Clinical Data Comparison for FDA-Approved Gene Therapies in Sickle Cell Disease

Abstract

Abstract Sickle cell disease (SCD) is a severe inherited hemoglobinopathy with limited curaWve treatment opWons. In December 2023, the U.S. FDA approved two autologous gene therapies, lovo-cel (bluebird bio) and exa-cel (Vertex/CRISPR TherapeuWcs), offering potenWally transformaWve outcomes. We performed a comparaWve analysis of these therapies based on published clinical trial design, paWent eligibility, manufacturing requirements, and reported efficacy and safety outcomes. Overall, parWcipants treated with lovo-cel had more severe baseline disease, reflected by a higher median rate of vaso-occlusive events (VOEs), despite the use of a more stringent VOE definiWon. MobilizaWon of hematopoieWc stem cells (HSCs) with single-agent plerixafor proved challenging in both trials, with most parWcipants requiring mulWple mobilizaWon and apheresis cycles. A greater proporWon of exa-cel parWcipants required three or more apheresis procedures, driven by higher CD34+ cell dose targets needed to compensate for CRISPR-associated HSC loss. Both therapies demonstrated greater than 90% resoluWon of severe VOEs, with near-complete resoluWon in pediatric parWcipants. A small subset of parWcipants experienced VOEs post-treatment, including events occurring beyond the primary efficacy assessment period. Notably, no recurrent strokes were reported among lovo-cel treated parWcipants with a history of overt stroke. Both therapies provide durable, clinically meaningful benefit and represent a major advancement in SCD management. However, differences in trial populaWons, cell collecWon logisWcs, and manufacturing have important implicaWons for real-world applicaWons. ConWnued long-term follow-up and the establishment of standardized post-treatment registries will be criWcal to fully assess durability, monitor late effects, and inform paWent selecWon.