We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs).
This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.
Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events.
LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.