A recent study assessed the efficacy and safety of an oral drug for the treatment of moderate-to-severe plaque psoriasis.
Background and Objectives: BI 730357 is a novel, orally available small-molecule retinoic acid–related orphan receptor gamma t (RORγt) inhibitor targeting a key regulator of Th17 cells involved in psoriasis pathogenesis. By modulating this pathway, the drug aims to reduce inflammation and plaque formation. The study’s objective was to evaluate its efficacy, safety, and tolerability.
Study Design: Published in The Journal of Investigative Dermatology, the study was a two-part, double-blinded, randomized phase II trial. Part 1 assessed fasting conditions with doses ranging from 25 mg to 200 mg qd, while Part 2 evaluated fed conditions at doses of 400 mg qd and 200 mg bid or placebo. A total of 274 patients participated, with non-responders allowed to escalate doses. Some transitioned to a long-term extension (LTE) phase to assess sustained efficacy and safety.
Key Findings: The co-primary endpoints were achieving a ≥75% reduction in the Psoriasis Area and Severity Index (PASI 75) and a static Physician’s Global Assessment (sPGA) score of 0/1 (clear or almost clear) at 12 weeks. In Part 1, 30.0% of patients receiving 200 mg qd achieved PASI 75 compared with 0% of those receiving placebo (P = .0062). Similarly, 27.5% in the 200 mg qd group achieved an sPGA score of 0/1 (P = .0095). Notably, efficacy plateaued at doses ≥200 mg qd, with a maximum treatment effect of approximately a 50% relative change in PASI score.
Patient-reported outcomes showed mixed results. Changes in Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Scale (PSS) were modest and not significantly different from placebo in some groups.
Safety Profile: The drug was well-tolerated, with drug-related adverse events (AEs) occurring in ≤15.8% of patients in the core trial and ≤18.5% during the LTE phase. Serious adverse events (SAEs), such as severe worsening of psoriasis and fractures, were observed but were not attributed to the drug. No severe adverse reactions were directly linked to BI 730357.
Study Termination: The LTE trial was prematurely terminated after the study sponsor discontinued BI 730357’s development. This decision was based on limited efficacy and findings from a non-human carcinogenicity study, where human relevance could not be excluded.
Conclusion: While BI 730357 demonstrated moderate efficacy with an acceptable safety profile, its efficacy plateau and lack of a full clinical response at higher doses suggest limitations in its therapeutic potential. Further investigation into RORγt inhibition’s role in psoriasis treatment may provide insights into these challenges.
This study provides a foundation for understanding the potential and limitations of RORγt inhibitors in managing plaque psoriasis.
The authors disclosed no conflicts of interest.
