Methods of treating sjogren's syndrome using a bruton's tyrosine kinase inhibitor

#The present disclosure relates to methods for treating Sjögren's syndrome using a Bruton's tyrosine kinase (BTK) inhibitor.

#Sjögren's syndrome (SjS) is a systemic autoimmune disease of unknown etiology characterized by lymphoid infiltration and progressive destruction of exocrine glands (Brito-Zerón P., et al, (2016) Treating the Underlying Pathophysiology of Primary Sjögren Syndrome: Recent Advances and Future Prospects. Drugs p. 1601-1623).

#Although the disease primarily affects the lacrimal and salivary glands, the inflammatory process can target any organ with approximately 15% of patients showing severe extraglandular manifestations (Baldini C., et al (2014) Primary Sjögren's syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford) p. 839-44). The clinical presentation is most often primarily characterized by exocrinopathy of salivary and lacrimal glands presenting with dryness of the mouth and eyes. However, symptoms can be very heterogeneous and range beyond dryness to also include musculoskeletal pain and fatigue affecting nearly all patients, to severe, extra-glandular and systemic involvement (characterized by peri-epithelial lymphocytic infiltration and immune complex deposition) in a more limited subset. The mechanism underlying the development of SjS is the destruction of the epithelium of the exocrine glands, as a consequence of autoreactive B cells and T cells (Brito-Zerón P., et al, (2016) Treating the Underlying Pathophysiology of Primary Sjögren Syndrome: Recent Advances and Future Prospects. Drugs p. 1601-1623). The high prevalence of autoantibodies, especially against Ro/SSA, even at a very early stage suggests that autoreactive B cells participate in the pathomechanism of SjS (Nocturne G., et al, (2018) B cells in the pathogenesis of primary Sjögren syndrome. Nat Rev Rheumatol p. 133-145).

#FIG. 1: Blood concentration-time course of compound (I) after single ascending doses 0.5 mg-600 mg

#FIG. 2: Blood concentration-time course of compound (I) after multiple ascending doses of 10 mg-400 mg, q.d. dosing

#FIG. 3: Blood concentration-time course of compound (I) after multiple ascending doses of 100 mg b.i.d. and 200 mg b.i.d.

#Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a member of the TEC kinase family. BTK is expressed in cells of both the adaptive and innate immune system including B cells, macrophages, basophils, mast cells and thrombocytes. BTK is indispensable for signaling through the Fc epsilon receptor (FcεR1 for IgE) and the activating Fc gamma receptors (FcγR for IgG), as well as the B cell antigen receptor (BCR). BTK inhibition has been shown to be an effective concept to treat B cell malignancies. The covalent BTK inhibitors ibrutinib (Imbruvica®), acalabrutinib (Calquence® and zanubrutinib (Brukinsa®) are approved for the treatment of certain B cell malignancies (Thompson P A, et al, (2018) Bruton's tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL). Expert Opin Investig Drugs p. 31-42). BTK inhibition has shown promising efficacy on B cell autoimmunity in preclinical and clinical studies (Tan S L., et al, (2013) Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives. Pharmacol. Ther. p. 294-309; Whang J. A., et al. (2014) Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov. Today p. 1200-4; Satterthwaite A. B. (2017) Bruton's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles in the Pathogenesis of Lupus. Front Immunol p. 1986; Rip J., et al, (2018) The Role of Bruton's Tyrosine Kinase in Immune Cell Signaling and Systemic Autoimmunity. Crit. Rev. Immunol. p. 17-62). Therefore, inhibition of BTK is an attractive therapeutic concept to treat various autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, chronic urticaria, atopic dermatitis, asthma, and primary Sjögren's Syndrome (Tan S L, Liao C, Lucas M C, et al (2013) Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives. Pharmacol. Ther. p. 294-309; Whang J A, Chang B Y (2014) Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov. Today p. 1200-4).

#In addition, BTK levels were shown to be increased in circulating B cells of a significant percentage of patients with SjS, in association with high serum rheumatoid factor (RF) levels (Corneth O B J et al. (2017) Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease. p. 1313-1324).

#N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is a BTK inhibitor referred to herein as Compound of Formula (I):