Treatment with oral Oxbryta (voxelotor) leads to rapid and sustained rises in hemoglobin levels, reduces red blood cell destruction (hemolysis), and improves overall health in adolescents and adults with sickle cell disease (SCD), according to full, nearly 1.5-year data from the Phase 3 HOPE clinical trial.
The findings support the long-term benefits of Oxbryta, which was approved conditionally in the U.S. as the first treatment to tackle the underlying cause of SCD — the clumping and sticking of mutant hemoglobin molecules into rigid, long rods (polymers) that deform red blood cells.
“The sickle cell disease community, which for decades has been dramatically underserved, deserves treatments that address the sickling and destruction of red blood cells due to hemoglobin polymerization — the root cause of this disease,” Ted W. Love, MD, president and CEO of Global Blood Therapeutics (GBT), the therapy’s developer, said in a press release.
“The HOPE Study is the longest registrational trial to date among recently approved therapies for sickle cell disease, and these results further demonstrate that by sustainably improving both the hemolysis and anemia manifestations of the disease, Oxbryta has the potential to be a safe and effective disease-modifying treatment in patients with sickle cell disease,” said Jo Howard, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, and the study’s first author.
The trial “represents a significant milestone in advancing the treatment of SCD, and we are building on this groundbreaking trial with our commitment to increase access to Oxbryta and develop novel therapeutics that can transform SCD into a well-managed disease,” Love added.
Full data from the trial was reported in the study, “Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, Phase 3 trial,” published in The Lancet Haematology.
Oxbryta works by increasing the affinity of hemoglobin — the protein inside red blood cells that is responsible for oxygen transport — to oxygen, thereby preventing hemoglobin polymerization and red blood cell sickling.
In addition to its U.S. approval for SCD patients ages 12 and older, the therapy also is under regulatory review in Europe for the same indication.
GBT is planning to request Oxbryta’s label expansion to include younger children, ages 4–11, based on data from a Phase 2a trial called HOPE KIDS-1 (NCT02850406), which is assessing the safety, pharmacological properties, and early efficacy of Oxbryta in children and adolescents.
An international, confirmatory Phase 3 trial, called HOPE-KIDS 2 (NCT04218084), designed to support Oxbryta’s accelerated approval in the U.S., also is underway.
The therapy’s approval in the U.S., at a daily dose of 1,500 mg, was based on data from the Phase 3 HOPE trial (NCT03036813), which evaluated the safety and effectiveness Oxbryta compared to a placebo in 274 SCD patients ages 12–65.
Participants were assigned randomly to receive either 900 mg (92 patients) or 1,500 mg (90 patients) of Oxbryta or a placebo (92 patients), daily for up to 72 weeks (nearly 1.5 years).
Previously reported results from the first six months showed that the trial met its main goal, with a significantly greater proportion of Oxbryta-treated patients attaining a hemoglobin increase of at least of 1 gram per deciliter (g/dL), compared with those on a placebo (51% vs. 7%).
HOPE’s newly published, full data concerned Oxbryta’s long-term safety and effectiveness measures, including changes in hemoglobin levels, hemolysis markers, rate of painful vaso-oclusive crises (VOCs), and patients’ well-being and functioning — as assessed with the Clinical Global Impression of Change scale — up to week 72.
Results showed that compared with a placebo, both doses of Oxbryta resulted in rapid and significant increases in hemoglobin levels, which were maintained up to week 72.
Most (80% Oxbryta-treated patients achieved a hemoglobin raise of at least 1 g/dL at one or more time points during the study, compared with a fourth (25%) of those in the placebo group.
Greater hemoglobin improvements were observed with the higher, approved dose of the therapy, which maintained mean levels of about 10 g/dL throughout the study, “an important finding given the graded inverse association observed between hemoglobin concentration and end-organ damage,” the researchers wrote.
The higher dose also led to significant reductions in the levels of hemolysis markers.
In addition, Oxbryta-treated patients had fewer VOCs, consistent with the trends at six months, and were three to four times less likely to experience an acute anemic episode (classified as a 2 g/dL or greater drop in hemoglobin levels).
Among the 162 patients whose changes in well-being were assessed, 74% of those taking 1,500 mg of Oxbryta had their overall clinical status rated as “moderately improved” or “very much improved” by their clinician at study’s end, compared with 47% of those in the placebo group, representing a statistically significant difference.
Oxbryta was found to be generally well-tolerated over the long-term, with similar rates of adverse events between groups (about 25% for serious adverse events) and no new safety concerns identified.
The most frequently reported SCD-unrelated adverse events in any group included headache, diarrhea, joint pain, upper respiratory tract infection, and pain in the arms or legs. Six (2%) patients died during the study (two in each group), all of which were deemed unrelated to treatment.
Oxbryta “provided significant, durable increases in hemoglobin concentrations and reductions in markers of hemolysis and a favorable safety profile,” the team wrote, adding that “long-term use is appropriate to treat hemolytic anemia, thereby potentially mitigating the morbidity and mortality of sickle cell disease.”
A post-hoc analysis of HOPE also found that the approved dose of Oxbryta lessened, or fully healed, patients’ painful leg ulcers, one of the most common and painful complications of SCD for which there is no standard treatment.
Leg ulcer resolution was generally associated with increases in hemoglobin levels and reductions in the levels of hemolysis markers, further highlighting the potential of Oxbryta to meaningfully affect major patient outcomes.
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