Accelerated approval of Oxbryta® (voxelotor): A case study on novel endpoint selection in sickle cell disease.

Sickle cell disease (SCD) is an inherited disease characterized by hemolysis, anemia, and vaso-occlusion leading to substantial morbidity and mortality. Development of prior pharmacologic therapies exclusively utilized vaso-occlusive crisis (VOC) as a clinical efficacy endpoint; however, this focus on VOC did not capture the full extent of disease symptomatology and complications and slowed the development of new therapies. Voxelotor, a hemoglobin S polymerization inhibitor, was recently approved in the United States for the treatment of SCD in adults and adolescents 12 years of age and older through an accelerated approval pathway. The rapid approval and availability of voxelotor was facilitated in a collaborative effort with the US Food and Drug Administration (FDA), using hemoglobin, a biologic surrogate endpoint, as reasonably likely to predict clinical benefit. Use of this new endpoint was supported by FDA-led multistakeholder discussions with physician and patient communities to identify unmet needs and potential clinical trial endpoints, as well as by a company-sponsored analysis of external patient-level data to demonstrate a correlation between hemoglobin change and stroke risk. A two-part phase 3 study was used to allow for rank ordering of key secondary endpoints based on a planned interim analysis. Continued open communication with the FDA was essential to gain agreement on hemoglobin as a novel endpoint and to address the unmet and urgent need of new therapies for SCD.