OP0059 MAVRILIMUMAB (ANTI GM-CSF RECEPTOR Α MONOCLONAL ANTIBODY) REDUCES RISK OF FLARE AND INCREASES SUSTAINED REMISSION IN A PHASE 2 TRIAL OF PATIENTS WITH GIANT CELL ARTERITIS

Abstract

Background:T helper (Th)1 and Th17 lymphocytes play a role in the pathogenesis of giant cell arteritis (GCA). Current treatments primarily target the Th17 axis, possibly leaving residual Th1 activity. Granulocyte macrophage colony stimulating factor (GM-CSF), a mediator of Th1 and Th17 cells, is a pathogenic factor in GCA.Objectives:To evaluate the efficacy and safety of the GM-CSF inhibitor mavrilimumab in patients with GCA.Methods:Randomized, double-blind, placebo-controlled phase 2 trial enrolling patients with active, biopsy- or imaging-proven new onset (N/O) or relapsing refractory (R/R) GCA. Active disease: GCA symptoms and erythrocyte sedimentation rate (ESR) (>30 mm/hr) and/or C-reactive protein (CRP) (≥1 mg/dL) elevation within 6 weeks from randomization. Corticosteroid-induced remission (resolution of GCA symptoms and CRP <1 mg/dL or ESR <20 mm/hr) was required by baseline. 3:2 randomization to mavrilimumab 150 mg or placebo subcutaneously every 2 weeks and protocol-defined 26-week prednisone taper starting at 20-60 mg/day.Primary efficacy endpoint: time to first adjudicated flare (ESR ≥30 mm/hr and/or CRP ≥1 mg/dL and GCA symptoms or new/worsening vasculitis on imaging) by Week 26 in all treated patients. Key secondary endpoint: sustained remission through Week 26. Safety up to Week 38 was assessed.Results:70 patients (35 N/O, 35 R/R) were enrolled (mavrilimumab [N=42] or placebo [N=28]). Mean (SD) age was 69.7 (7.48) years and 71.4% were female. Flare by Week 26 occurred in 8 (19%) and 13 (46.4%) patients receiving mavrilimumab and placebo, respectively (27.4 percentage points reduction). Median time to flare by Week 26 could not be estimated in the mavrilimumab group due to too few events (Not Estimable) and was 25.1 weeks [95% CI: (16.0, NE)] in the placebo group (HR [95% CI] 0.38 [0.15, 0.92]; p=0.0263) (Figure). Sustained remission at Week 26 occurred in 83.2% of patients receiving mavrilimumab and 49.9% of those receiving placebo (33.4 percentage points increase; p=0.0038). Results were consistent across disease type subgroups (HR for flare: N/O 0.29 [95% CI: 0.06, 1.31; nominal p= 0.0873]; R/R 0.43 [95% CI: 0.14, 1.30]; nominal p=0.1231), although not powered for significance (Table). Adverse events (AEs), mostly mild to moderate, were comparable between groups. There were 5 serious AEs (mavrilimumab 2 [4.8%], placebo 3 [10.7%]), none drug-related. No deaths or vision loss occurred. No adjudicated cases of pulmonary alveolar proteinosis were observed.Table 1.Efficacy at Week 26All Patients [1]SubgroupsN/OR/RMavrilimu-mab (N=42)Placebo (N=28)Mavrilimu-mab (N=24)Placebo (N=11)Mavrilimu-mab (N=18)Placebo (N=17)Patients with Flare, n (%)8 (19.0)13 (46.4)3 (12.5)4 (36.4)5 (27.8)9 (52.9)Time to Flare (weeks) [2]Median, 95% CINE (NE, NE)25.1 (16.0, NE)NE (NE, NE)NE (11.7, NE)NE (16.4, NE)22.6 (16.0, NE)HR (Mavrilimumab vs Placebo), 95% CI [3]0.38 (0.15, 0.92)0.29 (0.06, 1.31)0.43 (0.14, 1.30)P-value [4] [5]0.02630.08730.1231Sustained Remission (%), 95% CI [6]83.2 (67.9, 91.6)49.9 (29.6, 67.3)91.3 (69.3, 97.7)62.3 (27.7, 84.0)72.2 (45.6, 87.4)41.7 (17.4, 64.5)Difference in Proportions (95% CI) [7]33.3 (10.7, 55.8)28.9 (-2.7, 60.5)30.6 (-2.1, 63.2)P-value [5] [7]0.00380.07270.0668NE = Not estimable. [1] Total mITT population. Stratified by randomization strata. [2] Kaplan-Meier. [3] Cox proportional-hazards model; treatment as covariate. [4] Log-rank test. [5] N/O and R/R subgroups not powered for significance; nominal p values reported. [6] Kaplan-Meier Survival Estimates with standard error. [7] Two-sided p-value for the difference in sustained remission between 2 arms using normal approximation. Placebo arm is reference.Conclusion:Mavrilimumab was superior to placebo on the primary and secondary efficacy endpoints of time to flare and sustained remission at week 26 in patients with GCA. Mavrilimumab was well tolerated, and no new safety signals were observed.Disclosure of Interests:Maria C. Cid Speakers bureau: meeting attendance support from Roche and Kiniksa, Paid instructor for: educational from GSK and Vifor, Consultant of: consulting for Janssen, GSK, and Abbvie, Grant/research support from: research grant from Kiniksa, Sebastian Unizony Consultant of: consulting for Janssen and Kiniksa, Grant/research support from: research support from Genentech, Lara Pupim Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Fang Fang Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Joseph Pirrello Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Ai Ren Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Manoj Samant Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Teresa Zhou Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, John F. Paolini Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals