Voxelotor in Children With Conditional Cerebral Blood Flow Velocity: What HOPE Kids 2 Teaches Us About Efficacy, Mortality, and Malaria Risk in Africa

The sickle cell disease (SCD) community was taken by surprise by the 2024 withdrawal of voxelotor from the global market.A drug that had been embraced as the first disease-modifying, oral, once-daily therapy to increase hemoglobin (Hb) and reduce hemolysis in patients as young as 4 years old had its dosing paused and was ultimately withdrawn after a signal of excess mortality emerged across the voxelotor development program, including in RESOLVE (NCT05561140) and in the trial reported in this issue, HOPE Kids 2 [1].For clinicians who had started using voxelotor in adolescents with conditional transcranial Doppler (TCD) velocities, or who were awaiting its extension to younger children with elevated stroke risk, the timing was difficult and the results were conflicting: a well-conducted, randomized, placebo-controlled trial had met its primary efficacy endpoint while also showing more vaso-occlusive crises (VOCs) and more deaths in the active arm.HOPE Kids 2 is therefore an unusually important paper, a rare instance of a modern pediatric SCD trial that is simultaneously positive and sobering, and one that deserves careful reflection.Here, we discuss what the trial shows about efficacy, the safety signals for VOC and for mortality, an underexplored hypothesis linking voxelotor's mechanism to malaria susceptibility, and what these findings mean for clinical practice in Africa (Table 1).