Voxelotor Retrospective Study Uncovers Additional Adverse Effects

A recent retrospective study examined past usage of voxelotor, a recalled medication for sickle cell disease, and determined that more information is necessary before the chemical can be used without fear of side effects.1

Voxelotor, an oral small molecule inhibiting the polymerization of hemoglobin S (HbS), was approved by the US Food and Drug Administration (FDA) in 2019 to treat sickle cell disease; however, in 2024, a review of clinical data indicated that the drug’s risks outweighed its potential benefits.2 As a result, Pfizer announced on September 25, 2024, that it would be recalling voxelotor from all approved markets and discontinuing further trials or access programs.3

“The study underscored the reliability of using real-world data to enhance pharmacovigilance, despite limitations like potential reporting bias and the inability to establish causality,” wrote Ying Lin, department of hematopathology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical Center, and colleagues. “Findings highlighted the need for ongoing monitoring and further investigation into voxelotor’s long-term safety and efficacy.”1

The study utilized the FDA's Adverse Event Reporting System (FAERS), a database that collates voluntary safety reports submitted by healthcare professionals and patients worldwide. Any voxelotor-related adverse event reports submitted between 2019 and 2024 were collected, creating an initial total of 22,375,298 records. After excluding duplications, 18,613,992 records were retained; these would be split off into those who had taken voxelotor and hydroxyurea – the target drug population – and those who had not – the comparator drug population.1

According to the team, a primary goal of the investigation was to identify and contrast the adverse drug reactions (ADRs) of both voxelotor and hydroxyurea. These were measured with four individual algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinkage (MGPS).1

Of voxelotor’s ADRs, the top 5 ranked by ROR were sickle cell anemia with crisis (ROR = 3782.72; 95% CI, 3638.29-3932.88), acute chest syndrome (ROR = 709.84; 95% CI, 610.88-824.82), sickle cell disease (ROR = 675.08; 95% CI, 554.74-821.52), double heterozygous sickling disorders (ROR = 619.09; 95% CI, 147.95-2590.64), and retinopathy sickle cell (ROR = 238.11; 95% CI, 67.85-835.62).1

Of hydroxyurea’s ADRs, the top 5 ranked by ROR were skin ulcer (ROR = 769.35; 95% CI, 228.58-2589.46), anemia (ROR = 569.89; 95% CI, 172.86-1878.83), thrombocytopenia (ROR = 526.3; 95% CI, 335.76-824.98), platelet count increased (ROR = 399.77; 95% CI, 174.15-917.7), and dysphagia (ROR = 349.7; 95% CI, 108.57-1126.4).1

Notably, significant voxelotor ADRs were identified that were not labeled, including skin ulcer (ROR = 5.04; 95% CI, 4.18-6.07), osteonecrosis (ROR = 3.94; 95% CI, 3.30-4.72), priapism (ROR = 29.27; 95% CI, 23.65-36.23), and frequent bowel movements (ROR = 3.86; 95% CI, 3.12-4.79). However, when investigators conducted a comprehensive analysis using both reporting frequency and ROR, they found that skin ulcer and anemia should be classified as inherent clinical manifestations of sickle cell disease rather than drug-related adverse events.1

According to Lin and colleagues, these findings indicated that although voxelotor effectively targets hemoglobin S polymerization, its impacts on tissue oxygenation and blood flow dynamics could contribute to several adverse effects. This indicates a need for increased pharmacovigilance utilizing real-world data, despite the limitations caused by possible biases and lack of causality, with the team encouraging further research.1

“Future research should be focused on addressing these limitations to validate the drug’s benefit-risk profile comprehensively,” Lin and colleagues wrote.1

References

1. Lin, Y., Li, H., Dong, Y. et al. A retrospective research of adverse event reporting system events for voxelotor based on the FAERS database. BMC Pharmacol Toxicol 26, 74 (2025). https://doi.org/10.1186/s40360-025-00915-1

2. Blair HA. Voxelotor: First Approval. Drugs. 2020;80(2):209-215. doi:10.1007/s40265-020-01262-7

3. Iapoce, Connor. Voxelotor for Sickle Cell Disease Recalled After Safety Concerns. HCPLive. October 1, 2024. Accessed April 4, 2025. https://www.hcplive.com/view/sozinibercept-for-wet-amd-misses-primary-endpoint-in-phase-3-coast-trial