Ascending Dose Study Demonstrates Safety, Efficacy of Voxelotor in Sickle Cell Disease


Voxelotor, a first-in-class oral therapy, is both safe and effective in sickle cell disease, according to a phase 1/2 randomized study assessing the drug. These findings were consistent across all doses, ranging from 500 to 1000 mg.

Voxelotor, a first-in-class oral therapy, is both safe and effective in sickle cell disease (SCD), according to a phase 1/2 randomized study assessing the drug. These findings were consistent across all doses, ranging from 500 to 1000 mg.

The treatment, developed specifically for SCD, regulates the affinity of hemoglobin (Hb) for oxygen, resulting in a decrease in the concentration of deoxygenated sickle hemoglobin (HbS), which forms polymers. It’s hypothesized that because oxygenated HbS cannot polymerize, modifying HbS to increase the proportion of oxygenated to deoxygenated HbS in red blood cells would alter disease severity.

During the study, 38 participants were treated with voxelotor 500 mg, 700 mg, or 1000 mg per day or placebo for 28 days, and 16 participants were treated with voxelotor 700 mg or 900 mg per day or placebo for 90 days. A total of 4 patients from the 90-day cohort were subsequently enrolled in a separate extension study and treated with voxelotor 900 mg per day for 6 months. One of these patients was receiving placebo in the randomized study and then transitioned to 900 mg of voxelotor in the extension study.

Within 2 weeks of treatment, all doses of voxelotor resulted in an increase in median Hb level and/or a reduction in markers of hemolysis.

“The improvement in hemolytic anemia with voxelotor treatment is promising because chronic hemolytic anemia has increasingly become recognized as a critical driver of SCD pathophysiology via both chronic anemia and systemic hemolysis-related vasculopathy,” wrote the researchers. “Chronic hemolytic anemia is an independent and powerful predictor of chronic organ damage, including stroke, silent infarcts, renal failure, and pulmonary hypertension, as well as early mortality in SCD.”

For patients treated long term with 900 mg, these improvements were sustained throughout the 6 months of treatment, with a median increase in Hb of approximately 1 g/dL. Nearly half of these patients (46%) achieved an increase in Hb of >1 g/dL from baseline.

All treatment doses also resulted in reductions in the proportion of sickled red cells, including a statistically significant difference observed among patients treated long term. Treatment with 700 mg of the therapy resulted in a 73% reduction from baseline and treatment with 900 mg of the therapy resulted in a 79% reduction, compared with an increase of approximately 7% for those receiving placebo.

At 90 days, there were statistically significant improvements in unconjugated bilirubin (40% reduction) and reticulocyte counts (20% reduction), favoring voxelotor over placebo. While improvements were also seen for dense red blood cells, the difference was not statistically significant.

Safety and tolerability were also favorable for the drug, with no maximum tolerated dose identified. “Overall, voxelotor was well tolerated at doses up to and including 1000 mg per day for 28 days and 900 mg per day for 6 months,” explained the researchers.

Adverse events that were reported in 10% or more patients were typically grade 1 or 2 and included headache, diarrhea, and rash. According to the researchers all vaso-occlusive crisis events among patients taking voxelotor occurred while off treatment and were considered to be related to underlying SCD.


Howard Jo, Hemmaway C, Telfer P, et al. A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease [published online April 25. 2019]. Blood. doi: 10.1182/blood-2018-08-868893.

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