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Voxelotor: A New Option for Young Patients With Sickle Cell Disease?

December 30, 2021

Treatment with the hemoglobin S polymerization inhibitor voxelotor led to "a remarkable increase in hemoglobin levels" in young patients with sickle cell disease (SCD), according to preliminary results from a phase IIa study presented by Carolyn C. Hoppe, MD, of the Children's Hospital of Oakland Research Institute in California, at the 2017 ASH Annual Meeting. Patients also experienced improvement in clinical measures of hemolysis and total symptom burden, supporting voxelotor as a potential disease-modifying therapy for people with SCD.

In this ongoing, open-label, phase IIa trial, Dr. Hoppe and colleagues assessed the safety, pharmacokinetics, and efficacy of voxelotor (previously GBT440) in adolescents with SCD. Voxelotor is an oral, once-daily therapy that modulates hemoglobin affinity for oxygen, inhibiting hemoglobin polymerization.

"What sets this drug apart is that it was designed specifically for SCD," Dr. Hoppe said during a press briefing discussing the study's results. "This is one of the first drugs that intentionally targets the fundamental mechanism of SCD [to prevent] cells from sickling early on, eliminating all the downstream consequences of sickling."

The study enrolled patients 12 to 17 years of age with SCD. Patients who had a vaso-occlusive crisis (VOC), required chronic red blood cell transfusion therapy, or had cardiac abnormalities were excluded from the trial. The study is being conducted in two parts: In part A, children and adolescents are receiving a single dose of voxelotor 600 mg; in part B, patients are receiving multiple doses of voxelotor (900 mg and 1500 mg) administered over 24 weeks.

Dr. Hoppe reported results from 24 patients (median age = 14 years; range = 12-17 years) who received voxelotor 900 mg daily for 24 weeks. As of November 6, 2017 (data cutoff), 12 patients had been treated with voxelotor 900 mg for at least 16 weeks.

"The vast majority of patients (n=21; 88%) were receiving daily hydroxyurea, the standard of care for SCD," Dr. Hoppe reported, "and the patients were typical of what we see in in our clinic at this age." Almost half of patients (n=11; 46%) had no VOC in the year prior to study.

The median hemoglobin (Hgb) level at baseline was 8.7 g/dL (range = 6.3-10.9 g/dL). By 16 weeks of treatment, six of 11 evaluable patients (55%) experienced a >1 g/dL increase in Hgb (the study's primary endpoint). Data were not available for one patient, who was excluded from the efficacy analysis.

Patients also saw improvement in symptom burden, which was measured by total severity score (TSS) via self-completed patient diaries. "At week 16, 10 of 12 patients showed a reduction in TSS from baseline, including five patients who had a decrease in TSS to zero," Dr. Hoppe said. Greater improvements in hemoglobin levels appeared to correspond with better adherence and exposure to voxelotor, she added, commenting on results from the pharmacokinetic analysis.

Data on safety and tolerability among all 24 patients treated with voxelotor were "reassuring," Dr. Hoppe noted, and adverse events (AEs) "were similar to what we have seen in adults treated with this drug." Treatment-related AEs (occurring in ≥2 patients) included:

  • nausea (n=3; 12.5%)
  • headache (n=2; 8.3%)
  • rash (n=2; 8.3%)

There also were no serious AEs associated with voxelotor, and there were no drug discontinuations related to serious AEs.

The reliance on self-reported patient diaries to monitor changes in symptom burden is a limitation of the study's findings. The study also included a small number of patients, but Dr. Hoppe noted that the results were encouraging enough to support the evaluation of the higher voxelotor dose (1,500 mg). Some patients are moving into the phase III, randomized, double-blind HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) trial, which will evaluate voxelotor in up to 400 young patients with SCD who have had at least one episode of VOC in the prior year.

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


Hoppe CC, Inati AC, Brown C, et al. Initial results from a cohort in a phase 2a study (GBT440-007) evaluating adolescents with sickle cell disease treated with multiple doses of GBT440, a HbS polymerization inhibitor. Abstract #689. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.


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