Voxelotor increases Hb levels, reduces haemolysis in sickle cell disease
Treatment with voxelotor, an HbS* polymerization inhibitor, significantly increases haemoglobin (Hb) levels and reduces markers of haemolysis, including indirect bilirubin level and percentage of reticulocytes, compared with placebo in patients with sickle cell disease, according to the HOPE** trial.
“The [significant] increase in Hb levels and reduction in haemolysis occurred within 2 weeks after initiation of the trial drug, indicating a rapid pharmacodynamic and biologic effect,” said the researchers.
This phase III, multicentre, international, double-blind trial involved 274 adolescents (aged 12–17 years) and adults (aged 18–65 years) with sickle cell disease who were randomized in a 1:1:1 ratio to receive oral voxelotor at a dose of 1,500 mg (n=90, median age 24 years) or 900 mg (n=92, median age 24 years) or placebo (n=92, median age 28 years) once daily for 24 weeks. The primary endpoint was the percentage of patients who achieved an Hb response (defined as an increase in Hb level of >1.0 g/dL at 24 weeks from baseline). [N Engl J Med 2019;doi:10.1056/NEJMoa1903212]
In the intention-to-treat analysis, significantly more patients who received voxelotor 1,500 mg achieved a >1.0 g/dL increase in Hb levels compared with placebo at 24 weeks (51.0 percent vs 7.0 percent; p<0.001), irrespective of concurrent use of hydroxyurea or anaemia severity at baseline, said the researchers.
A higher percentage of patients on voxelotor 900 mg also achieved an increased Hb level than those on placebo at 24 weeks (33.0 percent vs 7.0 percent).
At 24 weeks of follow-up, patients treated with voxelotor 1,500 mg had a significantly greater reduction in the indirect bilirubin level (mean change from baseline, -29.1 percent vs -3.2 percent; p<0.001) and percentage of reticulocytes (mean change from baseline, -19.9 percent vs 4.5 percent; p<0.001) than those who received placebo.
The 900 mg voxelotor group also saw reductions in indirect bilirubin level (-20.3 percent vs -3.2 percent) and percentage of reticulocytes (-1.3 percent vs 4.5 percent) vs placebo.
With regards to the incidence rate of vaso-occlusive crisis, there was a trend towards fewer incidence of the total number of vaso-occlusive crises for both doses of voxelotor compared with placebo (179 [for 1,500 mg] and 183 [for 900 mg] vs 219).
“The absence of an increased incidence rate of vaso-occlusive crisis with voxelotor despite significant increases in the Hb level suggests that voxelotor raises Hb levels without negatively affecting blood viscosity,” said the researchers. “This may be due to the upstream mechanism of action of voxelotor (inhibition of HbS polymerization), which results in improved red-cell deformability and reduced blood viscosity with voxelotor in vitro.” [Clin Hemorheol Microcirc 2018;70:95-105]
Adverse events (AEs) of any grade were comparable between the treatment groups (94 percent and 93 percent vs 89 percent for voxelotor 1,500 and 900 mg vs placebo, respectively). The researchers reported that most AEs were not related to the trial drug, voxelotor, or placebo.
“We specifically chose to use an increase in Hb level of >1.0 g/dL as a primary endpoint because validated natural history studies indicated that an increase in Hb level significantly decreases the rate of multiorgan failure and death,” said the researchers.
“[Furthermore,] the Hb response and reduction in haemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the FDA***,” wrote Dr Alexis Thompson from the Northwestern University Feinberg School of Medicine, Chicago, US, in an editorial. [N Engl J Med 2019;doi:10.1056/NEJMe1906771]
“Long-term follow-up studies are planned to evaluate the effect of the increase in Hb level and decrease in haemolysis induced by voxelotor on morbidity and mortality among persons with sickle cell disease,” the researchers noted.
*HbS: Sickle haemoglobin
**HOPE: Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization