FRI0150 GS-9876, A NOVEL, HIGHLY SELECTIVE, SYK INHIBITOR IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: SAFETY, TOLERABILITY AND EFFICACY RESULTS OF A PHASE 2 STUDY
Authors: Alan Kivitz, Daksha Mehta, Franziska Matzkies, Afsaneh Mozaffarian, Rebecca Kunder, Julie A. DI Paolo, Neelufar Mozaffarian, Sean Hsueh, Jiyun Kim, Wendy Jiang, Lin Liu, John Sundy, Mark C. Genovese
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Spleen tyrosine kinase (SYK) mediates immunoreceptor signaling and is essential in activation of cells including B lymphocytes, monocytes, macrophages, dendritic cells, and osteoclasts. SYK may play an important role in the initiation and progression of autoimmune diseases, including rheumatoid arthritis (RA) and lupus. GS-9876 is a novel, potent, highly selective oral inhibitor of SYK in phase 2 trials for autoimmune diseases. <h3>Objectives</h3> To evaluate the efficacy, safety, and pharmacokinetics of GS-9876, and its impact on biomarkers relevant to RA as well as the SYK and JAK pathways. <h3>Methods</h3> Patients with active RA with prior inadequate response to methotrexate (MTX) or a biologic antirheumatic drug were randomized 1:1:1:1 to receive GS-9876 30 mg, GS-9876 10 mg, selective JAK1 inhibitor filgotinib (FIL) 200 mg, or matching placebo (PBO) once daily for 12 weeks on a stable background of oral MTX. The primary endpoint for GS-9876 was the change in DAS28(CRP) at week 12. Pharmacokinetics and various biomarkers were evaluated at several time points, including VectraDA and stimulation of whole blood in TruCulture (MyriadRBM) tubes. <h3>Results</h3> A total of 83 patients received the study drug and 79 completed the study. Fourteen patients (16.9%) were male and 69 (83.1%) were female. The majority were white (77, 92.8%). The mean (SD) age at baseline (BL) was 55 (11.5) years (range 18 to 73). The primary and secondary endpoints are reported in Table 1. For DAS28(CRP), the mean (SD) at BL was 5.75 (0.961) with a median of 5.69; a statistically significant reduction at week 12 was observed only in patients receiving FIL as compared to PBO (Table 1). Adverse events (AEs) were reported across all groups (37.5% in the combined GS-9876 arms, 38.1% in FIL, 40.9% in PBO). No deaths or serious AEs were reported. Plasma exposures of all study drugs were comparable to those observed in healthy subjects and historical data. <i>Ex vivo</i> stimulated whole blood identified differential responses between GS-9876 and PBO. <h3>Conclusion</h3> Clinical efficacy of GS-9876 in RA was not observed, but GS-9876 was safe and well-tolerated over a 12-week period in patients with RA on MTX. FIL showed favorable safety and clinical efficacy consistent with prior data, validating the study concept and design. Additionally, biomarker changes with GS-9876 support the continuation of studies in lupus-related diseases. <h3>References</h3> [1] Kivitz AJ, et al. ACR 2018. Abstract 2518. <h3>Disclosure of Interests</h3> Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Daksha Mehta: None declared, Franziska Matzkies Shareholder of: Gilead, Employee of: Gilead, Afsaneh Mozaffarian Employee of: Gilead Sciences, Inc., Rebecca Kunder Shareholder of: Gilead Sciences, Inc., Julie A. Di Paolo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Neelufar Mozaffarian Shareholder of: Gilead, Employee of: Gilead, Sean Hsueh Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., JiYun Kim Shareholder of: Gilead Sciences, Inc., Employee of: Bayer Healthcare, LLC, Gilead Sciences, Inc., Wendy Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lin Liu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., John Sundy Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm