<>Background/Purpose: Osteoarthritis (OA) may comprise multiple phenotypes, one of which is inflammation-driven OA. Consequently, a selected subpopulation of OA patients may benefit from optimally targeted anti-inflammatory treatment. Interleukin-1 (IL-1) is a potent catabolic cytokine thought to play a major role in the development and progression of OA both in terms of disease (structural progression) and symptoms (pain and functional deterioration). The anti-inflammatory effects of a novel human DVD-Ig targeting IL-1α and IL-1β (ABT-981) were evaluated in knee OA patients using a panel of biomarkers that are elevated in the presence of tissue degradation secondary to joint inflammation.

  <>Methods: This was a randomized, double-blind, placebo-controlled trial of the safety, pharmacokinetics, and pharmacodynamics of multiple subcutaneous injections of ABT-981 in knee OA patients (N=36). Three groups of patients (n=27) received 4 doses of ABT-981 or matching placebo (7:2) every other week (EOW) at 0.3, 1, and 3 mg/kg. Serum samples were collected on days 1, 5, 15, 19, 29, 33, 43, 47, and 57. The panel of inflammation and joint-degradation biomarkers included high-sensitivity C-reactive protein (hsCRP); matrix metallopeptidase (MMP)-9; vascular endothelial growth factor (VEGF); MMP degradation products of type I, II, and III collagen (C1M, C2M, and C3M) and CRP (CRPM); and circulating levels of citrullinated and MMP-degraded vimentin (VICM). Biomarker response for patients on active drug in each group was compared with the pooled placebo response across groups. Statistical analysis was performed on least-square means using SAS 9.2.

  <>Results: Mean serum hsCRP levels in all ABT-981 groups were significantly decreased vs placebo (p value range, 0.003–0.031). Mean serum C1M levels decreased in a dose-dependent manner (p=0.062, 0.027, and 0.015 for 0.3, 1, and 3 mg/kg groups, respectively). Mean serum C3M levels exhibited a nonsignificant decreasing trend in the 1 and 3 mg/kg groups (p=0.062 and 0.090, respectively). Mean serum CRPM levels were decreased with ABT-981; however, a statistical difference was only established from day 33 on (p value range, 0.097–0.025; Figure). No other markers showed significant changes or trends.

  <>Conclusion: Through inhibition of IL-1α and IL-1β, ABT-981 significantly reduced serum hsCRP and markers of joint metabolism that are elevated in inflammation-driven joint destruction diseases, suggesting a reduction in systemic inflammation. ABT-981 significantly decreased C1M, suggesting a dampening of inflammation-mediated joint destruction by reducing connective tissue turnover. The observed serum C3M and CRPM decreases suggest the potential of ABT-981 to ameliorate inflammation-mediated tissue destruction and chronic tissue inflammation. Thus, ABT-981 may provide clinical benefit to a selected subpopulation of patients with inflammation-driven OA.