Background
Phase 3, multicenter, double-blind, placebo-controlled trial. N=236 children aged 2–<15 yrs with SCD (HbSS/HbSβ) and conditional transcranial Doppler cerebral blood flow velocity (CBFV) 170–<200 cm/s (elevated stroke risk); 83% enrolled in sub-Saharan Africa. Voxelotor = oral HbS polymerization inhibitor.
Results
Interventions and follow up: Arm A: Voxelotor PO daily (weight-based dosing) for 96 weeks (n=120)
Arm B: Placebo (n=116)
Primary endpoint: Change in CBFV from baseline to Week 24
mFollow up: Median exposure 84 weeks in both arms; dosing paused May 2024 and trial discontinued September 2024
Results: CBFV change (Week 24): LS mean -12.06 vs -4.29 cm/s; difference -7.77 cm/s, 95% CI -13.18 to -2.37, P=.0048 — primary endpoint met; difference sustained through Week 48
Hemoglobin: Increased with voxelotor at Weeks 24 and 48
Stroke events: NR
Arm B: Placebo (n=116)
Primary endpoint: Change in CBFV from baseline to Week 24
mFollow up: Median exposure 84 weeks in both arms; dosing paused May 2024 and trial discontinued September 2024
Results: CBFV change (Week 24): LS mean -12.06 vs -4.29 cm/s; difference -7.77 cm/s, 95% CI -13.18 to -2.37, P=.0048 — primary endpoint met; difference sustained through Week 48
Hemoglobin: Increased with voxelotor at Weeks 24 and 48
Stroke events: NR
Adverse events
SCD-related (most common TEAE): sickle cell anemia with crisis 59.2% vs 37.9%
Deaths: 8 vs 2 (imbalance triggered dosing pause May 2024; all deaths judged unrelated to study drug by treating investigators)
Discontinuation: Trial terminated September 2024 when all voxelotor trials were stopped and the drug was withdrawn worldwide
Deaths: 8 vs 2 (imbalance triggered dosing pause May 2024; all deaths judged unrelated to study drug by treating investigators)
Discontinuation: Trial terminated September 2024 when all voxelotor trials were stopped and the drug was withdrawn worldwide
Conclusions
Voxelotor significantly reduced CBFV vs placebo in children with SCD and conditional TCD velocities, supporting a biologic effect of HbS polymerization inhibition on cerebral hemodynamics. However, an imbalance in deaths and vaso-occlusive crises led to trial termination and contributed to the worldwide withdrawal of voxelotor; the surrogate benefit did not translate into an approvable clinical benefit.
Key Limitations
Surrogate primary endpoint (CBFV, not stroke); early termination truncated follow-up and stroke-event assessment; unexplained excess of deaths and VOC on voxelotor; 83% of cohort from sub-Saharan Africa — supportive-care context may limit generalizability; published after the drug's withdrawal, limiting actionability.
Clinical Context
Voxelotor received accelerated FDA approval (2019, age ≥12; extended to 4–11 yrs 2021) on a hemoglobin surrogate. Pfizer voluntarily withdrew it worldwide in September 2024 after mortality imbalances in this and other trials (EMA review began July 2024). This publication provides the primary evidence behind that withdrawal. Hydroxyurea with TCD screening remains the standard for stroke-risk reduction in children with SCD and elevated TCD velocities.