Sickle Cell Disease and Voxelotor

According to results of phase 3 study, Voxelotor increased hemoglobin levels and reduced markers of hemolysis among sickle cell disease patients. Although two medications approved by the FDA are available (hydroxyurea and L-glutamine [Endari, Emmaus Life Sciences]), chronic medical complications and early death in persons with sickle cell disease remain a substantial burden. In particular, chronic organ dysfunction has become a leading cause of death in adults with sickle cell disease in the United States.

Voxelotor (GBT440, Global Blood Therapeutics) — a deoxygenated sickle hemoglobin polymerization inhibitor — reversibly binds with hemoglobin to help stabilize the oxygenated hemoglobin state. In a previous phase 1/phase 2 trial, voxelotor demonstrated favorable pharmacokinetics and dose-dependent increases in affinity of hemoglobin and oxygen with low-grade toxic effects.

For the current phase 3, international, multicenter, double-blind HOPE trial,  274 patients with sickle cell disease in a 1:1:1 ratio were assigned to receive once-daily voxelotor at a dose of 1,500 mg (n = 90; median age, 24 years; range, 12-59) or 900 mg (n = 92; median age, 24 years; range, 12-59), or placebo (n = 92; median age, 28 years; range, 12-64).

Most of the patients were black (n = 183) and 159 were female. A majority in each group had homozygous hemoglobin S and had experienced at least two vaso-occlusive crises within the past month. About two-thirds were receiving hydroxyurea.

The percentage of patients who demonstrated an increase in hemoglobin level of more than 1 g/dL at 24 weeks served as the study’s primary endpoint. Change in hemoglobin level from baseline to week 24, markers associated with hemolysis, and the incidence rate of vaso-occlusive crises served as secondary endpoints.

Median follow-up was 42.3 weeks (range, 0.1-73.3) in the 1,500-mg voxelotor group, 38.1 weeks (range, 4-72.4) in the 900-mg voxelotor group, and 37.2 weeks (range, 8.1-72.9) in the placebo arm.

Results of the intention-to-treat analysis showed hemoglobin response at 24 weeks among a significantly higher percentage of patients in the 1,500-mg voxelotor group (51%; 95% CI, 41-61) than the placebo group (7%; 95% CI, 1-12). One-third of patients (33%; 95% CI, 23-42) in the 900-mg voxelotor group responded to the treatment by week 24.

Researchers observed a higher percentage of responses among patients in the 1,500-mg voxelotor group than the placebo group regardless of concurrent hydroxyurea use or anemia severity at baseline.

Adjusted mean change in hemoglobin level from baseline to week 24 in the intention-to-treat analysis was 1.1 g/dL (95% CI, 0.9-1.4) in the 1,500-mg voxelotor group, 0.6 g/dL (95% CI, 0.3-0.8) in the 900-mg dose group and –0.1 g/dL (95% CI, –0.3 to 0.2) in the placebo group.

Fewer patients in the 1,500-mg and 900-mg groups experienced worsening anemia between baseline and 24 weeks than in the placebo group. Additionally, the 1,500-mg group demonstrated significantly greater reductions in indirect bilirubin levels and percentage of reticulocytes than the placebo group.

Grade 3 or higher adverse events occurred among 26% of patients in the 1,500-mg and placebo groups and 23% of patients in the 900-mg group. Investigators determined most adverse events were unrelated to treatment.

The absence of an increased incidence rate of vaso-occlusive crisis with voxelotor despite significant increases in the hemoglobin level suggests that voxelotor raises hemoglobin levels without negatively affecting blood viscosity. Longer-term follow-up is needed to further characterize the effect of voxelotor on the incidence of vaso-occlusive crisis.

The hemoglobin response and reduction in hemolysis 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.

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Source: HemOnc Source