Safety, tolerability, and pharmacodynamics of an anti-interleukin-1α/β dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study

• Published in: Osteoarthritis and cartilage Vol. 25; no. 12; pp. 1952 - 1961
• Main Authors: Wang, S.X., Abramson, S.B., Attur, M., Karsdal, M.A., Preston, R.A., Lozada, C.J., Kosloski, M.P., Hong, F., Jiang, P., Saltarelli, M.J., Hendrickson, B.A., Medema, J.K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2017
• Subjects: ABT-981; Clinical study; Interleukin-1; Osteoarthritis; Pharmacokinetic; Safety; ABT-981; Interleukin-1; Safety; Osteoarthritis; Pharmacokinetic; Clinical study
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1016/j.joca.2017.09.007

To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1α and IL-1β, in patients with knee osteoarthritis (OA). This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate OA of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of four SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of three SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. A total of 36 patients were randomized (ABT-981, n = 28; placebo, n = 8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 vs placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1α/IL-1β, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. ABT-981 was generally well tolerated in patients with knee OA and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven OA.