Novo Nordisk Submits FDA and EMA Applications for Etavopivat as Potential Disease-Modifying Treatment for Sickle Cell Disease
Novo Nordisk today announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for etavopivat, an investigational, once-daily oral medicine being developed for the treatment of sickle cell disease (SCD) in adolescents and adults aged 12 years and older.
Etavopivat is an orally available, selective activator of pyruvate kinase red blood cell isozyme (PKR), an important enzyme involved in red blood cell energy metabolism. If approved, the medicine could introduce a new treatment approach for people living with sickle cell disease by targeting underlying biological mechanisms associated with the condition rather than focusing exclusively on managing its symptoms.
The regulatory submissions represent an important milestone in Novo Nordisk’s efforts to expand its portfolio of treatments for serious hematological disorders and address the significant unmet medical needs of people living with sickle cell disease. The applications are supported by findings from the company’s HIBISCUS clinical development programme, which evaluated the efficacy and safety of etavopivat in adolescents and adults with SCD.
The FDA has previously granted etavopivat Fast Track, Rare Pediatric Disease, and Orphan Drug designations, recognizing its potential importance in addressing a serious condition with limited treatment options. The agency is expected to take action on the NDA in 2027.
In Europe, etavopivat has received Orphan Drug designation from the European Commission following a positive recommendation from the EMA’s Committee for Orphan Medicinal Products. The EMA is also expected to take action on the MAA in 2027. The application represents the formal regulatory process for seeking authorization to market a medicine within the European Union.
Novo Nordisk believes that etavopivat could provide a new disease-modifying treatment option for eligible patients if regulatory authorities determine that the clinical evidence supports its approval.
Novo Nordisk Highlights Potential to Address Unmet Needs in Sickle Cell Disease
Sickle cell disease remains a serious inherited blood disorder associated with substantial disease burden, recurrent pain episodes, organ complications, and reduced life expectancy. Although treatment options have improved in recent years, many patients continue to experience significant symptoms and limitations in their daily lives.
Vaso-occlusive crises (VOCs), one of the major complications of SCD, occur when sickled red blood cells obstruct blood flow through small blood vessels. These episodes can cause severe pain, tissue damage, and other potentially life-threatening complications. Repeated crises can also contribute to progressive organ damage and frequent hospital visits.
Commenting on the regulatory submissions, Martin Holst Lange, Executive Vice President, Chief Scientific Officer, and Head of Research and Development at Novo Nordisk, emphasized the significant challenges experienced by people living with the condition.
He noted that severe vaso-occlusive crises and other symptoms can have a profound effect on patients’ everyday lives, while available treatment options remain limited for many individuals.
Lange expressed optimism about the potential of etavopivat to provide a new disease-modifying treatment alternative if approved. He also emphasized the company’s commitment to working alongside the sickle cell disease community to advance health equity and address longstanding disparities affecting people with the condition.
The company’s approach reflects the importance of developing therapies that address the underlying disease mechanisms while also considering the broader healthcare challenges faced by patients, including access to diagnosis, treatment, specialist care, and long-term disease management.
HIBISCUS Clinical Programme Supports Regulatory Submissions
The NDA and MAA submissions are primarily supported by findings from Novo Nordisk’s HIBISCUS clinical development programme, which was designed to evaluate the efficacy and safety of etavopivat in people living with sickle cell disease.
The pivotal programme investigated whether once-daily treatment with etavopivat could reduce the frequency of vaso-occlusive crises and improve hemoglobin levels compared with placebo.
Two important efficacy measures were included in the clinical evaluation:
- The annualized rate of vaso-occlusive crises at week 52.
- The proportion of patients achieving a hemoglobin response of greater than 1 g/dL at week 24 compared with baseline.
The study also allowed participants to continue receiving standard-of-care treatment throughout the clinical trial. This approach enabled researchers to evaluate etavopivat in the context of ongoing disease management rather than requiring participants to discontinue their existing treatments.
In April 2026, Novo Nordisk announced topline results from the HIBISCUS programme, reporting that etavopivat demonstrated a 27% reduction in vaso-occlusive crises compared with placebo.
The findings also indicated an approximately four-month delay in the time to the first vaso-occlusive crisis among patients receiving etavopivat compared with those receiving placebo.
These results provide important clinical evidence supporting the company’s regulatory applications and its efforts to establish etavopivat as a potential disease-modifying treatment for SCD.
The reduction in VOC frequency is particularly relevant because recurrent crises represent a major source of pain, healthcare utilization, and long-term complications for patients.
Delaying the occurrence of the first crisis could also be clinically meaningful, potentially helping patients experience longer periods without acute disease-related episodes.
Novo Nordisk has indicated that more comprehensive findings from the HIBISCUS Phase 3 trial will be presented at a future scientific conference and published in a peer-reviewed medical journal.
The detailed results are expected to provide additional information about the treatment’s efficacy, safety profile, and potential clinical relevance across the adolescent and adult patient populations evaluated in the programme.
Understanding Sickle Cell Disease and Its Global Impact
Sickle cell disease is an inherited blood disorder caused by mutations in the gene responsible for producing hemoglobin, the protein in red blood cells that transports oxygen throughout the body.
The condition is characterized by the production of abnormal sickle hemoglobin, commonly referred to as HbS. Under certain conditions, HbS molecules polymerize, causing red blood cells to become rigid and assume a characteristic crescent or sickle shape.
Healthy red blood cells are generally flexible and can move through small blood vessels to deliver oxygen to tissues and organs. However, sickled red blood cells are less flexible and can become trapped in small blood vessels, restricting blood circulation.
This process contributes to the two major hallmarks of sickle cell disease: hemolytic anemia and vaso-occlusive crises.
Hemolytic anemia occurs when abnormal red blood cells break down more rapidly than normal cells. This reduces the overall availability of circulating red blood cells and can lead to fatigue, weakness, and other complications associated with insufficient oxygen delivery.
Vaso-occlusive crises occur when sickled cells obstruct blood flow, resulting in severe pain and potential tissue injury. Repeated episodes can cause damage to multiple organs and contribute to long-term disease progression.
Sickle cell disease affects approximately eight million people worldwide, with the majority living in low- and middle-income countries.
The geographical distribution of the disease highlights its significant global healthcare impact:
- Approximately 100,000 people in the United States are living with SCD.
- Around 110,000 people are affected in Europe.
- Approximately 5.7 million people live with the condition in sub-Saharan Africa.
- India accounts for approximately 1.28 million affected individuals.
- Around 618,000 people are living with SCD across the Middle East and North Africa.
The disease can cause a broad range of acute and chronic health complications. These include acute chest syndrome, stroke, kidney disease, liver complications, and cardiovascular problems.
Acute chest syndrome is particularly serious and can involve respiratory symptoms and reduced oxygen levels. Stroke is another major complication, especially among younger patients, while progressive organ damage can affect long-term health and quality of life.
Despite advances in treatment and supportive care, many people continue to experience recurrent pain episodes and significant disease-related complications. Life expectancy among people with sickle cell disease is also reduced by approximately 20 years compared with the general population.
The substantial disease burden and geographical distribution of SCD highlight the importance of developing additional treatment options that can address the underlying biological mechanisms of the condition.
Etavopivat Targets Red Blood Cell Energy Metabolism
Etavopivat is an investigational, once-daily, orally available, selective activator of pyruvate kinase red blood cell isozyme (PKR).
PKR is an important enzyme involved in glycolysis, the metabolic pathway through which cells generate energy. Red blood cells depend on glycolysis to produce adenosine triphosphate (ATP), which is essential for maintaining cellular function and membrane integrity.
In sickle cell disease, abnormalities in red blood cell metabolism contribute to the processes that cause hemoglobin polymerization, red blood cell sickling, and premature cell destruction.
Etavopivat is designed to address these abnormalities by increasing PKR activity, producing two important metabolic effects: reducing levels of 2,3-diphosphoglycerate (2,3-DPG) and increasing ATP production.
The reduction in 2,3-DPG is expected to improve the oxygen-binding affinity of hemoglobin.
Under normal circumstances, hemoglobin releases oxygen to tissues as needed. However, in sickle cell disease, increased 2,3-DPG levels can promote the release of oxygen from hemoglobin and contribute to conditions that favor sickle hemoglobin polymerization.
By reducing 2,3-DPG levels, etavopivat is designed to increase hemoglobin’s affinity for oxygen. This mechanism may help reduce the polymerization of sickle hemoglobin, potentially limiting the formation of rigid, sickle-shaped red blood cells.
The second mechanism involves increasing ATP production within red blood cells.
ATP plays an important role in maintaining cellular energy balance and preserving red blood cell membrane function. Increased ATP availability may help maintain membrane integrity and cellular deformability, allowing red blood cells to retain their flexibility as they circulate through blood vessels.
Improved red blood cell function and survival could potentially reduce the breakdown of abnormal cells and support higher hemoglobin levels.
Through these complementary mechanisms, etavopivat is being investigated for its potential to reduce vaso-occlusive events, improve hemoglobin levels, and modify important aspects of sickle cell disease progression.
The medicine’s mechanism of action distinguishes it from approaches that primarily focus on controlling pain or managing individual complications. Instead, etavopivat is intended to influence the metabolic processes associated with red blood cell dysfunction.
However, its potential clinical benefits will ultimately depend on the complete clinical evidence and regulatory assessment of its safety and efficacy.
FDA and European Regulatory Designations Support Development
Etavopivat has received several regulatory designations that recognize the seriousness of sickle cell disease and the potential importance of developing additional treatment options.
In the United States, the FDA has granted the investigational medicine three designations:
Fast Track designation: This designation is intended to facilitate the development and regulatory review of medicines addressing serious conditions with unmet medical needs. It can provide opportunities for more frequent communication with the FDA and potentially support an expedited development and review process.
Rare Pediatric Disease designation: This designation recognizes the development of treatments for serious or life-threatening rare diseases that primarily affect pediatric populations. It is intended to encourage the development of therapies for conditions where treatment options may be limited.
Orphan Drug designation: This designation supports the development of medicines intended to treat rare diseases or conditions. It can provide certain development incentives and potential regulatory benefits, subject to applicable requirements.
In Europe, the European Commission granted etavopivat Orphan Drug designation following a positive opinion from the EMA’s Committee for Orphan Medicinal Products.
These designations reflect the significant unmet medical need associated with sickle cell disease and support the continued development of etavopivat.
Nevertheless, regulatory designations do not represent marketing approval. The FDA and EMA will independently evaluate the submitted clinical and nonclinical evidence before determining whether the medicine can be authorized for use.
Novo Nordisk expects regulatory decisions on both applications in 2027.
Novo Nordisk Acquired Etavopivat Through Forma Therapeutics Acquisition
Etavopivat became part of Novo Nordisk’s research and development portfolio through the company’s acquisition of Forma Therapeutics in 2022.
The acquisition expanded Novo Nordisk’s presence in hematology and provided access to investigational medicines targeting serious blood disorders.
By incorporating etavopivat into its development portfolio, Novo Nordisk gained an opportunity to advance a treatment candidate focused on improving red blood cell metabolism and addressing the underlying biological processes associated with sickle cell disease.
The subsequent HIBISCUS clinical development programme has been central to evaluating the medicine’s potential and generating the evidence required for regulatory submissions.
The latest NDA and MAA filings represent the continuation of this development strategy and move etavopivat closer to potential regulatory authorization.
HIBISCUS Programme: Evaluating Efficacy and Safety in Adolescents and Adults
The HIBISCUS programme is designed to investigate etavopivat as a potential disease-modifying treatment for people living with sickle cell disease.
The pivotal HIBISCUS study, registered under ClinicalTrials.gov identifier NCT04624659, was designed as a 52-week efficacy and safety Phase 2/3 clinical trial.
The study compared once-daily etavopivat with placebo in approximately 440 adolescents and adults aged 12 years and older who were living with SCD.
Eligible participants had experienced between two and 15 vaso-occlusive crises during the 12 months before enrollment. This patient population was selected to evaluate the medicine in individuals with a history of recurrent disease-related pain episodes.
Participants were permitted to continue receiving standard-of-care treatment throughout the trial.
The clinical programme included an initial 12-week Phase 2 interim evaluation, which helped determine the appropriate dose for the subsequent Phase 3 portion of the study.
Following completion of the interim evaluation, the selected Phase 3 dose was used in the main phase of the trial, which continued for 52 weeks.
The study assessed both efficacy and safety, with particular attention to the annualized rate of vaso-occlusive crises at week 52 and the proportion of participants achieving a hemoglobin increase greater than 1 g/dL at week 24.
These endpoints were intended to evaluate whether etavopivat could provide meaningful benefits across both acute disease manifestations and underlying hematological abnormalities.
The results formed the foundation for Novo Nordisk’s regulatory submissions to the FDA and EMA.
Regulatory Milestone Positions Etavopivat for Potential Approval in 2027
The submission of the NDA in the United States and the MAA in Europe represents a major milestone in the development of etavopivat and Novo Nordisk’s broader efforts to address unmet needs in hematology.
The applications are supported by the HIBISCUS clinical programme, which demonstrated a 27% reduction in vaso-occlusive crises and an approximately four-month delay to the first crisis compared with placebo in the announced topline findings.
The company’s next priority will be to work with regulatory authorities as they review the submitted applications and evaluate the available clinical evidence.
Detailed Phase 3 results are expected to be shared at a future scientific conference and published in a peer-reviewed journal, providing the medical community with additional information about the medicine’s clinical performance.
If approved, etavopivat could offer adolescents and adults aged 12 years and older a new once-daily oral treatment option designed to address important biological mechanisms involved in sickle cell disease.
For Novo Nordisk, the regulatory submissions also represent an important step in expanding its research and development activities beyond its established focus areas.
With approximately eight million people worldwide living with sickle cell disease and substantial unmet medical needs across different regions, additional therapeutic approaches remain important.
As the FDA and EMA begin their respective reviews, etavopivat’s potential to improve red blood cell function, reduce vaso-occlusive crises, and support better disease management will remain central to its clinical and regulatory development.