A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease

In the 1940s, scientist Linus Pauling discovered the abnormality in the hemoglobin protein molecule that caused sickle cell disease. When deoxygenated, this abnormal hemoglobin protein (sickle hemoglobin or HbS) polymerizes and causes red blood cell sickling that leads to hemolysis, chronic anemia, inflammation, and vascular occlusion and damage. Although the life expectancy of patients with sickle cell disease has improved dramatically in the last 50 years (from teenage to more than 40 to 50 years), disease-modifying treatments for sickle cell disease are limited and do not directly target abnormal HbS polymerization.

In a phase 3 randomized, placebo-controlled trial published in NEJM, investigators compared the safety and efficacy of two different doses (900 mg and 1500 mg) of oral voxelotor, a HbS polymerization inhibitor in patients with sickle cell disease (age range, 12–65 years). The percentage of patients with a hemoglobin response at week 24 was significantly greater among patients who received the higher dose of voxelotor, compared with placebo. The percentage of patients with adverse events was similar across groups. These results demonstrate the effectiveness of a disease-targeting oral therapy for the millions of people worldwide who suffer from this disease and its many complications.

The following NEJM Journal Watch summary further explains the study and its findings.

Brady L. Stein, MD, MHS reviewing Vichinsky E et al. N Engl J Med 2019 Jun 14 Thompson A. N Engl J Med 2019 Jun 14

Red blood cell sickling and hemolysis due to polymerization of sickle hemoglobin upon deoxygenation is a hallmark abnormality in those with sickle cell anemia. Accordingly, inhibition of polymerization is a rational therapeutic target, and a prior phase I/II study of voxelotor previously demonstrated safety. Here, investigators conducted an industry-sponsored, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of voxelotor (1500-mg and 900-mg doses) in 274 patients with sickle cell anemia.

Eligible patients were aged 12 to 65 years and had confirmed sickle cell disease and between 1 and 10 vaso-occlusive crises (VOCs) in the prior year. Hydroxyurea was permitted if the dose was stable for 3 months, and two thirds of patients were receiving it at baseline.

Results were as follows:

• The primary endpoint (proportion with hemoglobin increase of >1 g/dL at week 24) was higher in patients taking voxelotor 1500 mg compared with placebo (51% vs. 7%, P<0.001), regardless of baseline anemia severity or hydroxyurea use.

• Improvement in hemolysis, reflected by percentage decrease in indirect bilirubin (−29.1% vs. −3.2%; P<0.001) and reticulocytes (−19.9% vs. +4.5%; P<0.001), was observed with voxelotor 1500 mg compared with placebo.

• There was no significant decrease in the frequency of VOCs.

• Headache and diarrhea were the most common adverse events.
  
  

Comment: There is a great need for disease-modifying treatments beyond hydroxyurea in patients with sickle cell anemia, who can have extensive morbidity and shortened life expectancy. Here, inhibition of polymerization is linked to rapid improvements in hemolytic anemia. However, there was less impact on VOC incidence, which is a major source of morbidity for this patient population. Hopefully, longer-term follow-up studies will demonstrate that improving the hemoglobin level by at least 1 g/dL will have important clinical impacts, including on quality of life. Nevertheless, this is a promising strategy.

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Angela Castellanos is a general pediatrician and was a 2018-2019 editorial fellow at the NEJM.