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For sickle cell disease, novel oral agent voxelotor improved hemoglobin characteristics in the phase III HOPE trial.

Levels of normal hemoglobin levels rose more than 1.0 g/dL from baseline at week 24 -- a degree associated with significantly decreased rates of multiorgan failure and death in natural history studies, and considered a "response" -- for 51% of patients randomized to the 1,500 mg of voxelotor group compared with 7% of those on placebo (P<0.001) in the intention-to-treat analysis for the primary endpoint.

The reduction was seen irrespective of baseline anemia severity and hydroxyurea use, with less worsening in anemia, Elliott Vichinsky, MD, of the University of California San Francisco Benioff Children's Hospital in Oakland, and colleagues reported.

"These findings are consistent with inhibition of HbS [sickle hemoglobin] polymerization and indicate a disease-modifying potential," the researchers wrote simultaneous with a presentation at the European Hematology Association conference in Amsterdam.

Voxelotor helps keep sickle hemoglobin from creating a polymer that, when deoxygenated, deforms red blood cells into the characteristic sickle shape that causes tissue damage and pain.

All four measures of hemolysis looked at in the study were also improved with voxelotor.

However, patient-oriented outcomes left a lot to be desired, commented Andrew Eisenberger, MD, of NewYork-Presbyterian Hospital/Columbia University Medical Center in New York City. He was not involved in the research himself, although his center was a trial site and some of his patients were enrolled.

"A 1 g increase in hemoglobin is nice, but if it doesn't make the patient overall better in ways that are important to us then I don't really think it's a therapy that's going to have a major role in the treatment of sickle cell patients in the future," he told MedPage Today.

Indeed, red-cell transfusions were no less frequent with the drug versus placebo (33% of patients on 1,500-mg voxelotor, 32% on 900-mg voxelotor, and 25% on placebo), and acute vaso-occlusive crises were only slightly less so (2.77, 2.76, and 3.19 per person-year, respectively).

Vichinsky and colleagues interpreted the findings on vaso-occlusive crises results as favorable for voxelotor because of thoughts the drug might increase them. Consequently, they wrote, the study "suggests that voxelotor raises hemoglobin levels without negatively affecting blood viscosity."

"Follow-up studies are needed to examine this very important, clinically relevant end point," noted an by Alexis Thompson, MD, MPH, of Northwestern University in Chicago.

Still, the effects 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," she concluded.

Statistical power to look at clinically-meaningful endpoints like rate of admission, complications, such as pain crises, and rate of infections like pneumonia just wasn't there, Eisenberger noted.

"The concept itself is elegant," he said. "It's a very rationally designed medication. We just don't know based on the numbers that we have. I'm far from convinced it's going to change patients' lives."

The phase III included 274 adolescents and adults with sickle cell disease randomized to a once-daily oral dose of 1,500 mg of voxelotor, 900 mg of voxelotor, or placebo for up to 72 weeks.

While the 900-mg voxelotor group also had a 33% hemoglobin response rate, it wasn't significant compared with placebo.

Inhibiting polymerization should have a true therapeutic effect by tackling the root cause of sickle cell disease and its complications, Thompson noted.

"The observed hemoglobin occupancy for the 1500-mg dose of voxelotor was 26.5%, which was therapeutically efficacious, with no evidence of impaired oxygen delivery," the researchers reported. "This finding was supported by the similar erythropoietin levels observed with voxelotor and placebo, a reduction in the percentage of reticulocytes with voxelotor, and no pattern of adverse events suggestive of impaired tissue oxygenation."

Thompson said this "modest" inhibition "should increase delay time without deleterious shifts in the oxygen-binding curve, allowing red cells to transit through the microcirculation with less sickling and therefore improved oxygen delivery."

But again, Eisenberger noted, the trial wasn't powered to assess adverse events related to increased blood viscosity.

Overall adverse event were similar across the trial groups. Grade 3 or worse events occurred in 26% of participants on 1500-mg voxelotor, 23% on 900 mg, and 26% in the placebo group. No particular adverse event stood out as substantially more common with the active drug.