Discontinued therapies for sickle cell disease: status and future directions.

Abstract

Introduction: Over the past decade, the therapeutic landscape for sickle cell disease (SCD) has expanded beyond hydroxyurea to targeted small molecules, monoclonal antibodies, and transformative cellular and gene therapies. However, not every investigational approach survives the rigor of randomized trials, post-marketing surveillance, and commercial realities. High-profile discontinuations and trial failures have important implications for a disease community with longstanding unmet needs and a historical mistrust of biomedical research.

Areas covered: This review analyzes the proximate causes of discontinuation of SCD therapies, highlighting recurrent themes such as overreliance on surrogate endpoints, trial design limitations, post-marketing safety surveillance gaps, enrollment challenges, and corporate reprioritization, and draws lessons for future drug development. We place the most consequential cases in context and discuss how next-generation agents, trial design innovations, biomarker-based strategies, and equitable deployment might reduce the likelihood and impact of future discontinuations. Finally, we propose pragmatic recommendations to maximize patient benefit while minimizing avoidable harms.

Expert opinion: Recent advances in sickle cell therapies bring real promise alongside setbacks. Failures are part of progress, but better trial design, transparency, patient partnership, and shared data can reduce harm, strengthen trust, and ensure innovation translates into meaningful, durable patient benefit.