The Efficacy and Safety of Clazakizumab, an Anti–Interleukin‐6 Monoclonal Antibody, in a Phase IIb Study of Adults With Active Psoriatic Arthritis

Abstract

Objective To evaluate the efficacy of clazakizumab, a monoclonal antibody with high affinity and specificity for the interleukin‐6 (IL‐6) cytokine, in psoriatic arthritis (PsA). Methods In this randomized, double‐blind, placebo‐controlled, dose‐ranging study (ClinicalTrials. gov identifier: NCT01490450), patients with active PsA and an inadequate response to nonsteroidal antiinflammatory drugs were randomized (1:1:1:1) to receive subcutaneous placebo or clazakizumab 25 mg, 100 mg, or 200 mg every 4 weeks, with or without methotrexate. The primary end point was the response rate according to the American College of Rheumatology 20% criteria for improvement (ACR20) at week 16, with secondary efficacy end points at weeks 16 and 24. Results A total of 165 patients were randomized. At week 16, the ACR20 response rate was significantly higher with clazakizumab 100 mg versus placebo (52.4% versus 29.3%; P = 0.039). ACR20 response rates at week 16 were 46.3% with clazakizumab 25 mg (P = 0.101 versus placebo) and 39.0% with clazakizumab 200 mg (P = 0.178 versus placebo). ACR50/ACR70 response rates were numerically higher with clazakizumab versus placebo at weeks 16 and 24. Compared with placebo, clazakizumab treatment significantly improved musculoskeletal manifestations (joint signs and symptoms, enthesitis, and dactylitis), with minimal improvements in skin disease, without clear evidence of a dose response. Clazakizumab was well tolerated. Conclusion This is the first clinical trial of an IL‐6–targeted therapy in PsA. Clazakizumab may be an effective treatment option for musculoskeletal aspects of PsA, but because of the lack of a dose response in this study, further studies are required to confirm the appropriate dose. The safety profile is consistent with the pharmacology of IL‐6 blockade and prior clinical experience with this antibody in rheumatoid arthritis.

Interleukin 6 regulates psoriasiform inflammation–associated thrombosis

“…Treatment of psoriasis patients with TNF-α inhibitors is highly efficacious at improving the severity of the skin disease and normalizes psoriasis patient platelet counts by reducing systemic IL-6 levels (41). Similar normalization of platelet counts following IL-6 inhibition has recently been demonstrated (38). These findings are consistent with the decreases in platelet counts we observed in KC-Tie2xIL-6 -/-mice and support a role for elevated IL-6 and thrombocytosis in mediating the thrombosis outcome.…”

“…The lack of skin improvement we observe in KC-Tie2xIL-6 -/-(and K5-IL-17CxIL-6 -/-; see ref. 26) psoriasiform animal models is highly consistent with human trials, where blockade of IL-6 fails to improve psoriasis severity, and in some instances, causes psoriasis flares (24,(35)(36)(37)(38), perhaps due to increases in alternative proinflammatory cytokines (26). Differences in model systems may account for the different outcomes, such that IL-23 and imiquimod psoriasiform models are acute and elicited, whereas KC-Tie2 and K5-IL-17C models are chronic and occur spontaneously in response to transgene overexpression.…”

IL-6: To immunity and beyond

“…In a 24-week randomised, double-blind, placebo-controlled, dose-ranging study, patients with active psoriatic arthritis were randomised 1:1:1:1 to receive subcutaneous placebo or subcutaneous clazakizumab, an anti-IL-6 monoclonal antibody, at dosages of 25, 100, or 200 mg every 4 weeks with or without methotrexate 24. The primary endpoint was response rate according to ACR20 at week 16.…”

New Possibilities of Pharmacotherapy for Immunoinflammatory Rheumatic Diseases: A Focus on Inhibitors of Interleukin-17

“…На первый взгляд выглядит парадоксальным, но, хотя цитокины семейства ИЛ17 обладают широким (в определенной степени уни-кальным) спектром «провоспалительных» и деструктив-ных эффектов, при РА мАТ к ИЛ17А менее эффективны, чем ингибиторы других «провоспалительных» цитокинов (ФНОα, ИЛ6). В то же время при псориазе, ПсА и АС мАТ к ИЛ17А не только не уступают ингибиторам ФНОα, но даже превосходят их, а мАТ к ИЛ6 (клазакизу-маб) или его рецепторам (тоцилизумаб) малоэффектив-ны или действуют только в отношении мышечно-скелет-ных проявлений при ПсА [167]. Это существенно сужает возможности их применения в клинической практике.…”