Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Efficacy and Safety of E6011, an Anti-Fractalkine Monoclonal Antibody, in Active Rheumatoid Arthritis Patients with Inadequate Response to Methotrexate: Results of a Randomized, Double-blind, Placebo-controlled Phase 2 study.

Abstract

OBJECTIVE: Evaluate the efficacy and safety of E6011, a humanized IgG2 monoclonal antibody against human fractalkine (FKN), in a phase 2, double-blind, placebo-controlled study in rheumatoid arthritis (RA) patients. METHODS: Patients with moderate to severe RA with inadequate response to methotrexate (MTX) were randomly assigned to a placebo or E6011 100-mg, 200-mg, or 400/200-mg group at a 2:1:2:2 ratio. During the 24-week period, patients received the study drug subcutaneously at weeks 0, 1, 2, and then every 2 weeks. The primary endpoint was the American College of Rheumatology (ACR)20 response at week 12. RESULTS: Study drugs were administered to 190 patients (54: placebo; 28: 100-mg; 54: 200-mg; 54: 400/200-mg), and 169 patients completed treatment. A significant difference from placebo was not found in ACR20 response at week 12 (37.0%, 39.3%, 48.1%, and 46.3% in placebo, 100-mg, 200-mg, and 400/200-mg groups, respectively, at nonresponder imputation). As a secondary endpoint, ACR20 response in the 200-mg and 400/200-mg groups attained statistical significance at week 24 (35.2%, 39.3%, 53.7%, and 57.4%, respectively). Subsequent exploratory subgroup analysis revealed greater efficacy of E6011, particularly in subjects with higher baseline proportion of CD16+ monocytes; their ACR20 responses at week 24 were 30.0% (placebo), 46.7% (100-mg), 57.7% (200-mg), and 69.6% (400/200-mg). E6011 administered for 24 weeks was well tolerated. CONCLUSION: This is the first evidence that E6011, a novel cell trafficking inhibitor targeting the FKN-CX3 CR1 interaction, is modestly effective at 24 weeks treatment in RA patients, although the primary endpoint was not met.