SUCCESSES AND PITFALLS IN ORPHAN DRUG DEVELOPMENT FOR SICKLE CELL DISEASE.

Sickle cell disease (SCD) is a hereditary red cell disorder with large global burden problem. In the United States (US) and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the US and Europe over the last two decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 OD for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021) development of 34/57 ODs was completed. Four OD were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared to products targeting disease consequences. Large companies showed a fourfold higher success rate compared to small-medium enterprises. Failures in clinical development were mainly seen in Phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study endpoint, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical endpoints.