Background/Purpose: Interleukin (IL)-1 is a catabolic cytokine that plays an important role in pathogenesis and progression of osteoarthritis (OA). Two phase 1 clinical trials investigated the use of a novel human dual-variable domain−immunoglobulin (DVD-Ig^™) simultaneously targeting IL-1α and IL-1β (ABT-981).

Methods: ABT-981 was evaluated in a randomized, double-blind, placebo (PBO)-controlled single ascending dose (SAD) trial and a multiple ascending dose (MAD) trial (NCT01668511). In the SAD trial, 56 healthy subjects were divided into 7 cohorts. Each cohort received single intravenous (IV) or subcutaneous (SC) dose of ABT-981 (0.3, 1, 3, 10 mg/kg IV or 0.3, 1, 3 mg/kg SC) or PBO in a 6:2 ratio. In the MAD trial, 36 patients with mild/moderate knee OA were divided into 4 cohorts. Cohorts 1–3 received ABT-981 (0.3, 1, 3 mg/kg) or PBO in a 7:2 ratio every 2 weeks (EOW) for total of 4 SC injections; cohort 4 received ABT-981 (3 mg/kg) or PBO in 7:2 ratio every 4 weeks for total of 3 SC injections. Safety, tolerability, pharmacokinetics (PK), and anti-drug antibodies (ADAs)were assessed in both trials. In addition, a panel of serum/urine biomarkers of target engagement, inflammation and joint degradation were evaluated in the MAD trial.

Results: The incidence of adverse events (AEs) was similar with single-dose ABT-981 vs PBO via IV (66.7% vs 50.0%) or SC (55.6% vs 66.7%) routes and multiple SC doses of ABT-981 vs PBO (53.6% vs 62.5%). The most common AEs with ABT-981 vs PBO was diarrhea (IV: 20.8% vs 12.5%) and headache (SC: 22.2% vs 0%) in the first trial, and injection-site reaction (17.9% vs 0%) in the second trial. In MAD trial, absolute neutrophil count (ANC) decreased dose-dependently, starting at 48 hours and reaching nadir by 14 days; lowest ANC values observed with 3 mg/kg. One patient had a transient grade 2 neutropenia after 1 dose in 3 mg/kg EOW group, along with serious AE of grade 3 bronchitis/viral syndrome both considered possibly study-drug related.

In MAD trial, ABT-981 at all 3 doses significantly reduced serum levels of high-sensitivity C-reactive protein (hsCRP; P<0.05), matrix metalloproteinase (MMP)-degraded type 1 collagen (C1M; P<0.05 at 1 and 3 mg/kg ), IL-1α (P<0.001), and IL-1β (P<0.001). Serum concentrations of MMP-degraded type 3 collagen (C3M; 1 and 3 mg/kg) and MMP-degraded CRP (CRPM; 3 mg/kg) demonstrated decreasing trends (0.05<P<0.1) with ABT-981 treatment but did not reach statistical significance.

Conclusion: The results of these phase 1 trials demonstrate that ABT-981 was well tolerated and had dose-proportional PK in healthy subjects and patients with knee OA. The similar safety profiles between ABT-981 and PBO support phase 2 investigation of ABT-981 in patients with OA. Through simultaneous inhibition of IL-1α and IL-1β in patients with OA, ABT-981 significantly reduced serum hsCRP levels, indicating a reduction in systemic inflammation, and C1M levels, indicating a dampening of inflammation-mediated joint destruction. Additionally, the observed serum C1M, C3M and CRPM decreases suggest that ABT-981 may ameliorate inflammation-mediated tissue destruction and chronic tissue inflammation in patients with inflammation-driven OA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-1-studies-of-anti-interleukin-1-dual-variable-domain-immunoglobulin-in-healthy-subjects-and-patients-with-osteoarthritis/