Voxelotor Benefits Red Blood Cell Functionality in Pediatric Sickle Cell Disease

Satheesh Chonat, MD

Credit: Children's Healthcare of Atlanta

Voxelotor therapy in pediatric patients with sickle cell disease (SCD) was linked to improvements in red blood cell (RBC) functionality with increased RBC deformability after 12 weeks of treatment.¹

The trial was an ancillary to the phase 2a HOPE-KIDS 1 trial and involved 10 children aged 4 to 11 years with the homozygous HbS (HbSS) genotype of SCD. These results exhibited reduced RBC sickling and hemolysis after voxelotor treatment in children with SCD.

“The collective findings demonstrate that voxelotor has the potential to be the first RBC rheology-modifying HbS polymerization inhibitor for SCD management” wrote the investigative team, led by Satheesh Chonat, MD, Emory Children’s Center.

SCD is characterized by the polymerization of sickle hemoglobin under conditions of deoxygenation, leading to chronic anemia and hemolysis, and ultimately, severe morbidity and early mortality. Voxelotor, an HbS polymerization inhibitor that increases hemoglobin–oxygen affinity, received US Food and Drug Administration (FDA) approval in 2019, with an expansion for children as young as 4 years old in 2021.² Pivotal trial data have shown rapid and sustained improvements in hemoglobin and markers of hemolysis with voxelotor compared with placebo.³

The current study examined the effect of voxelotor therapy on RBC functionality by increasing RBC deformability in parallel with potential improvements to Hb levels and HB-oxygen affinity in a subgroup of pediatric patients in the phase 2a HOPE-KIDS 1 study.¹

An open-label, multicenter clinical trial, HOPE-KIDS 1 evaluated the pharmacokinetics, safety, tolerability, and treatment effect of weight-based voxelotor dosing in children with HbSS or sickle beta zero thalassemia (HBSβ0) SCD. In this trial analysis, whole blood samples from those treated with voxelotor were obtained to assess the effect of deoxygenation and reoxygenation on RBC deformability under shear stress.

A total of 10 patients with the HbSS genotype, and a mean baseline of 90 g/L, were included for analysis. Upon analysis, at week 24, 7 patients (70%) experienced a hemoglobin response (≥10 g/L increase from baseline), compared with 47% in the overall HOPE-KIDS 1 population. At each assessment, the mean Hb exceeded 100 g/L—by week 24, 6 of 10 patients experienced an Hb ≥100 g/L.

The analysis also found voxelotor reduced markers of hemolysis, including reticulocytes, indirect bilirubin, and lactate dehydrogenase) at weeks 12, 24, 36, and 48. Chonat and colleagues indicated the reductions in hemolysis markers at week 24 were higher in these patients than the overall HOPE-KIDS-1 population, similar to the trends seen in Hb response.

Regarding the primary outcome, improvements in RBC deformability were observed after voxeletor treatment using both osmotic and oxygen gradient ektacytometry. Improvements in RBC defomarability were sustained over 48 weeks, as demonstrated by the increases in minimal and maximal elongation index. Voxeletor treatment was additionally associated with reductions in the point of sickling.

Chonat and colleagues noted the few patients in the study, all obtained from a single study center, may not be representative of the larger patient population. They also suggested RBC defomability in SCD is greatest in early life, meaning these findings may not be generalizable for adults with the disease.

“Nonetheless, the collective findings demonstrate that voxelotor has the potential to be the first RBC rheology-modifying HbS polymerization inhibitor for SCD management,” investigators wrote.

References

1. _{Chonat S, Fields E, Baratz H, et al. Voxelotor improves red blood cell functionality in children with sickle cell anaemia: An ancillary study of the HOPE-KIDS 1 trial. EJHaem. 2024;5(1):125-130. Published 2024 Jan 30. doi:10.1002/jha2.831}
2. _{Center for Drug Evaluation and Research. FDA approves drug to treat sickle cell disease in pediatric patients. U.S. Food and Drug Administration. December 17, 2021. Accessed February 26, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-sickle-cell-disease-patients-aged-4-11-years.}
3. _{Barriteau CM, Badawy SM. Practical Guidance for the Use of Voxelotor in the Management of Sickle Cell Disease. J Blood Med. 2022;13:739-745. Published 2022 Nov 29. doi:10.2147/JBM.S362222}