Voxelotor Increases Hemoglobin, Decreases Hemolysis in Patients With Sickle Cell Disease

A report from the phase III HOPE trial found that once-daily voxelotor led to greater increases in hemoglobin (Hb) levels and larger reductions in hemolysis markers, compared with placebo, in patients with sickle cell disease (SCD). The findings were published in the New England Journal of Medicine.

Voxelotor is an inhibitor of deoxygenated sickle hemoglobin (HbS) polymerization, which is the central pathophysiological abnormality in SCD, lead author Elliott Vichinsky, MD, of the University of California, San Francisco, explained to ASH Clinical News. “Developing an HbS polymerization inhibitor has been a therapeutic strategy for the disease for decades, and voxelotor is the first clinically successful product of these investigations.”

The double-blind, placebo-controlled, randomized phase III HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) study compared the efficacy and safety of two dose levels of voxelotor (1,500 mg and 900 mg, administered orally once daily) with placebo in 274 patients with SCD.

At time of enrollment, patients were required to have Hb levels between 5.5 and 10.5 g/dL and have experienced between one and 10 vaso-occlusive crises (VOCs) in the previous 12 months. Patients who were receiving hydroxyurea (the standard of care for SCD) could participate if the dose was stable for at least 90 days prior to study entry. Those who were receiving regular red blood cell transfusions or had had a VOC within 14 days of study initiation were excluded from the trial.

The participants (age range = 12-65 years) were randomized to one of the following three groups:

  • once-daily voxelotor 1,500 mg (n=90)
  • once-daily voxelotor 900 mg (n=92)
  • placebo (n=92)

Treatment was administered for up to 72 weeks, and patients had an end-of-trial visit at four weeks following the final dose of the drug or placebo.

In the 1,500-mg voxelotor group, 900-mg voxelotor group, and placebo group, the median durations of follow-up were 42.3 weeks (range = 0.1-73.3), 38.1 weeks (range = 4.0-72.4), and 37.2 weeks (range = 8.1-72.9), respectively.

A significantly higher proportion of patients in the voxelotor groups achieved the primary outcome of Hb response (>1.0-g/dL increase from baseline at 24 weeks), compared with the placebo group (p<0.001):

  • voxelotor 1,500 mg: 51%
  • voxelotor 900 mg: 33%
  • placebo: 7%

By 24 weeks, patients who received voxelotor also experienced higher median increases in Hb levels (ranging from 0.7 to 1.25 g/dL), compared with those who received placebo (TABLE).

The investigators also measured laboratory markers associated with hemolysis, finding that patients in the voxelotor 1,500-mg group had significantly greater decreases in indirect bilirubin from baseline to 24 weeks, compared with the placebo group (mean change = −29.1% vs. −3.2%, respectively; p<0.001).

The increase in Hb and reduction in hemolysis occurred within two weeks after start of study drug, the authors reported, “indicating a rapid pharmacodynamic and biologic effect.”

In the safety analysis (including patients who received at least one dose of the drug or placebo), the investigators observed similar rates of any-grade adverse events (AEs) across all cohorts: 94% in the 1,500-mg group, 93% in 900-mg group, and 89% in placebo group. The proportions of patients who experienced a ≥grade 3 AE also were similar: 26% vs. 23% vs. 26%, respectively. The most commonly reported AEs unrelated to SCD included headache, diarrhea, and nausea.

The authors noted that treatment with voxelotor appeared to lower the annualized incidence rate of VOCs per person-years, from 3.19 in the placebo group to 2.77 and 2.76 in the 1,500- and 900-mg groups, respectively (p values for comparison not provided).

“The rapid response and lack of serious AEs [at a rate similar to placebo] were surprising and encouraging,” Dr. Vichinsky added. “These observations suggest voxelotor has the potential to change the natural history of SCD into a more benign condition.”

Potential limitations of the study include its relatively small sample size in each group, as well as the short duration of follow-up.

Dr. Vichinsky emphasized that voxelotor is one of the first drugs for SCD that targets the fundamental mechanism of SCD to prevent the sickling of cells – and eliminating the downstream consequences of sickling. “While pain is a signature complication of SCD, progressive multi-organ failure is the leading cause of severe morbidity and early mortality, and hemolysis and anemia are central to the pathogenesis of multi-organ failure,” he explained. Therefore, future drug development studies should focus on morbidity – not just pain management – as their primary outcomes.

The authors report relationships with Global Blood Therapeutics, which supported this trial.


Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019 June 14. [Epub ahead of print]