Anti-CD38 isatuximab Immunotherapy in Hidradenitis Suppurativa: a randomized, double-blinded, placebo-controlled, seamless phase 2a/2b trial

PROJECT SUMMARY Hidradenitis Suppurativa (HS) is a significant health concern affecting a notable portion of the U.S. population, with higher prevalence and severity in females and African Americans. Despite its significant impact on morbidity, current treatments often yield inconsistent results. CD38, a protein involved in immune regulation, was elevated on multiple cell types in various autoimmune and autoinflammatory conditions. Notably, anti-CD38 immunotherapy, available as daratumumab and isatuximab, has been FDA-approved for refractory multiple myeloma and used off-label for various autoimmune and autoinflammatory conditions, including lupus. Our preliminary findings indicate increased CD38 expression in HS patients, particularly in specific immune cells and skin lesions. Ex-vivo experiments with an anti-CD38 antibody showed promising reductions in inflammatory markers, emerging as a potential target for HS treatment. To test the therapeutic efficacy and safety of anti- CD38 immunotherapy isatuximab in patients with HS, we propose an investigator-initiated, randomized, double- blinded, placebo-controlled, seamless phase 2a/2b trial in patients with severe HS (Hurley stage III disease) who failed adalimumab and have high CD38 expression in the blood or skin. We hypothesize that anti-CD38 immunotherapy could be an effective and safe treatment for patients with HS. We will evaluate our hypothesis through the following aims: Aim 1 (Phase UG3): Accomplish the required milestones for the anti-CD38 immunotherapy clinical trial start-up phase, including finalizing regulatory compliance and protocols as well as securing operational readiness. Aim 2 (Phase UH3): Establish both the efficacy and safety of anti-CD38 immunotherapy in patients with HS by evaluating short-term efficacy as the primary endpoint [HS Clinical Response (HiSCR) 50 at Week 20] and long-term efficacy through multiple secondary endpoints by comparing valid outcome measures at Week 36. Safety and tolerability will be assessed as secondary endpoints by comparing adverse events in the treatment and placebo arms. Aim 3 (Phase UH3): Identify biomarkers to predict the response to anti-CD38 immunotherapy in HS using advanced profiling techniques. The results of this trial will inform the feasibility and effectiveness of anti-CD38 immunotherapy in HS management, guiding the design of future larger-scale clinical trials.