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SAT0448 Interleukin-1 Dual Variable–Domain Immunoglobulin Reduces Multiple Imflammatory Markers in Knee Osteoarthritis Patients
  1. S.X. Wang1,
  2. J.K. Medema1,
  3. M.P. Kosloski1,
  4. W. Liu1,
  5. M.J. Saltarelli1,
  6. M. Karsdal2
  1. 1AbbVie Inc., North Chicago, United States
  2. 2Nordic Bioscience, Herlev, Denmark

Abstract

Background 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). In a mouse OA model, simultaneous inhibition of IL-1α and IL-1β with mouse anti–IL-1α/β dual-variable domain–immunoglobulin (DVD-Ig) reduced OA progression more than inhibition of either IL-1 isoform alone.

Objectives To evaluate the anti-inflammatory effects of a novel human DVD-Ig targeting IL-1α and IL-1β (ABT-981) in knee OA patients, using a panel of biomarkers 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. A fourth group (n=9) received 3 doses at 3 mg/kg every 4 weeks; results for this group will be discussed separately. 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.

Conclusions Through simultaneous inhibition of IL-1α and IL-1β, ABT-981 significantly reduced serum hsCRP and markers of joint metabolism that are often 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. Additionally, the observed serum C3M and CRPM decreases suggest the potential of ABT-981 to ameliorate inflammation-mediated tissue destruction and chronic tissue inflammation. Consequently, ABT-981 may provide clinical benefit to a selected subpopulation of patients with inflammation-driven OA.

Disclosure of Interest S. Wang Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., J. Medema Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., M. Kosloski Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., W. Liu Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., M. Saltarelli Shareholder of: AbbVie, Inc., Employee of: AbbVie, Inc., M. Karsdal Consultant for: AbbVie, Inc., Employee of: Nordic Bioscience

DOI 10.1136/annrheumdis-2014-eular.5528

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