Safety and effectiveness of voxelotor in individuals with sickle cell disease in the RETRO and PROSPECT US registries.

Two registry studies, RETRO and PROSPECT, were conducted to evaluate real-world safety and effectiveness outcomes in US participants with sickle cell disease (SCD) who received voxelotor as standard of care. RETRO collected retrospective data of participants aged ≥12 years at 9 US sites for ∼1 year after voxelotor initiation. PROSPECT collected retrospective and prospective data of participants aged ≥4 years at 24 US sites, with a 5-year follow-up planned. Both studies collected data for 1 year before voxelotor initiation. RETRO enrolled 216 participants. PROSPECT enrolled 265 participants before voxelotor was withdrawn from global markets in September 2024; of these, 260 participants received voxelotor. The mean ± standard deviation (SD) voxelotor treatment duration was 50.52 ± 25.1 and 143.2 ± 65.6 weeks in RETRO and PROSPECT, respectively. Safety analyses included all participants who received voxelotor. The mean ± SD observed change in hemoglobin from baseline was from 0.6 ± 1.6 to 0.8 ± 1.5 g/dL in RETRO (∼1 year) and from 0.1 ± 1.7 to 0.7 ± 1.5 g/dL in PROSPECT (54 months). After starting voxelotor, decreases were observed from baseline in hemolysis markers (absolute/percentage reticulocyte counts, total/indirect bilirubin) across all RETRO time points and most PROSPECT time points. Acute pain crisis (APC) was the most common SCD complication (annualized incidence rates before and after voxelotor, respectively: RETRO: 1.33 and 1.54; PROSPECT 4.78 and 3.15). No new safety findings were identified. Despite inherent limitations of registry studies, voxelotor treatment increased hemoglobin and decreased hemolysis markers in US clinical practice, with no evidence of increased frequency of APC. These studies were registered at www.ClinicalTrials.gov as NCT04930328 and NCT04930445.