Etavopivat Phase 3 results support potential approval in sickle cell disease
Novo Nordisk plans regulatory submissions after positive trial
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A global, late-stage clinical trial testing etavopivat in people with sickle cell disease (SCD) has hit its main goals, showing that the experimental oral therapy improved hemoglobin levels and reduced the risk of painful episodes compared with a placebo.
Based on these positive results from the Phase 3 portion of the Phase 2/3 HIBISCUS clinical trial (NCT04624659), Novo Nordisk — which acquired etavopivat in 2022 — is planning to begin regulatory submissions in the second half of 2026 seeking the therapy’s approval for SCD.
“Sickle cell disease severely impacts the lives of millions of people,” Martin Holst Lange, MD, PhD, executive vice president, chief scientific officer, and head of research and development at Novo Nordisk, said in a company press release. “We are very excited that etavopivat has the potential to be a first and best-in-class therapy and transform the lives of people with sickle cell disease, who currently have limited therapeutic options.”
How sickle cell disease affects red blood cells
SCD is marked by an abnormal form of hemoglobin, the protein that red blood cells use to carry oxygen. The mutated hemoglobin tends to clump together in cells, deforming them into a sickle shape.
These deformed blood cells are more likely to be destroyed — resulting in anemia or low hemoglobin levels — and to get stuck in blood vessels, blocking blood flow and triggering painful episodes called vaso-occlusive crises (VOCs).
Etavopivat is designed to boost the activity of an enzyme called pyruvate kinase. By increasing this enzyme’s activity, the therapy aims to lower levels of 2,3 diphosphoglycerate (2,3 DPG), a molecule that can make it harder for hemoglobin to bind to oxygen, while also increasing ATP levels, which helps red blood cells maintain their structure and flexibility.
In doing so, the oral therapy aims to help mutated hemoglobin better bind to oxygen, which can help prevent the protein from clumping and deforming blood cells.
Etavopivat has received orphan drug designation in both the U.S. and the European Union, as well as fast track and rare pediatric disease designations in the U.S. for the treatment of SCD. These statuses are meant to accelerate the therapy’s clinical development and regulatory review.
The HIBISCUS study was designed to test etavopivat in about 450 people with SCD ages 12 to 65. In its initial Phase 2 portion, 60 participants were randomly assigned to receive either 200 or 400 mg of etavopivat or a placebo, once daily for up to one year.
Early trial data pointed to higher-dose benefits
Data from that part showed that the higher dose was particularly effective at increasing hemoglobin levels and reducing the risk of VOCs compared with the placebo. This dose was then selected for the subsequent Phase 3 portion, where 385 participants were randomly assigned to receive etavopivat or a placebo for up to one year. Participants were also allowed to continue standard-of-care SCD therapies.
This part of the study had two main goals. First, it aimed to show that etavopivat was superior to the placebo at reducing VOCs over one year. This goal was met, with results showing etavopivat-treated patients had a 27% reduced risk of VOCs compared with those given the placebo. The median time to first VOC was significantly longer with etavopivat than placebo (about nine months vs. about five months).
The second goal was to evaluate whether etavopivat was superior to the placebo at increasing hemoglobin levels by at least 1 g/dL after six months. Results showed nearly half (48.7%) of patients given the experimental therapy — but only 7.2% of those on the placebo — experienced such an increase.
Participants treated with etavopivat also were significantly less likely to need a blood transfusion, according to exploratory analyses.
Novo Nordisk said that etavopivat was overall well-tolerated, with a safety profile similar to what was seen in previous etavopivat trials.
Next steps include regulatory plans, further studies
Detailed results from the trial’s Phase 3 portion are expected to be presented at a scientific meeting this year, according to the company.
A global Phase 3 trial, called HIBISCUS 2 (NCT06612268), is also testing the therapy against a placebo in up to 408 people with SCD, ages 12 and older. Main goals are to assess changes in VOCs, organ damage, exercise tolerance, and fatigue.
Participants who complete either HIBISCUS or HIBISCUS 2 may enroll in an open-label extension study, called FLORAL (NCT06609226), where all will receive the experimental therapy for an extended period.
Etavopivat is also being tested in pediatric patients with SCD, ages 12 to 18, in a Phase 1/2 trial called HIBISCUS KIDS (NCT06198712), which is recruiting at sites in Canada and certain countries in Europe, Asia, and Africa.
