Efficacy and Safety of the TYK2/JAK1 Inhibitor Brepocitinib for Active Psoriatic Arthritis: A Phase IIb Randomized Controlled Trial

Abstract

Objective Brepocitinib is a TYK2/JAK1 inhibitor in development for the treatment of several immunologic diseases. The efficacy and safety of oral brepocitinib were assessed in participants with moderately‐to‐severely active psoriatic arthritis (PsA) for up to 52 weeks. Methods In this placebo‐controlled, dose‐ranging, phase IIb study, participants were randomized to receive 10 mg, 30 mg, or 60 mg of brepocitinib once daily or placebo, advancing to 30 mg or 60 mg of brepocitinib once daily at week 16. The primary endpoint was the response rate according to the American College of Rheumatology criteria for 20% improvement (ACR20) in disease activity at week 16. Secondary endpoints included response rates according to the ACR50/ACR70 response criteria, 75% and 90% improvement in the Psoriasis Area and Severity Index (PASI75/PASI90) score, and minimal disease activity (MDA) at weeks 16 and 52. Adverse events were monitored throughout the study. Results Overall, 218 participants were randomized and treated. At week 16, the brepocitinib 30 mg and 60 mg once daily groups had significantly greater ACR20 response rates (66.7% [P = 0.0197] and 74.6% [P = 0.0006], respectively), versus the placebo group (43.3%), and significantly higher ACR50/ACR70, PASI75/PASI90, and MDA response rates. Response rates were maintained or improved through week 52. Adverse events were mostly mild/moderate; serious adverse events (15) in 12 participants (5.5%) included infections in 6 participants (2.8%) in the brepocitinib 30 mg and 60 mg once daily groups. No major adverse cardiovascular events or deaths occurred. Conclusion Treatment with brepocitinib at dosages of 30 mg and 60 mg once daily was superior to placebo at reducing signs and symptoms of PsA. Brepocitinib was generally well tolerated throughout the 52‐week study, with a safety profile consistent with those found in other brepocitinib clinical trials.

Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis

“…In the phase 2 trial investigating BREP, one malignancy was observed (uterine leiomyoma) in the BREP 60 mg OD arm compared with no events in the other treatment arms. 10 No malignancy occurred during the 16 weeks of the DEUC phase 2 trial. 11 …”

“…Exploratory analyses also showed benefit for BREP-treated patients in achieving MDA and improvement of enthesitis (only for BREP 60 mg once daily) and dactylitis outcomes (only for BREP 10 mg and 60 mg once daily), as well as physical function and fatigue. 10 …”

“…One basal cell carcinoma occurred in the BREP 60 mg once daily arm compared with no events in the other arms. 10 …”

“…With an increasing depth of understanding immunological pathways of PsA, the body of evidence on the efficacy of new molecules targeting different modes of action (MOAs), such as inhibition of the p19 subunit of interleukin (IL)-23 6–8 and IL-17, 9 but also Janus Kinase (JAK) including the tyrosine kinase 2 (TYK2) pathway, has significantly increased in recent years. 10–12 …”

Inflammatory Cytokines in Psoriatic Arthritis: Understanding Pathogenesis and Implications for Treatment

“…New findings from a phase 2 randomized controlled trial indicate that both 30 mg and 60 mg doses of brepocitinib administered once daily were more effective in alleviating PsA signs and symptoms than placebo. Over the course of a 52-week study, brepocitinib had a favorable safety profile and was well tolerated by the participants [125].…”