Etavopivat may reduce VOC rate, increase hemoglobin in SCD
HIBISCUS study is assessing treatment's safety, effectiveness
Etavopivat, Novo Nordisk’s investigational oral therapy for sickle cell disease (SCD), may reduce the incidence of vaso-occlusive crises (VOCs) and increase hemoglobin levels.
That’s according to data from the phase 2 part of the Phase 2/3 HIBISCUS trial (NCT04624659), which is assessing the treatment’s safety and efficacy in adolescents and adults with SCD.
The data was delivered during a presentation at the Annual Meeting and Exposition of the American Society of Hematology (ASH) this month in San Diego and virtually. The presentation was titled, “Etavopivat reduces incidence of vaso-occlusive crises in patients with sickle cell disease: HIBISCUS trial phase 2 results through 52 weeks.” The results were used to determine the dose for the phase 3 part, which will test the therapy in a larger group.
“Although additional studies are needed, emerging results from HIBISCUS may mark a significant step forward in achieving this ambition and potentially providing people living with sickle cell disease with an option that can help manage symptoms and disease progression,” Martin Holst Lange, MD, PhD, Novo Nordisk’s executive vice president and head of development, said in a company press release.
SCD is caused by mutations in the HBB gene that lead to an abnormal version of the protein that’s needed for red blood cells to carry oxygen through the bloodstream. When not bound to oxygen, this mutated hemoglobin protein forms clumps that cause red blood cells to acquire a sickle-like shape.
Etavopivat, formerly FT-4202, is a once-daily oral therapy that’s designed to activate the enzyme pyruvate kinase. When active, this enzyme increases red blood cells’ energy production and lowers the levels of 2,3 diphosphoglycerate (2,3 DPG), a molecule that reduces hemoglobin’s affinity for oxygen. Etavopivat should increase hemoglobin’s affinity for oxygen, reducing red blood cell sickling and decreasing VOCs frequency.
Results of HIBISCUS study
HIBISCUS is assessing etavopivat’s safety and efficacy in adolescents and adults, ages 12-65, with SCD. In the phase 2 part, 60 patients were randomly assigned to either 200 or 400 mg of etavopivat, or a placebo.
The trial’s main goals are to assess the effects of treatment on hemoglobin levels after six months and on the rates of painful VOCs after a year. VOCs occur when sickled cells block blood flow to the point that tissues become deprived of oxygen, leading to substantial pain.
After six months, the proportion of patients who achieved a hemoglobin response, defined as a minimum increase of 1 g/dL in hemoglobin levels from the study’s start, was higher in the etavopivat groups (38% in the 200 mg group, 25% in the 400 mg group) than in the placebo group (10.5%).
After a year, the annualized VOC rates decreased from a mean of 3.3 in the 12 months before treatment to 1.07 in the 200 mg group and 1.06 in the 400 mg group. In the placebo group, annualized VOC rates dropped to 1.97.
In the per-protocol population, that is, the patients who complied with study protocols by 80% or more, annualized VOC rates fell to 0.66 in the 200 mg group, 0.7 in the 400 mg group, and 1.77 in the placebo group.
In this population, a hemoglobin response was attained by 46% of the patients receiving 200 mg of etavopivat, 33% of those on 400 mg, and by 13% of those given a placebo.
Most reported adverse events were mild to moderate and resolved spontaneously. Two serious adverse events — increased levels of liver enzymes and low hemoglobin levels — were considered possibly or probably related to treatment. Two patients in the 200 mg group discontinued treatment due to increased liver enzymes and a cerebrovascular accident.
The phase 3 part of HIBISCUS is expected to enroll about 380 patients who will be randomized to receive 400 mg of etavopivat or a placebo. The participants can continue treatment in an open-label extension part and may roll over for a long-term study after the trial.
“We need more treatment options for people with sickle cell disease to help address the unmet need in this community. Etavopivat is a promising investigational treatment … and I look forward to seeing how this may impact the treatment landscape,” said Julie Kanter, MD, co-director of the Lifespan Comprehensive Sickle Cell Center, and professor at the University of Alabama at Birmingham.
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