SAT0110 Efficacy and Safety of Pateclizumab (Anti-Lymphotoxin-Alpha) in Dmard-Ir Patients: Results of a Randomized, Double-Blind, Placebo-Controlled Head-To-Head Phase 2 Study with Adalimumab

Abstract

Background Pateclizumab (formerly MLTA3698A), a novel humanized IgG1 antibody against soluble and membrane isoforms of lymphotoxin-alpha, is being investigated as a targeted therapy for rheumatoid arthritis (RA). Objectives To compare the efficacy and safety of subcutaneous Pateclizumab (PTZ) vs placebo (PBO) and adalimumab (ADA) in patients with active RA and an inadequate response to DMARDs. Methods RA patients on oral DMARDs were randomized (2:2:1) to receive PTZ 360 mg, ADA 40 mg, or PBO every 2 weeks. The primary endpoint, DAS28-ESR, was evaluated at 12 weeks. Pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PTZ were assessed. Results 217 patients were enrolled, 85 received PTZ, 85 received ADA, and 44 received PBO. Baseline demographics [mean (±SD)], age 50 years (±13.3), disease duration 8.7 yrs (±8.1), and clinical characteristics, were balanced across treatment arms. Mean baseline characteristics included a SJC of 18.6/17.4/15.8, TJC of 28.6/28.1/23.2, HAQ scores of 1.8/1.7/1.8, CRP values of 2.2/2.2/2.4 mg/dL, and DAS28-ESR scores of 6.95/6.82/6.79, for PTZ/ADA/PBO, respectively. RF/anti-CCP status and use of methotrexate or leflunomide as DMARD agent were comparable across groups at baseline. 86% of PTZ, 87% of ADA, and 77% of PBO subjects completed 10 weeks of dosing for the efficacy analyses. PTZ 12wk DAS28-ESR response (-1.96) was not significantly different from PBO (-1.66), while ADA (-2.63) differed significantly from both PBO (P<0.01) and PTZ (p<0.01). PTZ 12wk ACR20 response (60%) differed significantly (P=0.03) from PBO (40%), but ACR50 or ACR70 did not. ADA 12wk ACR20 (68%), ACR50 (51%) and ACR70 (31%) differed significantly from PBO (40%, 21%, and 7.0% respectively). CXCL13, a PD biomarker that decreases with TNFα or lymphotoxin-alpha blockade [Emu et al, 2011], significantly decreased at 12wk with PTZ (p<0.01) or ADA (p<0.01) compared with PBO, demonstrating pharmacological target engagement. The PK profile of pateclizumab was comparable to popPK model predictions [1]. Overall, adverse events (AE) and infectious AE were comparable between PTZ, ADA, and PBO groups. 1% of PTZ patients, 6% of adalimumab patients and 2% of PBO patients discontinued due to AEs. Infections were the most common AE, occurring with comparable frequency in PTZ (29.1%), ADA (36.5%), and PBO (34.9%) patients. Serious AEs occurred in 0% of PTZ, 5.9% (n=5) of ADA, and 2.3% (n=1) of PBO patients, with serious infection in 2.3% (n=1) of ADA patients and none in PTZ and PBO patients. Treatment-emergent anti-therapeutic antibodies were uncommon in PTZ-treated patients (4 positive / 86 total exposures) and were not associated with changes in PK or safety. Conclusions Pateclizumab treatment of DMARD-IR RA patients was associated with modest improvement in the signs and symptoms of RA, and was inferior to adalimumab after 12 weeks of treatment. Statistically significant treatment effects of pateclizumab were only detected for the secondary endpoint of ACR20. Pateclizumab had a safety profile comparab...