SAT0089 SAFETY AND EFFICACY OF LY3337641, A BRUTON’S TYROSINE KINASE INHIBITOR IN PATIENTS WITH RHEUMATOID ARTHRITIS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 2-PART PHASE 2 STUDY
Authors: Mark C. Genovese, Alberto Spindler, Akira Sagawa, Won Park, Anna Dudek, Alan Kivitz, Jeannie Chao, William Barchuk, Ajay Nirula
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> LY3337641 is an irreversible covalent inhibitor of Bruton’s tyrosine kinase (BTK), a key signaling molecule in the B-cell-receptor and Fc-receptor pathways and mediator of B-cell– and myeloid-cell–dependent inflammatory arthritis.<sup>1,2</sup> RA-JUVENATE was a multicenter, randomized, double-blind, placebo-controlled, 2-part Phase 2 trial with long-term extension (LTE) in adult patients (pts) with rheumatoid arthritis (RA). <h3>Objectives</h3> The objective of this analysis is to present the primary results from Part B of the study. <h3>Methods</h3> In Part A, 36 pts with at least mildly active RA were randomized 1:1:1:1 to receive oral LY3337641 5, 10, or 30 mg or placebo (PBO) once daily (QD) for 4 weeks (wks) with the primary objective of safety and tolerability. There were no safety signals to preclude moving to Part B; pts in Part A were not eligible to participate in Part B. In Part B, 250 pts with active moderate to severe RA were randomized 1:1:1:1 receive oral LY3337641 5 (N=63), 10 (N=62), or 30 mg (N=63) or PBO (N=62) QD for 12 wks. The primary endpoint of Part B was the proportion of pts achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at Wk 12. A logistic regression model was used to compare each LY3337641 dose to PBO for primary and secondary endpoints. Nonresponder imputation was used to impute missing data. After an interim analysis showed a low likelihood of demonstrating significant efficacy at the conclusion of the trial, the sponsor discontinued Part B of the study, including the LTE. Efficacy results (except analysis of low disease activity and remission) included pts who completed through Wk 12 at the time of study discontinuation; safety was results included all pts who received ≥1 dose of study drug. <h3>Results</h3> Of the 250 pts (mean age 51.0 years; 86.4% female; mean disease duration 11.2 years) randomized in Part B, 189 (75.6%) completed 12 weeks and 180 entered the LTE (72.0%); 61 discontinued study treatment in Part B.. The most common reasons for discontinuation were study terminated by sponsor (27 [10.8%]), withdrawal by subject (8 [3.2%]), adverse event (8 [3.2%]), and lack of efficacy (4 [1.6%]). There was no statistically significant difference in the ACR20 response between any treatment group of LY3337641 and PBO at Wk 12 (p&gt;0.05 for all comparisons; Table); a high placebo rate was noted, but no underlying reason was identified in post hoc analyses. There were 5 serious adverse events: 2 in PBO pts (joint dislocation and cholecystitis acute) and 3 in 30-mg pts (foot fracture, multiple injuries, and venous thrombosis). There was 1 death (30-mg pt, multiple injuries after 4-story fall down elevator shaft). There were no safety findings that precluded continuation of the study. <h3>Conclusion</h3> Although there were no safety findings that precluded continuation of the study, the study sponsor determined that the observed benefit-risk profile of LY3337641 in the study did not warrant its continuation. <h3>References</h3> [1] Di Paolo JA, et al. Nat Chem Biol. 2011;7:41-50 [2] Chakravarty SD, et al. Clin Immunol. 2013;148:66-78. <h3>Disclosure of Interests</h3> Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Alberto Spindler: None declared, Akira Sagawa Paid instructor for: ONO Pharmaceutical co., ltd, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AYUMI Pharmaceutical, ISSEI PHARMACEUTICAL CO., LTD., CHUGAI PHARMACEUTICAL CO.,LTD., Asahi Kasei Pharma Corporation, Janssen Pharmaceutical, Won Park Consultant for: Celltrion, Inc, Anna Dudek: None declared, 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, Jeannie Chao Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Lai Shan (Melanie) Chan Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, William Barchuk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ajay Nirula Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company