Etavopivat Submitted to FDA After 27% VOC Reduction in Phase 3 SCD Trial

Etavopivat, an investigational once daily oral therapy for adolescents and adults with sickle cell disease (SCD), has been submitted to the US Food and Drug Administration (FDA) for approval.

Novo Nordisk announced the new drug application (NDA) on November 13, 2026, along with a marketing authorization application (MAA) to the European Medicines Agency (EMA).¹

The submissions are based on the phase 3 HIBISCUS trial, in which etavopivat reduced vaso-occlusive crises (VOCs) by 27% and delayed time to first VOC by approximately 4 months vs placebo, on top of standard of care in patients aged ≥12 years.¹ The FDA is expected to act on the NDA in 2027.¹

“For people living with sickle cell disease, severe vaso-occlusive crises and other symptoms can have a profound impact on everyday life, and treatment options remain limited,” Martin Holst Lange, executive vice president, chief scientific officer and head of Research & Development at Novo Nordisk, said in a statement. “If approved, we are hopeful that etavopivat can provide a new disease-modifying treatment option for people living with sickle cell disease, and we will continue to work alongside the community to help advance health equity and overcome the longstanding disparities that impact those affected by this disease.”¹

How Etavopivat Works: Oral PKR Activation in Sickle Cell Disease

Etavopivat is a selective activator of pyruvate kinase red blood cell isozyme (PKR), a key enzyme in glycolysis.¹ In SCD, PKR activation lowers 2,3-diphosphoglycerate (2,3-DPG) levels and increases adenosine triphosphate (ATP) production.¹

According to Novo Nordisk, lowering 2,3-DPG improves hemoglobin-oxygen affinity, which may limit sickle hemoglobin polymerization and red blood cell (RBC) sickling. The rise in ATP is intended to support RBC membrane integrity and survival.¹ Novo Nordisk acquired etavopivat through its 2022 acquisition of Forma Therapeutics.¹

HIBISCUS Phase 3 Trial Design in Adolescents and Adults With SCD

HIBISCUS (NCT04624659) is a randomized, placebo controlled phase 2/3 trial. It enrolled patients aged ≥12 years with SCD who had 2 to 15 VOCs in the 12 months before enrollment.¹ A 12 week phase 2 interim readout informed dose selection. Participants were then randomized to the 52 week phase 3 portion, and standard of care treatment was permitted throughout.¹

The phase 3 portion compared etavopivat 400 mg once daily with placebo in 385 patients.² It had 2 primary endpoints:

• Annualized VOC rate at week 52
• Hemoglobin response, defined as an increase of >1 g/dL, at week 24¹

Earlier, in the phase 2 portion of HIBISCUS, etavopivat was associated with fewer VOCs, improvements in hemolysis and fatigue, and increases in hemoglobin vs placebo.

Etavopivat Results: VOC Reduction and Hemoglobin Response in HIBISCUS

Topline phase 3 results announced in April 2026 showed that etavopivat met both primary endpoints.² In addition to the 27% reduction in VOCs, 48.7% of patients treated with etavopivat achieved a hemoglobin increase of >1 g/dL at week 24, compared with 7.2% of those receiving placebo.²

In an exploratory analysis, etavopivat also reduced the risk of blood transfusion. Its topline safety profile was consistent with previous etavopivat trials.² More detailed HIBISCUS results will be presented at a future scientific conference and published in a peer reviewed journal.¹

Etavopivat Regulatory Timeline and Oral PK Activators in SCD

The FDA previously granted etavopivat Fast Track, Rare Pediatric Disease and Orphan Drug designations. The European Commission granted it Orphan Drug designation and is also expected to act on the MAA in 2027.¹

The broader HIBISCUS program also includes:

• HIBISCUS 2 (NCT06612268), a 52 week phase 3b trial expected to enroll 510 patients aged ≥12 years
• FLORAL (NCT06609226), an open label extension collecting long term safety data¹

Etavopivat is not the only oral pyruvate kinase activator under FDA review for SCD. Agios Pharmaceuticals submitted a supplemental NDA for mitapivat under the accelerated approval pathway. The FDA extended its target action date for mitapivat from November 1, 2026, to February 1, 2027.³

References

1. Novo Nordisk. Novo submits etavopivat, an investigational once-daily therapy for adolescents and adults living with sickle cell disease, to the FDA and EMA for approval. PR Newswire. Published November 13, 2026. Accessed November 13, 2026.

2. Novo Nordisk A/S. Novo Nordisk: Etavopivat is the first in a new class of drugs to meet both co-primary endpoints in the phase 3 HIBISCUS trial, substantially reducing vaso-occlusive crisis events and improving haemoglobin response in sickle cell disease. GlobeNewswire. Published April 20, 2026. Accessed November 13, 2026.

3. FDA delays PDUFA action on Agios’ mitapivat sNDA for SCD. GEN: Genetic Engineering & Biotechnology News. Accessed November 13, 2026.