Novo Nordisk's etavopivat meets dual endpoints in Phase III sickle cell disease trial

Novo Nordisk reported that etavopivat met both co-primary endpoints in the Phase III HIBISCUS trial, reducing vaso-occlusive crisis events by 27% and producing a hemoglobin response in 48.7% of patients versus 7.2% on placebo. If these results support an eventual approval, the oral pyruvate kinase-R activator would be the first new oral disease-modifying agent for sickle cell disease in roughly a generation.

Trial specifics

HIBISCUS is a randomized, double-blind, 52-week efficacy and safety trial enrolling 385 patients aged 12 years or older with sickle cell disease, comparing etavopivat 400 mg once daily against placebo on top of standard of care.

On the primary VOC endpoint, etavopivat reduced the annualized rate of vaso-occlusive crises by 27% versus placebo, with median time to first VOC extending from 20.9 weeks on placebo to 38.4 weeks on treatment — approximately a four-month delay. The hemoglobin co-primary endpoint showed 48.7% of etavopivat-treated patients achieving a greater than 1 g/dL increase at week 24, compared with 7.2% on placebo, an adjusted rate difference of 41.2%. An exploratory analysis also showed a reduction in transfusion risk, though no numerical estimate was provided. Safety was described as consistent with earlier etavopivat trials, with no new signals identified.

Research context

The dual-endpoint profile is the aspect of these data that most distinguishes etavopivat from what currently exists on the market. Hydroxyurea, approved by the FDA in 1998 and still the backbone of SCD pharmacotherapy, reduces VOC frequency through fetal hemoglobin induction but does not consistently produce the kind of hemoglobin response measured in HIBISCUS. L-glutamine (Endari), approved in 2017, targets oxidative stress in red blood cells and reduces painful crises but has not demonstrated a hemoglobin improvement signal of this magnitude. No approved oral agent has met both a VOC reduction and a hemoglobin response endpoint as co-primary outcomes in a single Phase III trial.

The competitive picture has also shifted in etavopivat's favor through attrition. Pfizer voluntarily withdrew voxelotor (Oxbryta) worldwide in September 2024 following safety concerns, removing the only approved hemoglobin-targeting small molecule from the market. Crizanlizumab (Adakveo), the anti-P-selectin antibody approved by the FDA in 2019 for VOC prevention, had its EU and UK authorizations revoked in 2023 and 2024 respectively after the confirmatory STAND trial failed, and its commercial footprint has contracted substantially even in the US. The gene therapies exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia), both approved in December 2023, address the disease at a more fundamental level but require myeloablative conditioning, specialized infrastructure, and carry per-patient costs that make them inaccessible to the majority of the approximately eight million people living with SCD globally, most of whom are in low- and middle-income countries.

Etavopivat works by allosterically activating erythrocyte pyruvate kinase-R (PKR), a glycolytic enzyme. PKR activation lowers 2,3-diphosphoglycerate levels and increases ATP production in red blood cells. Lower 2,3-DPG improves hemoglobin-oxygen affinity, reducing the polymerization of sickle hemoglobin that drives both hemolytic anemia and vaso-occlusion. The ATP increase preserves red cell membrane integrity and deformability. This mechanism is distinct from every approved SCD therapy and places etavopivat in a class without a currently marketed comparator, though mitapivat, another PKR activator developed by Agios, has been studied in SCD and thalassemia in separate programs. Cross-trial comparisons are limited by differences in patient populations, endpoints, and trial designs.

Etavopivat originated at Forma Therapeutics, which Novo Nordisk acquired in 2022. The FDA has granted it Fast Track, Rare Pediatric Disease, and Orphan Drug designations. The European Commission has also granted Orphan Drug designation based on a positive opinion from the EMA's Committee for Orphan Medicinal Products.

The 27% VOC reduction reported in HIBISCUS is a topline figure from a sponsor press release, and full data — including confidence intervals, subgroup analyses, and complete safety tables — have not yet been presented at a scientific conference or published in a peer-reviewed journal. Novo Nordisk said detailed results will be presented at a conference later in 2026. The magnitude of the VOC reduction, while statistically superior to placebo, will require context from the full dataset before its clinical meaning can be fully assessed, particularly given the heterogeneity of VOC rates across SCD populations and the variability in how crises are defined and captured across trials.

The parallel HIBISCUS2 trial, a Phase III study enrolling 408 patients aged 12 and older, is ongoing. The open-label extension study FLORAL is collecting long-term safety data from participants across the etavopivat program.

Novo Nordisk plans to submit etavopivat for its first regulatory approval in the second half of 2026.

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