL) or ANC <1.5 χ 109 / L (can be repeated if 1.2-1.5 x 109 / L) o Platelet count <100 x 109 / L (can be repeated if 80-100 x 109 / L) or IgG <500 mg / dL (should not be repeated). History of treatment with a non-TNF-inhibiting biologic agent against RA, including anti-IL6-targeted therapy (e.g., tocilizumab, sarilumab, sirukumab), anti-IL1-targeted therapy (e.g., anakinra), or T-cell-targeted therapy (e.g. for example, abatacept), including biosimilar equivalents • History of treatment with any TNF inhibitor (for example, infliximab, etanercept, ADA, golimumab, or certolizumab), including biosimilar equivalents and approved investigational biosimilar agents • Any condition that is a contraindication to the treatment with ADA according to the approved local label • History of anaphylactic or other serious allergic reaction to ADA. Clinical evaluations

[0525] Efficacy assessments included self-questionnaires prior to completion of non-PRO assessments and prior to administration of study treatment. Except for the visit on day 28, the sequence of evaluations where effectiveness is evaluated were standardized as follows:

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

[0527] Laboratory samples for safety, efficacy, biomarkers, and pharmacokinetics should be collected after patient self-assessments are completed (except where specified).

[0528] Biomarkers were assessed in serum or plasma samples at baseline and at weeks 1, 4, and 12 in patients with available samples (cohort 1: n=438; cohort 2: n=86). The biomarkers evaluated in this evaluation were chemokine ligand 4 (CCL4) [C-C motif], IL-6, and TNF-like cytokine 1A (TL1A). Total levels of IgM, IgG, rheumatoid factor (RF) IgM autoantibody, CCL4, TL1A, IL-6, and anti-CCP autoantibody (ACPA IgG) were analyzed with immunoassays. CD19+ B cells and CD3+ T cells were analyzed by flow cytometry. The proportion of patients achieving an ACR50 response at week 12 and change in DAS28 score at week 12 were assessed with respect to seropositivity (RF and / or ACPA positive at baseline) or baseline RF levels in both cohorts. . To select which biomarkers to evaluate in this trial, BTK-dependent myeloid biomarkers were identified using peripheral blood CD14* monocytes stimulated with immune complexes in the presence or absence of BTK inhibitor. Briefly, gene expression levels in human monocytes were assessed under unstimulated conditions; with human serum albumin immune complex stimulation; with stimulation and a low concentration of a BTK inhibitor with characteristics similar to fenebrutinib; or with stimulation and a high concentration of the QRQQnn / l 7A7 / R / Y BTK inhibitor. Genes were screened for upregulation by immune complex stimulation of at least 2-fold, followed by subsequent knockdown by BTK inhibitor ICgo concentration of at least 1.5-fold. Genes with cytokine activity were selected. A heat map reflecting gene expression is provided in Figure 32. The colored bar represents normalized gene expression.

[0529] Investigator-conducted assessments: joint counts and clinician's global assessment of arthritis visual analog scale (VAS), safety assessments (adverse events, vital signs, concomitant medications, review of laboratory data). For cohort 1 only: injection of comparator drugs SC; for cohorts 1 and 2: study drug administered orally.

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

[0531] The DAS 28 is calculated according to the following formulas: DAS 28(4)-ESR = 0.56 x SQRT(TJC28) + 0.28SQRT(SJC28) + 0.70 x In(ESR) + 0.014 x PtGA DAS 28(4)-CRP = 0.56 x SQRT(TJC28) + 0.28SQRT(SJC28) + 0.36 x ln(CRP + 1) + 0.014 xPtGA + 0.96 • Total score: range, 0.49-9.07 • Disease remission < 2.6 • Disease activity: Low < 3.2; moderate d> 3.2 and <5.1; high > 5.1 (PtGA = patient global assessment of disease activity; In = natural logarithm; SQRT = square root)

[0532] ACR Evaluations. The ACR definition for calculating improvement in RA (ACR20) is calculated as a 20% improvement in tender and swollen joint counts and a 20% improvement in 3 out of 5 measurements of the remaining set of ACR-scores: evaluations global patient and doctor, pain, disability and acute phase reaction. Similarly, ACR50 and ACR70 are calculated with respective improvement percentages. Sponsor, based on the component parts, will calculate the ACR score.

[0533] The specific components of the ACR assessments used in this study are as follows: tender / painful joint count (68), swollen joint count (66), patient assessment of arthritis pain, global assessment of arthritis patient, Physician Global Assessment of Arthritis, CRPyHAQ-DI.

[0534] Swollen and tender / painful joint count: An evaluation of 66 joints was performed to determine swelling and 68 joints to determine tenderness. The joints were evaluated and QRQonn / i ζηζ / Ε / γ classified as inflamed / non-inflamed and tender / non-tender by pressure and manipulation of the joints on physical examinations. Joint prosthesis or arthrodesis or fused joints are not taken into account when determining swelling or tenderness. The response to pressure / motion at each joint was assessed using the following scale: present, absent, or not performed. The 68 joints evaluated for tenderness / pain were as follows: • Upper part: temporomandibular, sternoclavicular, acromioclavicular • Upper extremity. Shoulder, elbow, wrist (includes radiocarpal, carpal and carpometacarpal considered as a unit), metacarpophalangeal (MCPI, II, III, IV, V), interphalangeal of the thumb, proximal interphalangeal (PIPII, III, IV, V), distal interphalangeal ( DIP II, III, IV, V) • Lower extremity. Hip, knee, ankle, tarsus (includes subtalar, transverse tarsus and tarsometatarsal considered as a unit), metatarsophalangeal (MTP I, II, III, IV, V), interphalangeal of the big toe, PIP (PIP II, III, IV, V)

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

[0536] Data were collected for physician-reported and patient-reported outcomes PRO (patient assessment of arthritis pain, patient global assessment of arthritis, HAQ-DI, SF-36v2, and FACIT scale-fatigue and ClinRO (Physician Global Assessment of Arthritis) questionnaires and were completed at the specified time points of the study (i.e., weeks 1, 2, 6, 4, 8,10, and 12).

[0537] Demographic and baseline characteristics of patients in both cohorts are presented in Figures 30A-30B-2. Results

[0538] The results of the study are presented in Tables 1 and 2 below: QRQQnn / l 7Π7 / Β / Υ Table 1: ACR50 endpoint at week 12 (cohort 1) Parameter·: (N=iO9} lOOm·? SID (N=llΰ) fS=110) ΑΣ5Α (51=111} week 12 day 84 n 4$ responders 7 (37.5% j 95% of C. k :5.72, 25.28) 165 30 (27.5%) (19.14, 35.91} 38 (34.5%) (25.66, 41.43) 110 (7.95, 21.13) í 27.10, 44« 97$ weighted difference compared to pJace^o s. so 95% 0© C. L of weighted difference --5.54, 21.54) va-or p v.iM.d 12.93 (2.37, 23.48) •3.15154 (9.21, 3Ü.79) 0.0003 t10.61 . 32.62} ί'.ΟΰΟΙ

[0539] Table 1 shows that the study met its primary ACR50 endpoint in both the 150 mg QD as in the 200 mg BID of cohort 1 and that the results were statistically and clinically significant. The maximum difference in ACR50 response rates was 2.0% (150 mg QD). Table 2; ACR50 Endpoint at Week 12 (Cohort 2) QRQonn / i ζηζ / Ε / γ Parameter.’ acksb week 12 day 84 n respondents ^55 of C. í. 8 5δ pS.3%) £ (12.0%} (12.75, 37.25) (2.95, 21.01} weighted difference in comparison with placebo 13.8S 95% of C J. of weighted difference (-6.86, 28.55} p value 0.0650

[0540] Table 2 shows that the study met its primary ACR50 endpoint in cohort 2 and that the results were statistically and clinically significant. The maximum difference in ACR50 response rates was 2.0% (150 mg QD).

[0541] The secondary efficacy endpoint of ACR50 over time for cohort 1 showed a dose-response relationship at week 8 and week 12. See Figure 1. ACR50 response rates for cohort 2 appear stabilized starting at week 8, and the endpoint was achieved at weeks 2, 8, and 12. See Figure 2. Figure 3 represents the percentage of patients achieving an ACR 20 / 50 / 70 response in the visit by treatment compared to non-responders. The responses of ACR20 and 70 are also summarized in Figures 24A and 24B. Clinically meaningful improvements were observed with fenebrutinib compared to placebo for other secondary outcomes in both cohorts, including DAS28-ESR, CDAI, SDAI, and DAS low disease activity at week 12. Primary efficacy endpoint responses and secondary at week 12 are summarized in Figures 31A-31B-2. Results for the comparison of fenebrutinib with placebo and adalimumab for other secondary and exploratory outcomes showed comparable benefit for 200 mg twice daily of fenebrutinib and adalimumab at week 12; these outcomes included ACR20, ACR70, DAS28-ESR, Boolean remission, quality of life assessments, and individual components of the ACR response rate. See Figures 24A - 26C.

[0542] The outcomes of each cohort as measured by ACR HAQ-DI score parameters, total tender joint counts (TJC), total swollen joint counts (SJC), patient general assessment (GA), general assessment (GA ) of the doctor and the patient's pain, all shown over time, are presented in Figure 4 - Figure 15 and in Figures 21C, 25A and 25B.

[0543] Statistically significant DAS28 improvements compared to placebo were observed in each of the fenebrutinib 150 mg QD and 200 mg BID groups of Cohort 1, as measured by the DAS28-3-CRP score shown in Table 3. The fenebrutinib 150 mg QD and 200 mg BID groups showed significant differences compared to placebo starting at week 4. See Figure 16. Table 3 QRQQnn / l 7Π7 / Β / Υ Paraíiwtrc: cas 28-3 (CRPj QD BID PSD ADA (8=11 week 12 n adjusted mean difference (d) 95% of C. i. of difference value p rd O O ¢3-, ir» m r~> F-. , » “ 0 * ÍM 1 1 Éü 9 ¢5 1 57 -1.74 -S .57 Ο.0··3Ο3 Ί* o ¢3 143 1 1 • te O O © tu -λι « I ---1 ííi ω » Μ 152 -L .18 ή! ΰ K-i r-· | o o - o <>1 & λ & 1 1 O ' pd V 7

[0544] Statistically significant DAS28 improvements compared to placebo were observed in the fenebrutinib 200 mg BID group of Cohort 2, as measured by the DAS28-3-CRP score shown in Table 4. The group of fenebrutinib showed significant differences compared to placebo starting at week 2. See Figure 17. Table 4 Parameter: sas 23-3 week 12 S 47 44 adjusted mean -i,»® -1.2® óifer^ncja ss«d© C. i value s .Be difference (-1.14, -3.37$

[0545] Clinically and statistically significant reductions in CRP compared to baseline at week 8 were observed in the fenebrutinib 200 mg BID arm of Cohort 1 (59% CRP BL at week 8 and week 12). Cohort 2 also showed reduced CRP levels at week 8 and week 12 in the fenebrutinib group. See Figure 18 and Figure 25D.

[0546] Clinically and statistically significant reductions in ESR compared to baseline were observed at week 12 in the fenebrutinib 200 mg BID arm of Cohort 1 (63% ESR BL at week 12). Cohort 1 also showed reduced ESR levels at weeks 2, 4, and 8 in the fenebrutinib group. Cohort 2 showed reduced ESR levels at week 8 and week 12 in the fenebrutinib group. See Figure 19 and Figure 25C.

[0547] The CCL4 myeloid-enriched biomarker was reduced in all fenebrutinib treatment groups of Cohort 1 relative to placebo beginning at week 2 as shown in Table 5. Similar results were observed in Cohort 2. Table 5: CCL4 reduction as initial % QRQQnn / l 7Π7 / Β / Υ Fenebrutinib 50 mg QD 150 mg Fenebrutinib QD 200 mg Fenebrutinib BID Placebo ADA Week 2 78%* 73%* 71%* 98% 66%* Week 4 84%* 79%* 74%* 93% 65%* Week 12 78%* 86%* 76%* 94% 63%* indicates statistically significant result.

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

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

[0550] Total IgM was reduced in all fenebrutinib treatment groups of cohort 1 relative to placebo and ADA treatment, starting at week 4 as shown in Table 6. Table 6: Total IgM reduction as initial % Fenebrutinib 50 mg QD 150 mg fenebrutinib QD 200 mg fenebrutinib BID Placebo ADA Week 4 94% 91%* 92%* 98% 100% Week 8 91%* 88%* 86%* 98% 100% Week 12 88% * 86%* 84%* 100% 103% indicates statistically significant result.

[0551] Total IgG was reduced in the medium to high dose fenebrutinib treatment groups of cohort 1 relative to placebo and ADA treatment, starting at week 4 as shown in Table 7. Table 7: Total IgG reduction as initial % Fenebrutinib 150 mg QD Fenebrutinib 200 mg BID Placebo ADA Week 4 977o* 957o* 1007o 1007o Week 8 94%* 92%* 997o 1057o Week 12 957o* 93%* 1017o 1077o * indicates statistically significant result. QRQQnn / l 7Π7 / Β / Υ

[0552] Rheumatoid factor (RF) IgM autoantibody levels were significantly reduced by fenebrutinib treatment at week 12 (66% in the 150 mg QD group; 64% in the 200 mg BID group; 92% in placebo). The largest reductions in total IgM, IgG, and RF IgM were observed in the fenebrutinib 200 mg twice daily groups in Cohorts 1 and 2. In Cohort 1, treatment with fenebrutinib 200 mg twice daily resulted in a median reduction of -29% RF IgM relative to placebo at week 12. Absolute reductions in immunoglobulin levels were -22 mg / dL for total IgM and -115 mg / dL for IgG with fenebrutinib 200 mg twice daily relative to placebo at week 12 in cohort 1. At week 12, patients in cohort 2 treated with fenebrutinib 200 mg twice daily had similar reductions in IgM and IgG totals (-17 and -101 mg / dL, respectively, with respect to placebo). Total IgM, IgG, and RF IgM are also summarized in Figures 22A-22B and 27. Treatment with adalimumab (cohort 1) reduced RF IgM levels by -20% compared to placebo at week 12 (Figure 22B, left), but did not reduce total IgM or IgG levels (Figure 22A). ACPA IgG levels tended to decrease with fenebrutinib treatment, but did not change significantly compared to placebo in cohort 1 (Figure 22B, right). In contrast, at week 12, ACPA IgG levels were reduced by -24% with fenebrutinib 200 mg twice daily compared to +15% in the placebo group in cohort 2 (Figure 27).

[0553] The B cell chemokine CXCL13 was reduced in all fenebrutinib treatment groups of cohort 1 relative to placebo beginning at week 4 as shown in Table 8. Similar results were observed in cohort 2. Table 8: CXCL13 reduction as initial % Fenebrutinib 50 mg QD 150 mg Fenebrutinib QD 200 mg Fenebrutinib BID Placebo ADA Week 4 637o* 657o* 677o* 907o 497o* Week 12 627o* 587o* 627o* 847o 467o* * indicates statistically significant result.

[0554] The percentage change in CD19 B cells and CD3 T cells compared to baseline is shown in Figures 23C and 23D, respectively, for cohort 1 and in Figures 28C and 28D, respectively, for cohort 2 ( for all figures, significance compared to placebo is indicated by *). At week 1, there was a transient increase in peripheral CD19- B cells in fenebrutinib-treated groups (45-79% compared to placebo) in cohort 1 and cohort 2, and levels returned to pre-treatment ranges. at week 12 (-4-13% compared to placebo). CD3+ T cells were numerically higher at week 1 following treatment with fenebrutinib compared to placebo (+10-15%) in cohort 1 and cohort 2.

[0555] With respect to screening for seropositive status, Higher baseline RF levels were associated with an increase in the proportion of ACR50 responders in the fenebrutinib 200 mg twice daily group in both cohorts. See Figures 29A-28B.

[0556] While the overall safety profile of fenenbrutinib in this study was comparable to placebo and ADA, there were more numerical grade 3 LFT increases in the fenebrutinib groups. The result suggests that monitoring liver function in patients receiving fenebrutinib may be justified.

[0557] Dose simulations based on the patient population of this study indicated a potential optimal fenebrutinib dose range of 200-400 mg QD or 100-200 mg BID. In addition to the doses analyzed in this study, a dose of 200 mg QD or 100 mg BID may be appropriate.

[0558] Overall, this study demonstrated that fenebrutinib treatment helped patients with moderate to severe RA compared to placebo. Significant improvements in clinical responses were observed in methotrexate-resistant patients receiving fenebrutinib compared to those receiving placebo, as reflected by ACR50 scores at week 12. Treatment with fenebrutinib resulted in improved treatment outcomes compared to placebo in patients who had previously had unsuccessful treatment with a TNF inhibitor.

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

[0560] Reductions in autoantibodies indicate that fenebrutinib may affect autoreactive B cells; 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 results in a transient increase in the number of peripheral B cells, followed by an inhibitory effect on peripheral B cells. B as supported by subsequent increases in the level of autoantibodies.

[0561] Without being limited to theory, the efficacy results of this study may reflect the direct effect of BTK inhibition on the development and proliferation of autoreactive B lymphocytes, a reduction of the underlying inflammatory pathology in rheumatoid arthritis mediated the effect of BTK inhibition on myeloid cells, or a combination of both mechanisms. EXAMPLE 2 A PHASE II, MULTICENTRIC, RANDOMIZED, DOUBLE-BLIND PILOT-CONTROLLED STUDY QRQQnn / l 7Π7 / Β / Υ PLACEBO AND DOSE VARIATION OF FENEBRUTINIB IN PATIENTS WITH RESISTANT CHRONIC SPONTANEOUS URTICARIA (CSU)

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

[0563] The study consists of two cohorts. The primary objective of Cohort 1 of this study was to evaluate the efficacy of orally administered fenebrutinib 200 mg BID compared to placebo as add-on therapy for CSU patients who were symptomatic despite H1-antihistamine therapy.

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

[0565] The secondary efficacy objectives of this study were as follows: • Assess the proportion of well-controlled patients (UAS7 < 6) at day 57. • Assess the change from baseline in UAS7 on day 29 (week 4).

[0566] The exploratory efficacy objectives of this study were as follows: • Change from baseline in weekly itch score at day 29 • Change from baseline in weekly itch score at day 57 • Change from baseline in weekly wheal score at day 57 • Proportion of well-controlled patients (UAS7 < 6) at day 29 • Proportion of patients achieving a complete response (UAS7 = 0) at day 29 • Proportion of patients achieving a complete response (UAS7 = 0) at day 57 • Proportion of patients achieving MID on UAS7 at day 57 (>11 point reduction from baseline) • Proportion of patients achieving MID on weekly itch score at day 57 (>5 point reduction from baseline) • Time to achieve MID in UAS7 (reduction from baseline > 11 points) • Time to achieve MID in weekly itch score (reduction from baseline > 5 points) • Number of angioedema episodes • Use of rescue medication • Change from Baseline in UCT Score at Day 57 QRQQnn / l 7Π7 / Β / Υ

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

[0568] The pharmacokinetic objective of this study is to characterize the pharmacokinetics of fenebrutinib in patients by measuring plasma concentrations at specified time points. Exploratory PK endpoints included the relationship between drug exposure measurements and fenebrutinib pharmacodynamic effects, efficacy, and safety; the impact of selected covariates on measures of exposure and / or response to fenebrutinib; and the impact of genetic polymorphisms on fenebrutinib exposure measurements.

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

[0570] This pilot and dose-ranging study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to determine the efficacy and safety of fenebrutinib as an adjunctive treatment for adult patients aged 18-75 years diagnosed with CSU and symptomatic despite treatment with H1 antihistamines (including doses up to 4 times the dose approved by local treatment guidelines). The study consists of two cohorts. In cohort 1, 41 patients from multiple sites were enrolled. After screening, eligible patients were randomly assigned in a -2:1 ratio to receive fenebrutinib at 200 mg orally (PO) twice daily (BID) (n=28) or matched placebo (n=13). ) for 8 weeks and maintained stable treatment doses with reference H1 antihistamines in the study. In a dose-varying cohort, Cohort 2, approximately 120 patients were enrolled and randomly assigned in a 1:1:1:1 ratio to receive 50 mg PO per day (QD), 150 mg PO QD, 200 mg PO BID of GDC-0853, or placebo, respectively, for 8 weeks while maintaining stable doses of study baseline H1 antihistamine treatment.

[0571] Both cohorts consist of three study periods over 14 weeks: (i) a screening period (day 14 to day -1), (i) a treatment period [day 1 to day 57 (week 0 to week 8)] and (iii) a follow-up period [day 57 to day 85 (week 8 to week 12)].

[0572] Patients in both cohorts have a screening period of approximately 2 weeks to establish their study eligibility and baseline symptom scores. During the screening period, patients should maintain stable doses of their prescreening cotreatment with reference H1 antihistamines (i.e., up to 4 times the dose approved by local treatment guidelines). The screening period will consist of visits on day -14 and day-7. Patients must meet all of the following criteria to enter the screening period: • Documented treatment with a regimen that includes reference H1 antihistamines for CSU in the QRQQnn / l 7Π7 / Β / Υ day -14 and for at least 3 consecutive days immediately preceding day -14 • Willingness and ability to complete an electronic symptom diary (electronic urticaria patient diary) twice daily during screening period to establish the patient's 7-day urticaria activity score (LIAS7).

[0573] To be eligible for randomization in both cohorts, during the 7 days prior to randomization, patients must have 7 consecutive days of electronic patient diary entries with urticaria and a UAS7 score of > 16 (range: 0 - 42).

[0574] The primary efficacy endpoint was measured at week 8 (day 57). Patients must have maintained stable doses of their pre-randomization H1 antihistamine treatment throughout the treatment period. After completing the 8-week treatment period, all patients in both cohorts entered a 4-week safety follow-up period in which no fenebrutinib treatment was administered as patients maintained stable doses of their treatment with fenebrutinib. H1 antihistamine prior to randomization.

[0575] During the study, patients were able to receive a single dose of loratadine (maximum 10 mg) or cetirizine (maximum 10 mg) within a 24-hour period as a rescue medication if symptoms worsened. If rescue treatment is required, it should not exceed 4 times the dose approved by local treatment guidelines. Patients receiving 4 times the approved background dose should receive the alternative rescue medication. Patients should record the use of this medication in their electronic diary. Inclusion criteria

[0576] Patients must meet the following criteria for study entry: • Willingness to provide written informed consent, adhere to visit schedules, comply with study drug regimen, and comply with other study requirements • Age: 18-75 years, inclusive • Diagnosis of CSU resistant to H1 antihistamines at time of enrollment randomization, as defined by all of the following parameters: Presence of itching and hives for > 6 consecutive weeks at any time before enrollment, despite current use of H1 antihistamines, consistent with standard of care (i.e., up to 4 times the dose approved by local treatment guidelines) during this period of time UAS7 score > 16 during the 7 days before randomization (day 1) Patients must have received stable daily doses of H1-antihistamines, consistent with standard treatment for CSU beginning at least 3 consecutive days immediately prior to the screening visit through Day 1 and must document current use at all visits. Diagnosis of CSU for > 6 months • Willingness and ability to complete an electronic urticaria patient diary during the study QRQQnn / l 7Π7 / Β / Υ • Complete 7 days of urticaria patient electronic diary entries within 7 days prior to randomization • No evidence of active, latent, or inadequately treated tuberculosis (TB) infection, as defined defined as follows: A negative Quant¡FERON-TB-Gold® (QFT) test (for Germany only: QFT is the preferred test) at the screening visit or within 3 months prior to screening If QFT is not available, a negative Mantoux purified protein derivative (PPD) skin test as defined by Centers for Disease Control and Prevention guidelines may be performed at the screening visit or within 3 months prior to screening, AND • Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should be screened with QFT only. An undetermined QFT test must be repeated. One positive QFT test or two consecutive undetermined QFT results should be considered a positive diagnostic TB test. An undetermined QFT followed by a negative QFT should be considered a negative diagnostic TB test. • For women of childbearing potential (including those who have had their tubes ligated): Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 4 weeks after the last dose of study drug. • For men: agree to remain abstinent (refrain from heterosexual intercourse) or use birth control and agree to refrain from donating sperm. Exclusion criteria

[0577] Patients meeting any of the following criteria were excluded from study entry: • Treatment with omalizumab or other monoclonal antibody therapies used to treat CSU within 4 months prior to screening or no primary response to omalizumab • Use of an investigational nonbiologic drug or participation in an investigational study with a nonbiologic drug within 30 days prior to study drug administration on Day 1 (or within 5 half-lives of the investigational product, whichever is longer) • Use of an investigational biologic treatment or participation in an investigational study with a biologic treatment within of 90 days or 5 half-lives, whichever is longer, prior to study drug administration on Day 1 • Prior treatment with fenebrutinib or other BTK inhibitors • Patients whose urticaria is due to physical urticaria alone QRQonn / i ζηζ / Ε / γ • Other diseases with symptoms of urticaria or angioedema, including urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma or leukemia • Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis or other disease associated with itching, such as psoriasis • Routine doses (daily or every other day for 5 consecutive days or more) of the following medications within 30 days before screening: systemic or cutaneous (topical) corticosteroids (prescription or over-the-counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide • Previous use of IV steroids for the treatment of laryngeal angioedema • IVIG or plasmapheresis within 30 days before screening • History of anaphylactic shock without a clearly identified preventable antigen (e.g. , due to food allergy) • Hypersensitivity to fenebrutinib or any component of the formulation • Major surgery within 8 weeks before screening or planned surgery before completion of the study (12 weeks after randomization) • Need for any medication prohibited concomitant: Systemic or cutaneous (topical) corticosteroids (prescription or over-the-counter), hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide within 30 days before screening if used routinely (daily or every other day for 5 consecutive days or further) Doxepin within 30 days before screening Omalizumab or other monoclonal antibody treatments used to treat CSU within 4 months before screening IVIG within 30 days before screening Plasmapheresis within 30 days before screening LTRA within 1 day prior to screening Astemizole, terfenadine, and ebastine within 1 day prior to screening • History of live attenuated vaccine within 6 weeks prior to randomization or requirement to receive these vaccines at any time during treatment with study drug. Seasonal flu and H1N1 flu vaccines are allowed if the inactivated vaccine formulation is administered. • Evidence of clinically significant cardiac, neurological, psychiatric, pulmonary, renal, hepatic, endocrine (including uncontrolled diabetes mellitus), metabolic or Gl disease that, in the opinion of the investigator, would compromise patient safety, interfere with interpretation of results of the study or otherwise it would prevent the patient's participation Any element that generates uncertainty must be reviewed with the Medical Monitor. QRQonn / i ζηζ / Ε / γ • Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, where flares are usually treated with oral or parenteral corticosteroids • History of vasculitis • Current liver disease • Any known active infection (except of fungal nail infections or oral herpes) • History of recurrent bacterial, viral, mycobacterial or fungal infections (defined as > 2 similar episodes requiring antimicrobial treatment within the previous 12 months), with the exception of recurrent oral or genital herpes ( herpes simplex virus 1 / herpes simplex virus 2) or uncomplicated urinary tract infections in women. • Any history of opportunistic infections that the Investigator or Sponsor believes raises safety concerns regarding the patient's participation in the study • Any major episode of infection requiring hospitalization or IV antimicrobial treatment within 8 weeks before and during the screening or treatment with oral antimicrobials within 2 weeks before and during screening. Antimicrobials include antifungal, antibacterial, and antiviral agents. • History or active presence of primary or secondary immunodeficiency, including known history of HIV infection • Evidence of chronic and / or active hepatitis B or C Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless of treatment status) Hepatitis B core antibody (HBcAb) positive • History of cancer, including solid tumors and hematologic malignancies, within 10 years before screening Basal or squamous cell carcinoma of the skin that was removed and considered cured and carcinoma in situ of the cervix treated with apparent success by curative treatment > 1 year before screening are not exclusive. • Pregnant, lactating women, or who plan to become pregnant during the study or within 4 weeks after completing the study • For women of childbearing potential (including those with tubal ligation): positive serum pregnancy test at screening or day 1. • History of alcohol, drug (e.g., tetrahydrocannabinol, marijuana), or chemical substance use within 12 months prior to screening as determined by the investigator • Need for systemic anticoagulation with warfarin, other oral or injectable anticoagulants, or antiplatelet agents other than NSAIDs, aspirin, or other salicylates QRQonn / i ζηζ / Ε / γ • History of pancreatitis not related to gallstones or chronic pancreatitis • History of hospitalization or transfusion for Gl hemorrhage • History of cerebrovascular accident (CVA) within 10 years or, any history of hemorrhagic stroke • History of spontaneous intracranial hemorrhage or history of traumatic intracranial hemorrhage within 10 years • Known bleeding diathesis • 12-lead ECG screening demonstrating clinically relevant abnormalities that may affect patient safety or interpretation of study results, including interval QT corrected by the Fridericia formula (QTcF) > 440 ms demonstrated by at least two ECGs > 30 minutes apart • History of ventricular arrhythmias or risk factors for ventricular arrhythmias, such as long QT syndrome and other generic risk factors ( for example, Brugada syndrome), structural heart disease (for example, severe left ventricular systolic dysfunction, severe left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia confirmed by a diagnostic test, anterior coronary artery bypass graft, or coronary lesions in > 70% diameter stenoses that cannot or have not been revascularized), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or a family history of sudden unexplained death or cardiac ion channel mutations (e.g. example, congenital long QT syndrome) • Current treatment with medications known to prolong the QT interval (see https: / / crediblemeds.org / index.php / login / dlcheck) at doses that have a clinically relevant effect on QT, as determined by the researcher; the investigator may contact the Sponsor to confirm if necessary • Any condition that possibly affects the absorption of oral drugs (for example, gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery, such as gastric bypass) Not excluded Procedures such as gastric banding that simply divide the stomach into separate chambers. • Any uncontrolled clinically significant laboratory abnormality that would affect safety, interpretation of study data, or patient participation in the study. • The following exclusion criteria are based on screening laboratory tests. Laboratory tests may be repeated once during the screening period unless otherwise indicated: Creatinine > 1.5 times the upper limit of normal (ULN; may be repeated if 1.5-2 x ULN) Creatinine clearance <70 mL / min / 1.73 m2 (can be repeated if 60-69 mL / min / 1.73 m2) as calculated by the Cockcroft-Gault equation QRQonn / i ζηζ / Ε / γ ALT or AST > 1.5 times the ULN (can be repeated if it is 1.5-3 x ULN) Total bilirubin > ULN (can be repeated if 1-3 x ULN) Hemoglobin < 11 g / dL (can be repeated if 10-10.9 g / dL) ANC < 1.5 x 109 / L (can be repeated if 1.2- 1.5 x 109 / L) Platelet count < 100 x 109 / L (can be repeated if 80-100 x 109 / L) IgG < 500 mg / dL (should not be repeated) Abnormalities in tests of hepatic synthesis function (e.g., PT, INR, PTT, albumin) that the investigator believes are clinically significant Clinical evaluations

[0578] The primary efficacy endpoint was the change from baseline in UAS7 at week 8 (day 57). Change in UAS7 (Table 9) is a summary of the average daily scores (am / pm) on the UAS (range: 0 - 6), which is a composite daily score with numerical intensity and severity ratings on a scale of 0 -3 (0 — no to 3 = intense / severe) for two domains: the intensity of itching and the number of hives / hives The patient records the UAS twice a day (morning and evening) in the electronic diary of the patient with urticaria. Table 9: Twice-daily patient assessment of CSU disease activity (UAS scale) QRQQnn / l 7Π7 / Β / Υ Score Wheals Pruritus (itching) 0 No No 1 Mild (1-6 hives / 12 hours) Mild 2 Moderate (7-12 hives / 12 hours) Moderate 3 Severe (> 12 hives / 12 hours) Severe

[0579] Continuous longitudinal efficacy endpoints will be analyzed using a mixed model for repeated measurements (MMRM) and descriptive statistics as appropriate. Additional model covariates will include baseline UAS7 and its interaction with visit. The model will manipulate missing data according to the missing-to-random assumption without the need for imputation.

[0580] Secondary efficacy measurements are as described above in the Study Objectives section of this Example 2 and apply the UAS7 score and the weekly itch score measurement. Weekly itch scores are measured as part of the study urticaria patient's electronic diary.

[0581] Electronic diary of the patient with urticaria Electronic diary of the patient with urticaria General instructions Answer each question as best as possible. There are no right or wrong answers. For each question, choose the answer that describes your experience. Pay attention to the time period of interest. Some questions are about the last 12 hours, while others are about the last 24 hours. Instructions for counting the number of hives and measuring the size of the largest hive Count each hive separately even if you have more than one hive grouped together with other hives. Use the ruler provided to measure the size of your largest welt. If you need help, ask someone to take this measurement for you. Please do not measure a group of hives as one hive. Today's date Day month Year Please complete this section each night throughout the duration of the study. (Please circle only one answer.) 2. Think about the last 12 hours. Please record the severity of the itching and the number of hives you may have in relation to your skin condition. Please count each hive separately even if you have more than one hive grouped together with other hives. Itching (severity) Hives (number) 0 = none 1 = mild 2 = moderate 3 = severe 0 = none 1 = 1 to 6 hives 2 = 7 to 12 hives 3 = more than 12 hives The next question is about calculating the size of your largest welt in centimeters (cm). Use the ruler provided to you to make this measurement. If your largest welt is located on your back or in a place that is difficult to access, please have someone else take these measurements for you. When measuring the size of the largest hive, please do not measure a group of hives as one hive._______________________ Largest welt (size) = none = less than 1.25 centimeters (cm) = between 1.25 centimeters (cm) and 2.5 centimeters (cm) = more than 2.5 centimeters (cm) Today's date Day month Year Please complete this section each morning throughout the duration of the study. (Please circle only one answer.) 1. Think about the last 12 hours. Please record the severity of the itching and the number of hives you may have in relation to your skin condition. Please count each hive separately even if you have more than one hive grouped together with other hives. QKQQnn / l 7Π7 / Β / Υ Itching (severity) Hives (number) 0 = none 1 = mild 2 = moderate 3 = severe 0 = none 1 = 1 to 6 hives 2 = 7 to 12 hives 3 = more than 12 hives The next question is about calculating the size of your largest welt in centimeters (cm). Use the ruler provided to you to make this measurement. If your largest welt is located on your back or in a place that is difficult to access, please have someone else take these measurements for you. When measuring the size of the largest hive, please do not measure a group of hives as one hive.______________________________ Largest welt (size) = none = less than 1.25 centimeters (cm) = between 1.25 centimeters (cm) and 2.5 centimeters (cm) = more than 2.5 centimeters (cm) Today's date - - Day month Year Please complete this section twice daily (am and pm) throughout the duration of the study (preferably at the same time each day). (Please circle only one answer.) 3. Please rate how much your hives or itching interfered with your sleep in the last 24 hours. No interference Mild, little interference with sleep Moderate, wakes occasionally, some interference with sleep Substantial, awake often, serious interference with sleep 4. Please rate how much your hives or itching interfered with your daily activities during the last 24 hours. This could include work, school, sports, hobbies, and activities with friends and family. No interference Mild, little interference with target activities Moderate, some interference with daily activities Substantial, serious interference with daily activities The next questions ask about your symptoms and how you treated them during the last 24 hours. 5. During the last 24 hours, did you use loratadine or cetirizine to control the symptoms of your skin condition such as itching or hives? 0- No = Yes 6a. During the past 24 hours, did you have any sudden swelling in your face (especially your eyelids or lips), in your mouth (including your throat or tongue), or in any other part of your body? This sudden swelling, also called angioedema, is located deeper under your skin than hives. 0-No (GO TO question 7) 1 = Yes 6b. If yes, how did you treat this sudden swelling? (Circle all that apply.) I didn't do anything (GO TO question 7) I took any prescription or non-prescription medication I called my doctor, nurse, or nurse practitioner I went to see my doctor, nurse or nursing professional I went to the emergency room of a hospital I was hospitalized 7. During the past 24 hours, did you or anyone else call your doctor, nurse, or nurse practitioner because of your skin condition? - No 1=Yes QRQQnn / l 7Π7 / Β / Υ Results

[0582] Cohort 1: Fenebrutinib treatment generated early activity (200 mg BID) initiated at week 1, which was maintained through week 8. See Figure 20. The secondary endpoint of UAS7 was achieved at week 4. The primary endpoint of UAS7 was not achieved at week 8, due to a surprisingly high placebo response. See Table 10 and Figure 20.

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

[0584] Patients experienced an improvement in weekly itch severity and weekly wheal scores at week 4 and week 8. See Table 11 and Table 12. Table 10: CSU Cohort 1 Results at Weeks 4 and 8 in UAS7 Efficacy endpoint Placebo (N=13) GDC-0853 200mg (N=28) UAS7 - Change from BL to week 4 Mean (SD) Median Range Treatment difference in LS means, 90¾ Cl, vaior p UAS7 - Change from BL to week 8 Mean (SD) Median Range treatment difference in LS means, 90% C>, p value -8.7 00.7) -21.1(11.3) -7.5 -22.5 -36. 7 -38, 3 -12.5 (-18.9, -6.1) Q.002 i::::: / :::::::: / ::) -19.0(12.5) -21.6(11.8) -16.8 -23.0 -42, -3 -42. 10.7 -4.3 (-11.3,2.7) C.305 Table 11: CSU Cohort 1 Results at Weeks 4 and 8, Weekly Itch Severity Placebo GDC-0853 20mg Efficacy endpoint j (N=13) BSD GnmdMf fie fe p-toaíw sswwl Cassbi® <ies<fe· BU fes® ® sswsa 4 ssss; >5.» 5 (5.4) -4.5 -OJi -18.5.5.5 19.1.5 5.5 (--8.5. -2.(9 9.(553 τιτιίιτίιίί^ΐ^ιτϊβ^Β^τ^τ^τ^τ^^ . .................................................. ...........................:<.................... ............ ...................................... .................................................. ........................... -Ό rs.?3 -8.4 (5.5.1 •83 -9.0 -25, 0 -21.1 g :: A| l i l i -13 H5.W Table 12: CSU Cohort 1 Results at Weeks 4 and 8, Wheal Score QRQQnn / l 7Π7 / Β / Υ weekly Efficacy Endpoint Placebo (N=13) GDC-0853 200mg BID (N=28) Weekly Hive Score - Change from BL to Week 4 25 Mean fSDJ -4.7 (5.9) -11.6 (6.8) Median -14.0 Range -21, 1.5 Treatment difference in LS means, 90% Cl, p value -7.5 (-11.2, -3.7) 0.002 Weekly wheal score - Change from BL to week 8 (7.7) -12.2(7.1) Median sssss®ís8í7s -14.0 Range -21.0 -21.9.7 Dite treatment gum in LS stockings. 90% CL value p -2.8 (-6.9.1.4) 0.269

[0585] As shown in Figure 33 summarizing UAS7 scores over time in patients with negative and positive UC indices, the greatest efficacy in cohort 1 was observed in patients administered fenebrutinib, who also gave positive on the UC index (sample size based on week 8, summarized in the graphs below). The results in Cohort 2 were consistent with this observation, as shown in Figure 34. In each Cohort 2 treatment group, there was greater efficacy (as assessed by UAS7 scores) in patients with positive UC index in compared to patients with negative UC index (UAS7 MID = 9.5-10.5; sample size based on week 4, summarized in the graphs below). Figure 35 summarizes the week 8 weekly itch scores (as treatment difference in LS means) for each treatment group of Cohort 1 and Cohort 2, as all participants and broken down between patients with index UC. positive and negative UC index. Administration of fenebrutinib reduced weekly itch scores in each group, as illustrated by data from all participants, but was particularly effective in patients who tested positive on the UC index. The 50 mg group showed a greater difference in efficacy between UC index positive and UC index negative patients at week 8. Week 8 UAS7 data for each treatment group from both cohorts are summarized in Figure 36 , again as all participants and also as UC index negative (<10) and UC index positive (> / =10) groups (as treatment effect on LS means, 90% CI).

[0586] Some patient samples were also evaluated specifically for anti-FcERI IgG autoantibodies, and the level of those autoantibodies over time in patients administered fenebrutinib compared to patients administered placebo is shown in Figure 37 Serum samples were collected at 0 and 8 weeks from patients receiving fenebrutinib (left) compared to placebo (right), with sample sizes for each group shown. Before direct FcERI immunoassay, samples were split and preincubated with equimolar concentrations of rhFcERI or an unrelated control protein. Reactivity levels were determined relative to a mouse monoclonal antibody standard. IgG anti-FcERI was defined as the difference in reactivity between the split samples, as shown in relative units (RU). The bold lines without markers represent the average number of patients with anti-FcERI positive at baseline. The dotted line represents the mean + 3 standard deviations of healthy volunteer samples. Some sample lines from anti-FcERI IgG negative patients overlap at the lower end of the assay range. Administration of fenebrutinib generated a significant reduction in anti-FcERI IgG autoantibodies. Without wishing to be bound by any theory, it is believed that anti-FcERI may be a driver of positive results in UC index testing, and is associated with resistant CSU. As shown in Figure 38, patients who tested positive for anti-FcERI autoantibodies generally showed a greater reduction in UAS7 over time when administered fenebrutinib at any dose in cohort 2, compared to patients who tested negative for anti-FcERI autoantibodies. anti-FcERI autoantibodies. EXAMPLE 3 A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO DETERMINE THE SAFETY AND EFFICACY OF FENEBRUTINIB IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE DISSEMINATED LUPUS ERYTHEMATOSUS

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

[0588] The primary efficacy objective of this study was to evaluate the efficacy of fenebrutinib at three dose levels compared to placebo used in combination with SOC in patients with moderately to active SLE. Severe QRQQnn / l 7Π7 / Β / Υ as measured by SRI-4 response at week 48.

[0589] The secondary efficacy objectives of this study were as follows: • Assess the clinical efficacy of fenebrutinib over time using SRI-4 as a measure of standardized disease activity: SRI-4 response at week 48 with sustained oral corticosteroid (OCS) dose reduction to < 10 mg / day and < day 1 dose during week 36 through week 48 SRI-4 response at week 24 with sustained OCS dose reduction to < 10 mg / day and < day 1 dose during week 12 through week 24 SRI-4 response at week 24 • To evaluate whether patients with high plasmablast signature levels have an improved clinical response to fenebrutinib relative to patients with low levels: SRI-4 response at week 48 SRI-4 response at week 48 with sustained OCS dose reduction to < 10 mg / day and < day 1 dose during week 36 through week 48 • Evaluate the clinical efficacy of fenebrutinib over time using BILAG-based Composite Lupus Assessment (BICLA) and SRI-6 as standardized disease activity measures: SRI-6 response at weeks 24 and 48 BICLA response in weeks 24 and 48

[0590] The exploratory efficacy objectives of this study were to evaluate the clinical efficacy of fenebrutinib over time with multiple standardized disease activity measures: • SRI-5, 7 and 8 response at week 48 • SRI-5-8 response at week 48 with sustained OCS dose reduction to < 10 mg / day and < day 1 dose during week 36 through week week 48 • Response SRI-5, 7 and 8 in week 24. • SRI-5-8 response at week 24 with sustained OCS dose reduction to < 10 mg / day and < day 1 dose during week 12 through week 24

[0591] Additional exploratory efficacy endpoints from this study were as follows: • Assess the ability of fenebrutinib to prolong the time to first SLE flare • Assess the ability of fenebrutinib to decrease the number of total SLE flares • Assess the clinical efficacy of fenebrutinib over time based on individual SRI components • To evaluate whether patients with high plasmablast signature levels have an improved clinical response to fenebrutinib relative to patients with low levels • To evaluate the ability of fenebrutinib to improve cutaneous manifestations of SLE • To evaluate the ability of fenebrutinib to prevent systemic damage QRQQnn / l 7Π7 / Β / Υ • Assess the ability of fenebrutinib to improve arthritis • Assess the ability of fenebrutinib to improve fatigue • Assess the ability of fenebrutinib to improve patient global assessment • Assess whether fenebrutinib reduces steroids.

[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 of this study is to characterize the pharmacokinetics of fenebrutinib in patients. Exploratory PK endpoints included the relationship between drug exposure measurements and fenebrutinib pharmacodynamic effects, efficacy, and safety; the impact of selected covariates on measures of exposure and / or response to fenebrutinib; and the impact of genetic polymorphisms on fenebrutinib exposure measurements.

[0594] The exploratory biomarker targets of this study were as follows: • To assess the effect of fenebrutinib-induced changes on biomarkers and efficacy. • To evaluate whether biomarkers, including plasmablasts, autoantibodies, and other inflammatory biomarkers, measured at baseline can identify patients with improved clinical response to fenebrutinib. • Evaluate whether the levels of the above biomarkers are associated with disease progression. Study design

[0595] The study was a multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-varying study to evaluate the safety and efficacy of fenebrutinib in combination with SOC treatment in patients with active SLE of moderate to severe. At screening and baseline (i.e., day 1) moderate-to-severe SLE was defined as having serological proof of SLE with 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 at week 56 or potential enrollment in an extension study open (OLE). Approximately 240 patients who met all eligibility criteria were randomized in a 1:1:1 ratio into one of the following 3 groups: • Group A: GDC-0853 200 mg twice daily (BID) • Group B: GDC-0853 150 mg once daily (QD) • Group C: placebo

[0597] All 3 groups received blinded study drug in combination with background SOC treatment. Randomization was stratified by disease activity at screening, initial oral corticosteroid (OCS) dose, and geographic region. All patients received blinded study drug twice daily (fenebrutinib, placebo, or both to remain blinded) from baseline to week 48 and were evaluated at visits QRQQnn / l 7A7 / R / Y at the site every 4 weeks (including a site-initiated phone call in week 1) during the treatment period.

[0598] Background SOC treatment may consist of an OCS (which must be stable for 2 weeks before screening, not to exceed 40 mg / day of prednisone or equivalent) and / or certain oral immunosuppression regimens (which must be stable for 2 weeks before screening). All immunosuppressive and antimalarial medications were stable during the trial unless dose reductions were necessary due to toxicity. All patients receiving immunosuppressive treatments were promoted to receive supportive treatment (e.g., folic acid, calcium, vitamin D). For patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), doses of ACE inhibitors or ARBs should be kept stable for at least 10 days before randomization and throughout the trial. that is possible.

[0599] For patients receiving OCS at baseline, there are two 12-week OCS reduction windows available to achieve the prespecified OCS reduction of <10 mg / day prednisone or equivalent. The dose at the end of each OCS stability window (i.e., the 12-week period immediately following the 12-week OCS taper window) will then remain stable for an additional 12 weeks.

[0600] In the case of an increase in SLE disease activity, there may be two temporary increases in the corticosteroid dose, called bursts, that can be administered if necessary. Only one burst can be administered during the burst window (defined as the first 10 weeks of each OCS reduction window) and only once per window. A burst is defined as a temporary increase in corticosteroid dose (up to 40 mg / d prednisone or equivalent for burst window 1, and up to 20 mg / d prednisone or equivalent for burst window 2) with a reduction up to the dose immediately preceding the burst, all within a 2-week period.

[0601] If additional treatment beyond the permitted burst treatment is needed due to active SLE, as identified by the investigator, the patient may receive escape treatment; however, such patients will be considered trial-defined non-responders for the purposes of the primary analysis. During permitted taper, burst, and escape treatments, patients will continue to receive their designated dose of study treatment. Beginning at the screening period, all patients must report their actual weekly OCS use, as instructed by study staff.

[0602] An unblinded BMI and scientific regulatory commission are used to monitor multiple safety evaluations. Additionally, an interim analysis is conducted after 50-80 patients in each treatment group have completed 24 weeks of treatment and have been assessed on SLE response index (SRI)-4, to perform an evaluation. preliminary risk-benefit profile of fenebrutinib and potentially allow early discontinuation for safety and / or safety concerns. QRQonn / i ζηζ / Ε / γ

[0603] Patient inclusion and exclusion criteria are described below. Patients must meet the following criteria for study entry: • Signed informed consent form, age 18-75 years inclusive and able to comply with study protocol • Compliance with SLE classification criteria according to current American College of Rheumatology (ACR) or Systemic Lupus International Collaborating criteria Clinics (SLICC) at any time before or during screening. • At least one serological marker of SLE at screening as follows: Antinuclear antibody (ANA) positive, tested by immunofluorescence assay with titer > 1:80; OR positive anti-double-stranded DNA (anti-dsDNA) antibodies; OR anti-Smith antibody positive • At both screening and day 1, moderately to severely active SLE, defined as meeting all of the following criteria unless otherwise indicated: Yo . A SLEDAI-2K score > 8 (screening only) with a clinical SLEDAI-2K score > 4.0 (both screening and day 1); Yo. Physician Global Assessment > 1.0 (out of 3); and i ii. You are currently receiving at least one standard oral treatment (e.g., corticosteroids, antimalarials, and / or immunosuppressants) for SLE within the dose ranges, as specified below: • If receiving OCS, the dose should be < 40 mg / day prednisone (or equivalent) and should be stable for at least 2 weeks before screening, as well as during screening • If receiving antimalarial or immunosuppressive treatments, you should only receive drugs from the following list within the specified dosage range; the dose and route of administration must be stable for 8 weeks prior to screening, as well as during screening: Azathioprine: 1 to 2.5 mg / kg / day Methotrexate: 7.5 to 25 mg / week Mycophenolate mofetil: 500 to 3000 mg / day Mycophenolic sodium: 360 to 2160 mg / day Hydroxychloroquine: 200 to 400 mg / day Chloroquine: 100 to 250 mg / day Quinacrine: 100 to 200 mg / day • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period of study drug and for a minimum of 60 days after the last dose of study drug or longer as required by local requirements for other reference medications. Women using estrogen-containing hormonal contraceptives for birth control should use QRQonn / i ζηζ / Ε / γ also a barrier method. • For men: agreement to remain abstinent (refrain from heterosexual relations) or use contraception and agree to refrain from donating sperm

[0604] Patients meeting the following criteria were excluded from study entry: • Proteinuria > 3.5 g / 24 h or equivalent using urine protein to creatinine ratio (uPCR) in a first morning urine sample • Active proliferative lupus nephritis (as assessed by the investigator) or evidence histology of class III or class IV lupus nephritis on renal biopsy performed within 6 months prior to screening (or during the screening period) • History of required hemodialysis or high-dose corticosteroids (>100 mg / d prednisone or equivalent) for the treatment of lupus kidney disease within 90 days of day 1 • Neuropsychiatric or central nervous system manifestations of lupus, 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-variable diet modification equation in kidney disease) < 30 mL / min or on chronic renal replacement therapy • History of receiving a transplant solid organ • Newly diagnosed transverse myelitis (within the last 24 weeks) • History of antiphospholipid antibody syndrome (APLS) with or without related disseminated intravascular coagulation at any time is not exclusive; presence of antiphospholipid antibodies or history of fetal death, but no history of thromboembolism or current requirement for anticoagulation. • Evidence of active, latent, or inadequately treated Mycobacterium tuberculosis (TB) infection 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 the Centers for Disease Control and Prevention (CDC) guidelines, performed at the screening visit or within 12 weeks before screening and interpreted locally • Pregnant or lactating women (breastfeeding; within the last 12 weeks), or women intending to be pregnant, donate eggs or breastfeed, or participate in in vitro fertilization during this study • Illness significant and uncontrolled within 12 weeks prior to screening in any organ system (e.g., cardiac, neurological, pulmonary, renal, hepatic, endocrine [including uncontrolled diabetes mellitus], metabolic, Gl, or psychiatric [including risk of suicide]) unrelated to SLE, which, in the opinion of the Investigator or Sponsor, would preclude patient participation • Concomitant chronic conditions, in addition to SLE, (e.g., asthma, Crohn's disease) that QRQQnn / l 7Π7 / Β / Υ required oral, IV, or intramuscular (IM) steroids or immunosuppressive use within 24 weeks prior to screening or are likely to require these during the course of the study • History of pancreatitis unrelated to gallstones or chronic pancreatitis considered clinically by the investigator (for example, accompanied by unexplained upper abdominal pain or malabsorptive diarrhea) • Evidence of autoimmune myositis • History of cancer, including solid tumors and hematologic malignancies, within 10 years of screening; basal or squamous cell carcinoma of the skin that was removed and considered cured and carcinoma in situ of the cervix adequately treated by curative treatment more than 1 year before screening are not exclusive • History of alcohol, drug, or chemical substance use within 1 year before screening as determined by the investigator • Major surgery requiring hospitalization within 4 weeks of screening • History of cerebrovascular accident (CVA) within 10 years, or any history of hemorrhagic stroke, any history of spontaneous intracranial hemorrhage, or history of traumatic intracranial hemorrhage within 10 years • History of clinically uncontrolled cardiac arrhythmias • 12-lead ECG screening demonstrating clinically relevant abnormalities that may affect patient safety or interpretation of study results, including corrected QT interval using the Fridericia formula > 450 ms for female patients and > 430 ms for male patients demonstrated by at least two ECGs > 30 minutes apart • History of clinically significant ventricular arrhythmias or risk factors for ventricular arrhythmias, such as long QT syndrome and other genetic risk factors, heart disease, or family history of sudden unexplained death or cardiac ion channel mutations • Current treatment with drugs known to prolong the QT interval (except for antimalarials) at doses that have a clinically relevant effect on QT , as determined by the investigator • Any condition that possibly affects the absorption of oral drugs (for example, gastrectomy, clinically significant diabetic gastroenteropathy, 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 excluded • Need for systemic anticoagulation with warfarin or other oral or injectable anticoagulants (other than NSAIDs, aspirin (< 325 mg / day), or other salicylates) • Diathesis of known bleeding • Any history of hospitalization or transfusion for bleeding Gl QRQonn / i ζηζ / Ε / γ • History or active presence of primary or secondary immunodeficiency, including known history of HIV infection or IgG < 500 mg / dL • Any known active infection during screening up to and including the time of enrollment ( except for fungal nail infections or oral herpes) • History of recurrent treated bacterial, viral, mycobacterial or fungal infections, defined as > 2 similar episodes requiring antimicrobial treatment within the previous 52 weeks, except for the following: Oral or genital herpes (herpes simplex virus 11, herpes simplex virus 2) Uncomplicated cystitis or asymptomatic bacteriuria Uncomplicated viral, bacterial, or culture-negative bronchitis without pneumonia Bacterial or viral sinusitis Vaginal bacterial or fungal (yeast) infections • Any history of opportunistic infections that the Investigator or Sponsor believes raises safety concerns regarding the patient's participation in the study • Any major episode of infection requiring hospitalization or treatment with IV antimicrobials o IM within 4 weeks before or during screening or treatment with oral antimicrobials within 2 weeks before and during screening (except for prophylaxis for Pneumocystis jiroveci pneumonia) • History of severe and / or disseminated viral infections, particularly herpes viruses, such as HSV1, HSV2, varicella-zoster virus (VZV), cytomegalovirus; uncomplicated influenza during a flu season, cold sores and genital herpes are not excluded • Evidence of chronic and / or active hepatitis B or C • Use of any of the following medications and / or treatments within the indicated time period: Plasmapheresis or IV Ig in the last 12 weeks before screening B cell depleting treatment (for example, anti-CD20 or anti-CD19) within 24 weeks before screening Belimumab, blisibimod, tabalumab (or other anti-B cell activating factor [BAFF] agents), atacicept (or other anti-transmembrane activator and calcium modulator and cyclophilin ligand interactor [CAML] agents [TACI]), epratuzumab (or other anti-CD22 agents) or denosumab within 5 half-lives or 12 weeks (whichever is longer) before screening Cyclophosphamide or other alkylating agents within 12 weeks before screening Oral cyclosporin, tacrolimus, topical calcineurin inhibitors, anakinra (IL-1 inhibitor), sirolimus (IL-2 inhibitor), or other calcineurin inhibitors within 4 weeks before screening Thalidomide or thalidomide derivatives within 24 weeks before screening Tumor necrosis factor (TNF) antagonists, tocilizumab or other biological agents not mentioned QRQQnn / l 7Π7 / Β / Υ previously within 12 weeks prior to screening Any investigational drug within 4 weeks or 5 half-lives, whichever is longer, of screening Administration of any parenteral (IV), IM, or intra-articular steroid within 4 weeks prior to screening Any other immunosuppressive medication for SLE not listed in the inclusion criteria, within 12 weeks or 5 half-lives before screening, whichever is longer, unless approved by the Medical Monitor Live vaccinations within 6 weeks prior to randomization; seasonal influenza and H1N1 influenza vaccines are permitted if the inactivated vaccine formulation is administered • Use of any of the medications, herbal supplements, or foods in the categories listed below should be avoided within 1 week or 5 half-lives , whichever is longer, before randomization, based on potential drug interactions (CYP3A inhibitors / inducers) • Any of the following laboratory results, for which testing may be repeated once if initial results are out rank during screening: ASToALT>1.5x ULN Total bilirubin > 1.2 ULN - Amylase or lipase > 2 x ULN - Hemoglobin < 7 g / dL - Absolute neutrophil count (ANC) < 1.5 x 109 / L - Absolute lymphocyte count (ALC) < 0.5 x 109 / L - Platelet count < 50,000 / pL

[0605] Interim analysis: An interim analysis was performed after about 50 patients in each treatment group completed their 24-week SRI-4 response assessment. The purpose of the interim analysis was to conduct a preliminary benefit-risk assessment of fenebrutinib-treated groups compared to the placebo-treated group and to allow for potential discontinuation for futility and / or safety issues or to potentially inform the development plan. clinical for fenebrutinib.

[0606] A patient was considered an SRI-4 responder if the patient experienced: (i) a reduction in SLEDAI-2K from baseline of at least 4 points, (i) no worsening of BILAG (no new A domain and less than 2 new B domains) and (iii) no worsening in the patient's physician global assessment (PGA).

[0607] Interim results: 57% of patients in the fenebrutinib 200 mg BID group (28 patients) were SRI-4 responders at week 24. 49% of patients in the fenebrutinib 150 mg QD group ( 25 patients) were SRI-4 responders at week 24. 46% of placebo patients (23 patients) were also SRI-4 responders at week 24. These results demonstrate the efficacy of fenebrutinib in the treatment of SLE in this essay.

[0608] Fenebrutinib was safe and well tolerated at the interim analysis at each dose. Some patients in QRQQnn / l 7Π7 / Β / Υ 200 mg BID group showed signs of increases in ALT and AST.

[0609] Study Completion: Study completion 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 an OLE, if initiated, which last to occur. The maximum time period in this study for a patient is 61 weeks, which includes screening for up to 35 days, treatment for 48 weeks, and a safety follow-up period for 8 weeks (unless you enroll in a study OLE). Biomarkers

[0610] The following biomarkers were explored according to the biomarker objectives provided above in the Study Objectives. In Table 13, biomarkers are measured at baseline and at later time points during and after treatment. One set of biomarkers evaluated is the signature in plasmablasts. Plasmablasts are short-lived, rapidly dividing 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 signature in plasmablasts comprises the biomarkers IgJ, Mzbl and Txndc5. The gene expression of IgJ, Mzbl and Txndc5 can be measured, for example, a polypeptide expression by evaluating the level of mRNA for said gene in the blood of a patient with respect to a reference level. QRQonn / i ζηζ / Ε / γ Table 13: Proposed biomarkers for exploratory research Sample type Proposed biomarkers Plasma Markers including but not limited to: CCL3, CCL4 Serum Markers including but not limited to: CXCL13, CCL20 and autoantibodies Whole blood for FACS Cells including but not limited to basophils and plasmablasts RNA extracted from blood Markers including include, but are not limited to, signature in plasmablasts Blood for peripheral blood mononuclear cells for CyTOF analysis Cells and surface or activation markers, including, but not limited to, B and T lymphocyte subsets Blood for peripheral blood mononuclear cell lysate Markers that include, but are not limited to, phosphorylated and total BTK protein Urine Urine biomarkers including, but not limited to, CXCL13, TWEAK, BAFF, and lipids

[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 QD and 200 mg BID groups were 51% (95 Cl%: -8.5, 21.2) and 52% (95% Cl: -7.3, 22.4), respectively, compared to 44% for the placebo group. BICLA response rates at week 48 for FEN 150 mg QD and FEN 200 mg BID were 53% (95% Cl: -3.4, 26.8) and 42% (95% Cl: -14.2,16.1) , respectively, compared to 41% for the placebo group. QRQonn / i ζηζ / Ε / γ Table 14. Efficacy and safety results PBO (n=86) FEN 150 mg QD (n=87) FEN 200 mg BID (n=87) Primary Endpoint SRI-4 Response at Week 48 Responder, n (%) Treatment Difference Compared to PBO (%) 95% Cl P-value 38 (44) 44 (51) 6.4 (-8.5, 21.2) 0.37 45 (52) 7.5 (-7.3, 22.4) 0.34 Additional efficacy results SLEDAI at week 48a Reduction with respect to at baseline >4 points, n (%) Treatment difference compared to PBO (%) BILAG at week 48a Change from baseline Absence of new domain A and >1 new domains B, n (%) Treatment difference in compared to PBO (%) PGA at week 48a Change from baseline <0.3 point increase, n (%) Treatment difference compared to PBO (%) BICLA response at week 48b Responder, n (%) Difference in treatment compared to PBO (%) 95% Cl P value 62 (72) 83 (97) 83 (97) 33 / 80 (41) 68 (78) 6.1 84 (97) 0.0 82 (94) -2.3 45 / 85 (53) 11.7 (-3.4, 26.8) 0.086 70 (81) 8.4 84 (97) 0.0 83 (95) -1.1 35 / 83 (42) 0.9 (-14.2, 16.1) 0.879 Early study interruptions, n (% ) 22 (26) 21 (24) 22 (25) Escape treatment received0, n (%) 8(10) 7 (8.2) 10 (12) Safety, n (%) Total number of patients with at least one AE AE severe AE resulting in death0 64 (76) 8(10) 2(2) 77 (89) 4(5) 1 (D 68 (77) 12 (14) 0 a- Note: SLEDAI, BILAG and PGA are presented with the last observation made. Study interruptions are taken into account in the SRI-4 response, but not in the SRI-4 components. b- Depending on the population evaluable by BICLA. c- Escape treatment defined as receipt of medications for SLE that exceeds the limits in the protocol. d- Deaths due to salivary gland tumor (150 mg QD); respiratory failure (PBO); infected skin ulcer (PBO).

[0612] The biomarker results are summarized in Table 15. Treatment with both doses of fenebrutinib significantly reduced the levels of CD19í B lymphocytes, anti-dsDNA autoantibodies, IgG and a BTK-dependent RNA signature highly expressed in plasmablasts in the week 48 compared to placebo; C4 levels were modestly improved with fenebrutinib compared with placebo. These results indicate that inhibition of the BTK pathway and target was achieved by oral administration of fenebrutinib. Table 15. Summary of change in biomarkers from baseline to week 48. QRQQnn / l 7Α7 / Ε / ΥΙΛΙ | PBO 150 mg QD of FEN 200 mg BID of FEN Median biomarker levels at baseline Signature in plasma cells (-ACt) CD19+ B lymphocytes (cells / pL) Anti-dsDNA* (lU / mL) Total IgG (g / L) C3 (g / L) C4 (g / L) 1.29 (o=85) 136 (o=63) 154 (o=41) 14.1 (o=85) 1.03 (o=85) 0.18 (o=85) 1.22 ( o=87) 140 (o=71) 124 (o=47) 14.3 (o=86) 1.03 (o=87) 0.17 (o=87) 1.34(n=88) 126 (n=70) 180 (o= 48) 15.0 (o=87) 1.03(0=88) 0.16(o=88) Median (IQR) change from baseline at week 48 Plasma stem signature CD19+ B lymphocytes (cells / pL) Anti-dsDNA* ( lU / mL) Total IgG (g / L) C3 (g / L) C4 (g / L) -19.7% (-42.6 to 15.8) or=52 -0.50 (-38.3 to 28.8) or=38 +6.9 (- 27.3 to 78.2) o=31 -0.20 (-1.30 to 1.55) o=65 -0.02 (-0.12 to 0.08) o=65 0.00 (-0.03 to 0.02) o=65 -54.3%* (-74.7 to -20.6) o=53 -57.0* (-128.0 to-6.0) o=49 -38.3* (-91.7 to-3.9) n=36 -1.25* (-2.63 to 0.05) o=64 +0.01 (-0.12 to 0.12) o =67 +0.02* (-0.01 to 0.05) n=67 -51.7%* (-77.8 to-15.3) o=57 -57.5* (-121.0 to-24.8) o=48 -75.7* (-263.7 to -18.4) o=33 -1.56* (-3.73 to -0.68) o=64 -0.01 (-0.12 to 0.13) o=66 +0.01* (-0.01 to 0.05) o=66 Reference ranges: CD19+ B lymphocytes (80-616 cells / pL), anti-dsDNA (<30 lU / mL), IgG (5.6517.65 g / L), C3 (0.9-1.8 g / L), C4 (0.1 -0.4 g / L) *Patients who tested positive at baseline (>30 ILJ / mL) *indicates significant compared to PBO; Two-way controlled Kruskal-Wallis false discovery rate (p-value <=0.05).

[0613] While this disclosure has been described in some detail using illustrations and examples for clarity, the descriptions and examples should not be construed as limiting the scope of this disclosure. The disclosures of all patents and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

1. Use of fenebrutinib, or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat a human patient having moderately to severely active rheumatoid arthritis, wherein the patient has demonstrated an inadequate response to prior treatment with one or more conventional non-biologic DMARDs and wherein the medicament is adapted to be administered at a dose of about 150 to about 400 mg daily of fenebrutinib, or a pharmaceutically acceptable salt thereof.

2. Use according to claim 1, wherein the conventional non-biological DMARD in the above treatment is methotrexate.

3. Use according to claim 1 or 2, wherein the drug is adapted to be administered in combination with one or more additional therapeutic agents.

4. Use of fenebrutinib, or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat a human patient having moderately to severely active rheumatoid arthritis, wherein the patient has demonstrated an inadequate response or intolerance to previous treatment with one or more biological drugs for rheumatoid arthritis, wherein the medicament is adapted to be administered at a dose of about 150 to about 400 mg daily of fenebrutinib, or a pharmaceutically acceptable salt thereof.

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

6. Use according to any of claims 1-5, wherein the patient has a reduction in one or more symptoms of rheumatoid arthritis following treatment with fenebrutinib, or a pharmaceutically acceptable salt thereof.

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

8. Use according to claim 6, wherein the reduction in the patient's symptoms is a reduction in the patient's DAS28 score.

9. Use in accordance with any of claims 6-8, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within 0 to 4 weeks of treatment.

10. Use in accordance with any of claims 6-8, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within 0 to 8 weeks of treatment.

11. Use in accordance with any of claims 6-8, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within 0 to 12 weeks of treatment.

12. Use according to any of claims 1-11, wherein in addition a clinical or laboratory assessment criterion for the patient is measured in order to evaluate the efficacy of treatment with fenebrutinib or a pharmaceutically acceptable salt thereof.

13. Use according to claim 12, wherein the clinical assessment criterion is selected from the group consisting of the following patient criteria: ACR50 score, ACR 70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-fatigue score, CRP compared to baseline, and ESR compared to baseline.

14. Use according to claim 13, wherein the clinical or laboratory endpoint is measured after 4 weeks of treatment.

15. Use according to claim 13, wherein the clinical or laboratory endpoint is measured after 8 weeks of treatment.

16. Use according to claim 13, wherein the clinical or laboratory endpoint is measured after 12 weeks of treatment.

17. Use according to any of claims 1-16, wherein the presence of autoantibodies is identified in a patient blood sample prior to treatment with fenebrutinib, or a pharmaceutically acceptable salt thereof, in the patient having such autoantibodies.

18. Use according to claim 17, wherein the autoantibodies identified in the sample are selected from the group consisting of rheumatoid factor and anti-citrullinated peptide antibodies.

19. Use of fenebrutinib, or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat a human patient having chronic spontaneous urticaria, wherein the patient exhibits symptoms of the disease despite prior H1 antihistamine treatment, wherein the medicament is adapted to be administered at a dose of about 50 to about 400 mg daily of fenebrutinib, or a pharmaceutically acceptable salt thereof.

20. Use according to claim 19, wherein the patient has an average reduction in a weekly itch severity score from an initial value after treatment.

21. Use according to claim 19, wherein the patient has a reduction in urticaria activity score (UAS7) from an initial value after treatment.

22. Use according to claim 20 or 21, wherein the change from the initial value occurs within 0 to 4 weeks of treatment.

23. Use according to claim 20 or 21, wherein the change from the initial value occurs within 0 to 8 weeks of treatment.

24. Use according to claim 20 or 21, wherein the change from the initial value occurs within 0 to 12 weeks of treatment.

25. Use according to any of claims 19-24, wherein an H1 antihistamine is adapted to be administered to the patient concurrently. QRQQnn / l 7Π7 / Β / Y 101 26. Use according to any of claims 19-25, wherein the presence of autoantibodies is identified in a patient blood sample prior to administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient having such autoantibodies.

27. Use of fenebrutinib, or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat a human patient having moderately to severely active systemic lupus erythematosus, wherein the patient exhibits symptoms of the disease despite prior standard oral SLE treatment, wherein the medicament is adapted to be administered at a dose of about 150 to about 400 mg daily of fenebrutinib, or a pharmaceutically acceptable salt thereof.

28. Use according to claim 27, wherein the standard oral SLE treatment is selected from the group consisting of an oral corticosteroid, an antimalarial, and an immunosuppressant.

29. Use according to claim 27 or 28, wherein the drug is adapted to be administered in combination with an oral corticosteroid.

30. Use in accordance with any of claims 27-29, wherein the patient has a reduction in one or more clinical symptoms of SLE after treatment.

31. Use in accordance with any of claims 27-30, wherein the reduction in the patient's clinical symptoms is measured by the patient's SLE Response Index (SRI-4) score.

32. Use according to claim 30, wherein the reduction in one or more clinical symptoms of SLE occurs within 0 to 24 weeks of treatment.

33. Use according to claim 30, wherein the reduction in one or more clinical symptoms of SLE occurs within 0 to 48 weeks of treatment.

34. Use according to any of claims 1-33, wherein the medicament is adapted to be administered orally in the form of one or more tablets or capsules.

35. The use according to claim 34, wherein the medicament is adapted to be administered orally as a free base in the form of one or more tablets or capsules.

36. Use according to claim 34 or 35, wherein the drug is adapted to be administered orally as a free base in the form of one or more tablets.

37. Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in treating a human patient having moderately to severely active rheumatoid arthritis, wherein the patient has demonstrated an inadequate response to prior treatment with one or more conventional non-biologic DMARDs and wherein fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered at a dose of about 150 to about 400 mg daily.

38. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 37, wherein the conventional non-biological DMARD in the above treatment is methotrexate.

39. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 37 or 38 of QRQonn / i ζηζ / E / γ 102, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered in combination with one or more additional therapeutic agents.

40. Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in treating a human patient having moderately to severely active rheumatoid arthritis, wherein the patient has demonstrated an inadequate response or intolerance to prior treatment with one or more biological drugs for rheumatoid arthritis, wherein fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered at a dose of about 150 to about 400 mg daily.

41. Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to claim 40, wherein the rheumatoid arthritis diologic drug is selected from the group consisting of a TNF-alpha inhibitor, adatacept, tocilizumab, sarilumad, sirukumad, anakinra and any diosimilar equivalents thereof.

42. Phenedrutinid, or a pharmaceutically acceptable salt thereof, for use according to any of claims 37-41, wherein the patient has a reduction in one or more symptoms of rheumatoid arthritis following treatment with phenedrutinid, or a pharmaceutically acceptable salt thereof.

43. Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to claim 42, wherein the reduction in patient symptoms is measured by a reduction of at least 50% in the patient's score according to the American College of Rheumatology (ACR50).

44. Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to claim 42, wherein the reduction in patient symptoms is a reduction in the patient's DAS28 score.

45. Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to any of claims 42-44, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within 0 to 4 weeks of treatment.

46. ​​Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to any of claims 42-44, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within 0 to 8 weeks of treatment.

47. Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to any of claims 42-44, wherein the reduction in one or more symptoms of rheumatoid arthritis occurs within 0 to 12 weeks of treatment.

48. Phenedrutinid, or a pharmaceutically acceptable salt thereof, for use according to any of claims 37-47, wherein a clinical or laboratory endpoint is further measured for the patient in order to evaluate the efficacy of treatment with phenedrutinid or a pharmaceutically acceptable salt thereof.

49. Phenedrutinid, or a pharmaceutically acceptable salt thereof for use according to QRQQnn / l 7P7 / B / Y 103 claim 48, wherein the clinical endpoint is selected from the group consisting of the following patient criteria: ACR50 score, ACR 70 score, HAQ-DI score, DAS28 score, DAS28-3-CRP score, SF-36 score, FACIT-fatigue score, CRP compared to baseline, and ESR compared to baseline.

50. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 49, wherein the clinical or laboratory endpoint is measured after 4 weeks of treatment.

51. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 49, wherein the clinical or laboratory endpoint is measured after 8 weeks of treatment.

52. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 49, wherein the clinical or laboratory endpoint is measured after 12 weeks of treatment.

53. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 37-52, wherein the presence of autoantibodies is identified in a patient blood sample prior to treatment with fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient having such autoantibodies.

54. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 53, wherein the autoantibodies identified in the sample are selected from the group consisting of rheumatoid factor and anti-citrullinated peptide antibodies.

55. Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in treating a human patient having chronic spontaneous urticaria, wherein the patient exhibits symptoms of the disease despite prior H1 antihistamine treatment, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered at a dose of about 50 to about 400 mg daily.

56. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 55, wherein the patient has an average reduction in a weekly itch severity score from an initial value after treatment.

57. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 55, wherein the patient has a reduction in urticaria activity score (UAS7) from a baseline value after treatment.

58. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 56 or 57, wherein the change from baseline occurs within 0 to 4 weeks of treatment.

59. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to QRQQnn / l 7P7 / B / Y 104 claim 56 or 57, wherein the change from baseline occurs within 0 to 8 weeks of treatment.

60. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 56 or 57, wherein the change from baseline occurs within 0 to 12 weeks of treatment.

61. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 55-60, wherein an H1 antihistamine is adapted to be administered to the patient concurrently.

62. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 55-61, wherein the presence of autoantibodies is identified in a patient blood sample prior to administering fenebrutinib, or a pharmaceutically acceptable salt thereof, to the patient having such autoantibodies.

63. Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use in treating a human patient having moderately to severely active systemic lupus erythematosus, wherein the patient exhibits symptoms of the disease despite prior standard oral SLE treatment, wherein fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered at a dose of about 150 to about 400 mg daily.

64. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 63, wherein the standard oral SLE treatment is selected from the group consisting of an oral corticosteroid, an antimalarial, and an immunosuppressant.

65. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 63 or 64, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered in combination with an oral corticosteroid.

66. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 63-65, wherein the patient has a reduction in one or more clinical symptoms of SLE following treatment.

67. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to any of claims 63-66, wherein the reduction in the patient's clinical symptoms is measured by the patient's SLE Response Index (SRI-4) score.

68. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 66, wherein the reduction in one or more clinical symptoms of SLE occurs within 0 to 24 weeks of treatment.

69. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 66, wherein the reduction in one or more clinical symptoms of SLE occurs within 48 to 105 weeks of treatment.

70. Fenebrutinib, or a pharmaceutically acceptable salt thereof, for use according to any of claims 37-69, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted for oral administration in the form of one or more tablets or capsules. 5 71. Fenebrutinib, or a pharmaceutically acceptable salt thereof for use according to claim 70, wherein the fenebrutinib, or a pharmaceutically acceptable salt thereof, is adapted to be administered orally as a lead dose in the form of one or more tablets or capsules.

72. Phenedrutinid, or a pharmaceutically acceptable salt thereof, for use according to claim 70 or 71, wherein the phenedrutinid, or a pharmaceutically acceptable salt thereof, is adapted for oral administration as a lead dose in the form of one or more tablets.