A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

Abstract

Objective. To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis.Methods. Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26.Results. The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom-and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations.Conclusion. The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.ClinicalTrials.gov identifier: NCT02087904.

Osteoarthritis year in review 2019: epidemiology and therapy

“…Primary end point was change in pain at 16 weeks. The first trial randomized 350 knee OA patients 26 . Only for one dose (100 mg) of lutikizumab a small statistical significant effect was seen at 16 weeks, but not at later time points.…”

Inflammasomes contributing to inflammation in arthritis

“…Other biologics have been developed to block the IL‐1 pathway, however, are currently not (yet) used in clinics. The monoclonal antibody lutikizumab (ABT‐981) has been engineered to target both IL‐1α and IL‐1β . Gevokizumab is an IL‐1β antagonistic antibody that binds strongly to IL‐1β without inhibiting its recruitment to the IL‐R.…”

“…The monoclonal antibody lutikizumab (ABT-981) has been engineered to target both IL-1α and IL-1β. 133 Gevokizumab is an IL-1β antagonistic antibody that binds strongly to IL-1β without inhibiting its recruitment to the IL-R. It prevents the engagement of the IL-1β-IL-1R signaling complex through its allosteric modulation properties.…”

Advances in Disease Mechanisms and Translational Technologies: Clinicopathologic Significance of Inflammasome Activation in Autoimmune Diseases

“…New developments in cytokine blockade include several drugs. Lutikizumab, which is a dual IL‐1α and IL‐1β antibody, is being evaluated in several diseases including erosive hand osteoarthritis (OA) and knee OA . While trial results do not support use of IL‐1 blockade in OA, the drug may have other indications.…”