Can Voxelotor Offer New HOPE for Sickle Cell Disease?

Treatment with voxelotor led to a dose-dependent increase in hemoglobin (Hb) levels in patients with sickle cell disease (SCD), with most patients responding to treatment also experiencing an increase in Hb levels >1 g/dL from baseline to 12 weeks, according to results from the ongoing, double-blind, placebo-controlled, randomized phase III HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) study.

Based on these data, presented at the 2018 ASH Annual Meeting, the U.S. Food and Drug Administration agreed to review voxelotor through an accelerated approval pathway.

“These longer-term efficacy and safety data continue to support the potential of voxelotor to be a disease-modifying treatment for SCD,” Elliott Vichinsky, MD, from University of California, San Francisco’s Benioff Children’s Hospital in Oakland, said during his presentation. He specifically acknowledged the “major improvements in anemia and hemolysis” as having “the potential to prevent the chronic organ damage that is the leading cause of death in patients with SCD in the U.S.”

Voxelotor is an oral, once-daily therapy that modulates hemoglobin affinity for oxygen, inhibiting hemoglobin polymerization and potentially interrupting the molecular pathogenesis of SCD. As such, it 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.

This trial was undertaken following the encouraging preliminary results from the phase IIa HOPE trial presented at the 2017 ASH Annual Meeting, in which 55 percent of patients experienced an Hb increase >1 g/dL after 16 weeks of treatment with voxelotor 900 mg.

At the time of data presentation, results from part A of the trial were available, which encompassed the first 154 patients randomized in the trial (median age = 28 years; range = 12-59 years). Eligible participants had SCD (HbSS, HbSC, HbSβ0 thalassemia, or other variants), Hb levels between 5.5 and 10.5 g/dL, and experienced at least one but fewer than 10 veno-occlusive crises (VOCs) in the 12 months prior to study entry.

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 a VOC within 14 days of study initiation were excluded from the trial.

Participants received either one of two doses of voxelotor (900 mg/day [n=52] or 1,500 mg/day [n=52]) or placebo (n=50) for at least 12 weeks.

Most patients were receiving hydroxyurea at the time of study entry (ranging from 67% in the voxelotor 900 mg group, 62% in the voxelotor 1,500 mg group, to 64% in the placebo group).

Treatment duration was similar between each group, with patients receiving voxelotor for a median of 21.9 weeks (range = 1.7-65.1 weeks) and placebo for a median of 22.4 weeks (range = 1.7-44.7 weeks).

At week 12, the proportion of patients who experienced an Hb increase of at least 1 g/dL was higher in the voxelotor group, and the increases were observed in a dose-dependent manner:

  • placebo: 9.1%
  • voxelotor 900 mg: 33% (p=0.016 vs. placebo)
  • voxelotor 1,500 mg: 65% (p<0.0001 vs. placebo)

By 12 weeks of treatment, voxelotor-treated patients also experienced higher median increases in Hb levels (ranging from 0.7 to 1.25 g/dL), compared with placebo (TABLE). Dr. Vichinsky highlighted the increases in Hb seen in the voxelotor 1,500 mg group at 24 weeks: Hb increased to a mean of 10 g/dL, which is “consistent with a clinically meaningful improvement in anemia.”

“In addition to the large improvements in hemolytic anemia,” he added, “I am greatly encouraged in seeing a very good safety profile.” Treatment-related adverse events included diarrhea (n=3 at 900 mg; n=3 at 1,500 mg, and n=1 on placebo), nausea (3, 2, and 3 patients, respectively), and vomiting (2, 0, and 3 patients, respectively).

Patients receiving voxelotor saw improvements in symptom burden (a secondary endpoint measured by a patient-reported symptom diary), though these details were not provided during the presentation, and the reliance on self-reported patient diaries represents a limitation of the study’s findings. The results also are potentially confounded by the concomitant administration of hydroxyurea.

The authors report financial relationships with Global Blood Therapeutics, the manufacturer of voxelotor.


Vichinsky E, Hoppe C, Howard J, et al. Results from part A of the Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization (HOPE) trial (GBT440-031), a placebo-controlled randomized study evaluating voxelotor (GBT440) in adults and adolescents with sickle cell disease. Abstract #505. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.

TABLE. Hemoglobin Levels in the Treatment Groups

Measure Baseline 12 Weeks
  Placebo (n=50) Voxelotor 900 mg (n=52) Voxelotor 1,500 mg (n=52) Placebo (n=44) Voxelotor 900 mg (n=40) Voxelotor 1,500 mg (n=40)
Mean (standard deviation) 8.55 g/dL (0.945) 8.34 g/dL (1.102) 8.64 g/dL (1.127) –0.14 g/dL (0.943) 0.9 g/dL (1.014) 1.24 g/dL (1.327)
Median 8.48 g/dL 8.3 g/dL 8.6 g/dL –0.05 g/dL 0.70 g/dL 1.25 g/dL
Range 6.10-10.35 g/dL 6.25-10.75 g/dL 5.9-10.83 g//dL –3.10 to 1.90 g/dL –0.75 to 3.55 g/dL –0.7 to 5.1 g/dL