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): Table 1
Authors: D.L. Gossage, B. Cieslarova, S. Ap, H. Zheng, S. Zhao, Y. Xin, P. Lal, G. Chen, V. Smith, J.S. Sundy
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> 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<sub>4</sub> mAb that inhibits MMP9 activity with picomolar specificity. <h3>Objectives</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> 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: <h3>Conclusions</h3> 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. <h3>Acknowledgement</h3> 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. <h3>Disclosure of Interest</h3> 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.