Background
Phase III double-blind placebo-controlled RCT. 274 patients aged ≥12 years with SCD (HbSS or HbSβ0) and hemoglobin 6.0–10.5 g/dL, with ≥1 VOC in the prior 12 months. Randomized 1:1:1 to voxelotor 1500 mg, voxelotor 900 mg, or placebo daily for 24 weeks. Voxelotor (GBT440; Oxbryta) is a hemoglobin S polymerization inhibitor designed to stabilize oxygenated HbS and reduce sickling. FDA-approved October 2019; voluntarily withdrawn globally September 2024.
Interventions and follow up
Arm A: Voxelotor 1500 mg orally once daily for 24 week
Arm B: Placebo orally once daily for 24 week
Primary endpoint: Hemoglobin response (≥1 g/dL increase from baseline at week 24)
mFollow up: 24 week
Arm B: Placebo orally once daily for 24 week
Primary endpoint: Hemoglobin response (≥1 g/dL increase from baseline at week 24)
mFollow up: 24 week
Results
Hgb response (≥1 g/dL): 51% (1500 mg) vs 7% (placebo), P<.001
Median Hgb increase: +1.1 g/dL (voxelotor) vs +0.6 g/dL (placebo)
Indirect bilirubin: −29.1% (voxelotor) vs +3.2% (placebo) — hemolysis reduction
VOC rate: 2.77 vs 2.76 events/year — not significantly different (P=.94)
Median Hgb increase: +1.1 g/dL (voxelotor) vs +0.6 g/dL (placebo)
Indirect bilirubin: −29.1% (voxelotor) vs +3.2% (placebo) — hemolysis reduction
VOC rate: 2.77 vs 2.76 events/year — not significantly different (P=.94)
Adverse events
Main adverse events: Diarrhea 26% vs 16%, headache 26% vs 20%, nausea 17% vs 12%, rash 19% vs 11%. Grade ≥3 AEs: 40% (voxelotor) vs 45% (placebo). No significant hepatotoxicity or thromboembolic events. Discontinuation due to AEs: 5% vs 6%.
Conclusions
Voxelotor significantly improved hemoglobin and reduced hemolysis markers in SCD but did not reduce VOC rates. FDA approved October 2019 based on the surrogate Hgb endpoint; subsequently withdrawn September 2024 after post-marketing data failed to confirm clinical benefit and raised a signal of possible harm.
Key Limitations
Key Limitations: Primary endpoint (Hgb response) is a surrogate not validated for clinical benefit; 24-week duration too short for meaningful VOC assessment; VOC rate was numerically identical between arms. The post-marketing IMPROVE trial (Phase 3b, N=334, placebo-controlled) showed no reduction in VOC at 72 weeks and a possible increase in pain events in the voxelotor arm. Accelerated approval based on surrogate endpoint without confirmatory clinical benefit — a now-cautionary example of surrogate-based approval.
Clinical Context
FDA approved October 2019 for SCD ≥12 years under accelerated approval based on Hgb surrogate. Pfizer voluntarily withdrew voxelotor (Oxbryta) globally September 2024 following the IMPROVE trial failure. No longer commercially available. Crizanlizumab (Adakveo) was similarly withdrawn in April 2023 after a larger Phase 3 (STAND) failed to confirm benefit. As of 2024, hydroxyurea, chronic transfusion, exa-cel (Casgevy, FDA Dec 2023), and lovo-cel (Lyfgenia, FDA Dec 2023, commercially discontinued April 2024) represent the available SCD disease-modifying options.
References