SAT0159 Results of A Phase 1b Study of The Safety, Tolerability, and Pharmacokinetics of The MMP9 Inhibitor GS-5745 in Patients with Rheumatoid Arthritis (RA)

Background Active matrix metalloproteinase-9 (MMP9) degrades matrix proteins and promotes inflammation. MMP9 knockout mice are also protected from collagen-induced arthritis disease progression. Furthermore, elevated levels of MMP9 are present in the synovial fluid of patients with RA suggesting that targeting of MMP9 may have therapeutic benefit. GS-5745 is a humanized IgG 4 mAb that inhibits MMP9 activity with picomolar specificity. Objectives To determine the safety and tolerability of GS-5745 in adult subjects with RA. Secondary objectives were to investigate the PK of GS-5745, and to assess the effect of GS-5745 on RA disease activity measures. Methods This multi-center, randomized, double-blind, placebo-controlled study enrolled 18 subjects who met the ACR criteria for RA and had a mean screening CRP ≥8.0 mg/L. Subjects were randomized 4:1 to receive GS-5745 400 mg or placebo (PBO) infusions every 2 weeks for a total of 3 infusions. Concurrent biologic DMARD use was excluded, but subjects continued their stable conventional DMARD therapy. A 28 swollen and tender joint count, patient assessment of pain, and patient and physician global assessment of health were obtained. Results Eighteen subjects (15 active and 3 PBO) were enrolled and received 3 doses of GS-5745 or PBO. The median plasma half-life of GS-5745 was 5.7 days. Mean free plasma MMP9 levels in the GS-5745 cohort were reduced by 90% from 126.1 ng/mL at Baseline to 13.2 ng/mL (2.18) at Day 43; compared to a 17% increase from 76 ng/mL at Baseline to 89 ng/mL at Day 43 in the PBO cohort. DAS 28-CRP low disease activity or remission at Day 43 occurred in 4/15 patients receiving GS-5745 versus 0/3 receiving PBO There were no SAEs. All adverse events were of Grade 1 or 2 severity. AEs occurring in ≥10% of active treated subjects included hypertension and nasopharyngitis, both 13%. Changes in additional RA disease activity measures are shown in the tab: Conclusions Short term treatment with GS-5745 in patients with RA was well tolerated. Improvement in selected measures of RA disease activity was observed after 3 doses of GS-5745. Mean free plasma MMP9 was reduced by 90% compared to baseline in the GS-5745 group at Day 43. These results support further studies evaluating GS-5745 in RA. Acknowledgement We would like to thank study investigators Drs. E. Peterfai, B. Rojkovich, P. Sramek, I. Varkonyi, their study staff and the study subjects who volunteered for this trial. Disclosure of Interest D. Gossage Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., B. Cieslarova: None declared, S. Ap Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., H. Zheng Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., S. Zhao Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Y. Xin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., P. Lal Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., G. Chen Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., V. Smith Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., J. Sundy Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.