Background: Voxelotor, a hemoglobin S polymerization inhibitor, was approved in 2019 for the management of sickle cell disease (SCD). Given its relative novelty, data on its safety and efficacy is very limited. Thus, we aim to assess the effects of voxelotor on hemoglobin (Hb) levels, hemolysis markers, vaso-occusluisce crises (VOCs), and adverse events.

Methods: The PubMed, Cochrane, Science Direct and Embase databases were searched systematically up to July 2025 to identify randomized controlled trials (RCTs) in which patients were randomly assigned to either group A (voxelotor 1,500 mg daily) or group B (voxelotor 900 mg daily), with a placebo used as the comparator. The key outcomes included changes in serum levels of Hb, indirect bilirubin, and reticulocyte count. The annualized rate of VOCs was assessed. Adverse events included diarrhea, fatigue, and headache. A random-effects model was utilized to ascertain pooled estimates. Statistical heterogeneity was assessed using the I² statistic; an I² value exceeding 50% was considered substantial, and sensitivity analysis was conducted on the respective outcome.

Results: Four RCTs comprising 1,012 participants with SCD were included in this study. Volextor significantly increased Hb levels in both groups, with an increase of 1.10 g/dL in patients receiving 1500 mg daily and 0.85 g/dL in those receiving 900 mg daily (p < 0.00001 for both). Both comparisons showed no statistical heterogeneity (I² = 0%). Moreover, treatment with 1500 mg of voxelotor significantly reduced markers of hemolysis, with a 17.9% and 18.1% decrease in indirect bilirubin and reticulocyte count, respectively (p < 0.0001 for both). The lower 900-mg dose showed a modest effect, with a 1.35-fold greater reduction in bilirubin compared to placebo (p = 0.02). Reticulocyte counts declined by 1.20-fold at this dose, but it was statistically insignificant (p = 0.07). Surprisingly, voxelotor showed an insignificant impact on the rate of the VOCs compared to placebo. The 1500 mg group showed an absolute risk reduction (ARR) of –0.41 (p = 0.36), and the 900 mg group demonstrated an ARR of –0.19 (p = 0.69). When determining the safety profile, the incidence of diarrhea was significantly higher in the voxelotor-treated cohorts, specifically at the 1500 mg dose (p = 0.04). Other adverse effects, such as fatigue, arthralgia, and headache, were equally common in voxelotor- and placebo-adjudicated participants.

Conclusion: Voxelotor has demonstrated significant improvements in Hb levels, indirect bilirubin levels, and reticulocyte counts, particularly at a 1500-mg dose, suggesting its potential to mitigate the morbidity linked to hemolytic anemia in SCD. Nevertheless, due to the insignificant effect on the rate of VOCs, it may be essential to employ adjunctive therapies to achieve a more substantial improvement of this outcome. The safety outcomes were also acceptable, with diarrhea being the most commonly reported adverse effect. These findings illustrate the efficacy of voxelotor in managing hemolysis in SCD and emphasize the need to address broader clinical outcomes for long-term disease control.

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2025
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