A PHASE 2 STUDY OF MONTHLY SUBCUTANEOUS LY2127399 (AN ANTI-BAFF MONOCLONAL ANTIBODY) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

Background: LY2127399 (LY), a human monoclonal antibody, neutralizes membrane-bound and soluble forms of B cell activating factor (BAFF), an essential survival factor for peripheral B lymphocytes. LYpreviously showed clinical efficacy in active rheumatoid arthritis (RA) when administered by intravenous infusion. Objectives: To assess safety and efficacy of 6 subcutaneous (SQ) LY doses in patients (pts) with active RA. Methods: 156 pts on stable doses of methotrexate were randomized toreceive placebo (Pb), 1, 3, 10, 30, 60 or 120mg of LY for 6 SQ injections every 4 weeks (wks) over 24wks. A Bayesian-adaptive randomization design was used to allocate pts more efficiently by using accumulating data to change randomization ratios to increase the power of the primary analysis. The primary analysis was to test for a significant dose-response relationship from 0 – 120mg LY based on logistic regression of ACR50 response rates at wk24with a prespecified type I error rate of 0.1. Pts who discontinued prior to wk24 were imputed as non-responders. Results: Baseline characteristics were comparable across groups. A significant dose response was detected for ACR20 (p=.044)and ACR50 (p=.059) at wk24. The 120mg dose group had significantly better efficacy than Pb in ACR20, DAS28-CRP change from baseline, good/moderate EULAR response but not for other parameters (Table). In LY arms mean mature naive B cells (IgD+/CD27-) transiently increased within 1wk then decreased below baseline by wk24 while memory B cells (IgD/CD27) increased and remained above baseline. The frequency of TEAEs was similar across groups (range 50% to 69%, p=.855). SAEs were reported in 12 (10.0%) LY and 4 (11.1%) Pb-pts. Infections occurred more frequently in LY-pts (31% vs. 19%). Serious infections were reported in 3 (2.5%) LY and 0 Pb-pts. A serious infectious event of H1N1 influenza pneumonia was reported in a subject 24 days after a single 30mg dose who initially improved and experienced fatal sepsis 6 months later. Decreases in mean IgM and IgA occurred at higher LY doses but were not associated with the occurrence of infections; decreases in mean IgG were not significant compared to Pb. Wk24Pb1mg3mg10mg30mg60mg120mg n=36n=30n=20n=15n=18n=13n=24 ACR20 Response (%)44.440.045.046.761.153.870.8* ACR50 Response (%)22.210.010.033.311.17.737.5 ACR70 Response (%)5.63.30.06.75.60.04.2 EULAR Response (Good/Moderate) (%)57.164.352.657.176.558.382.6* Mean Change in DAS28 (n)-1.448-1.539-1.026-1.678-1.536-1.642-1.915** (n=35)(n=28)(n=19)(n=14)(n=17)(n=12)(n=23) Median Change in CRP-30.2719.574.26-13.82-50.53-44.23-31.80 Median Change in ESR-9.19-28.68-9.58-4.76-22.02-34.38-32.39 *p<0.05 compared to Pb (one-sided Fisher's exact test). **p<0.05 compared to Pb (one-sided t-test from ANCOVA model using treatment and baseline value as covariate) Conclusions: The LY safety profile in this study was similar to available RA therapies and no unexpected safety signals were seen. The 120mg dose group demonstrated significant reductions in the signs and symptoms of RA, and thiswas not contingent on complete B cell depletion. These results support further exploration of LY to treat RA. References: 1. Genovese MC et al. [abstract]. Arthritis Rheum 2009;60 Suppl 10:1923 Disclosure of Interest: M. Genovese Grant/Research support from: Eli Lilly and Co, Consultant for: Eli Lilly and Co, E. Lee Speakers Bureau: Abbott, Pfizer, Warner-Chilcott, Genentech, Novartis, Takeda, P. Hrycaj: None Declared, J. Satterwhite Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, M. Veenhuizen Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, D. Disch Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, P.-Y. Berclaz Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, S. Myers Shareholder of: Eli Lilly and Co, Employee of: Eli Lilly and Co, O. Benichou Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and CoCitation: Annals of the Rheumatic Diseases, volume 70, supplement 3, year 2011, page 71Session: Abstract Session: RA – non-TNF biologics (Oral Presentations )