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Voxelotor increases hemoglobin levels, reduces hemolysis markers in sickle cell disease
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Voxelotor increased hemoglobin levels and reduced markers of hemolysis compared with placebo among patients with sickle cell disease, according to results of a randomized phase 3 study published in The New England Journal of Medicine and presented at European Hematology Association Congress in Amsterdam.
“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,” Elliott Vichinsky, MD, division chief of hematology and oncology at UCSF Benioff Children’s Hospital, and colleagues wrote. “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, Vichinsky and colleagues randomly assigned 274 patients with sickle cell disease in a 1:1:1 ratio 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,” Vichinsky and colleagues wrote. “Longer-term follow-up is needed to further characterize the effect of voxelotor on the incidence of vaso-occlusive crisis.”
The data support the primary endpoint of the HOPE trial — to reduce anemia and hemolysis, Alexis Thompson, MD, MPH, professor of pediatrics at Northwestern University’s Feinberg School of Medicine, wrote in an accompanying editorial.
“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,” Thompson wrote. – by John DeRosier
Reference:
Vichinsky E, et al. Abstract S147. Presented at: Congress of European Hematology Association; June 13-16, 2019; Amsterdam.
Disclosures: Global Blood Therapeutics funded this study. Vichinsky reports consultant roles with Bayer, Bluebird Bio, Global Blood Therapeutics, Ironwood Pharmaceuticals, Novartis and Pfizer. Please see the study for all other authors’ relevant financial disclosures. Thompson reports consultant roles with Bluebird Bio and Celgene.
Perspective
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Andrew Eisenberger, MD
This research represents a step in the right direction, because two of the findings are what we look for when treating sickle cell disease. There’s improvement in hemoglobin, which is good for someone who is anemic, and evidence of decreased red blood cell destruction, both of which are great outcomes.
However, I do not think this drug is ready for prime time.
As someone who takes care of hundreds of patients with sickle cell disease, I want to make sure that we are not just buffing the numbers. I want to see that we are improving patient outcomes in the form of reduced admissions for pain crises, reduced use of opioids and reduced incidence of pneumonia. The studies of hydroxyurea conducted 25 years ago showed that it decreased the number of transfusions and the number of admissions for pain crises. This study did not show any improvements in those definitive outcomes. Right now, the difference is about half a pain crisis a year, but without statistical significance.
I’m not sure if the FDA is going to approve an agent based on surrogate outcomes like an increase in hemoglobin and a decrease in red blood cell destruction, or if they are going to want more definitive evidence of improved patient outcomes.
As a clinician, I’m not convinced based on these data and would not prescribe the agent to all my patients. Hypothetically, there are also concerns that when blood counts are raised in patients with sickle cell disease, there are more complications related to blood viscosity. So, we need to ask if the potential harm could balance or even outweigh the potential good.
This is an expensive drug to develop. Putting something this expensive on the market without proven improvement in outcomes concerns me.
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