• Data indicated a trend toward reduced incidence of vaso-occlusive crises over 52 weeks and increased hemoglobin response at 24 weeks compared with placebo

• Results to be confirmed in the phase 3 component of the HIBISCUS trial

PLAINSBORO, N.J., Dec. 7, 2024 /PRNewswire/ -- Novo Nordisk today announced 52-week results from the phase 2 part of the ongoing phase 2/3 HIBISCUS study program of investigational etavopivat in people with sickle cell disease. These results were presented at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) in San Diego, California.

Results from this part of the study have been used to determine the dose for the ongoing phase 3 HIBISCUS study program. Based on the totality of data, proof of concept of etavopivat was established in sickle cell disease, indicating a trend towards reduced incidence of vaso-occlusive crises (VOCs — severe pain caused when blood vessels are blocked and deprive tissues of oxygen) over 52 weeks and increased hemoglobin response at week 24 compared with placebo.1,2 The results will attempt to be confirmed in the phase 3 component of the HIBISCUS trial.

"Due to decades of underfunding and the lack of a long-term, ongoing clinical registry, there have been few treatments approved for people living with sickle cell disease. As a result, affected individuals often face a lifetime of debilitating pain and reduced quality of life," said Dr. Julie Kanter, co-director of the Lifespan Comprehensive Sickle Cell Center and professor in the Division of Hematology and Oncology at the University of Alabama at Birmingham. "Acute pain crises are a recognized hallmark of sickle cell disease, resulting in significant pain that can lead to organ damage as well as emergency department visits and hospitalizations. 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 for patients with sickle cell disease and I look forward to seeing how this may impact the treatment landscape."

At week 52 in the intent-to-treat population (n=60), annualized VOC rates were 1.07 and 1.06 for the etavopivat 200 mg and 400 mg groups, respectively, and 1.97 for the placebo group.2 The median time to first VOC was 33.6 weeks for both etavopivat groups compared with 16.9 weeks for placebo.2 At week 24, hemoglobin response (>1 g/dL increase from baseline) was higher in the etavopivat groups with 38% and 25% responding in the 200 mg and 400 mg groups, respectively, compared with 10.5% in the placebo group.2 Patient-reported outcome measures using the PROMIS Fatigue Scale showed numerical improvements for participants receiving etavopivat compared with those receiving placebo.2

In the per-protocol population (defined as 80% or higher protocol compliance and completion of the double-blind period with no major protocol deviations), annualized VOC rates were 0.66 (n=13) and 0.7 (n=12) for the etavopivat 200 mg and 400 mg groups, respectively, and 1.77 (n=15) for the placebo group.2 Hemoglobin response at week 24 was 46% (n=6/13) and 33% (n=4/12) in the 200 mg and 400 mg groups, and 13% (n=2/15) in the placebo group.2

Two SAEs were identified to be possibly/probably drug-related, hepatic enzyme increase in one patient in the etavopivat 200 mg group and hemoglobin decrease in one patient in the etavopivat 400 mg group.2 Two SAEs leading to permanent discontinuation were reported in the etavopivat 200 mg group, hepatic enzyme increase and a cerebrovascular accident.2

"At Novo Nordisk, we have a 35+ year legacy and expertise in hematology and rare disease, and our ambition is to transform the standard of care for people with sickle cell disease by developing treatments that not only alleviate symptoms but also modify the course of the disease," said Martin Holst Lange, executive vice president and head of Development at Novo Nordisk.3 "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."

About sickle cell disease
Sickle cell disease is a debilitating, life-threatening group of rare, inherited red blood cell disorders caused by a mutation in the hemoglobin gene.4 This mutation causes red blood cells to become stiff and half-moon or 'sickle' shaped.4 Sickle cells are less effective at carrying oxygen, do not last as long as healthy cells, and risk getting stuck in blood vessels, leading to blockages known as vaso-occlusion.1,5-8 Sickle cell disease is characterized by acute and chronic pain, anemia, and fatigue alongside VOCs, which can require hospitalization and can lead to complications, including organ damage.4,7,8 Globally, there are almost 8 million people living with sickle cell disease.9

About HIBISCUS
HIBISCUS (NCT04624659) is a multi-center, phase 2/3, randomized, double-blind, placebo-controlled study program investigating the safety profile and efficacy of etavopivat in sickle cell disease.10 The phase 2 dose-determination cohort enrolled 60 patients with sickle cell disease, randomized 1:1:1 to receive etavopivat 200 mg, 400 mg, or placebo over 52 weeks.10 The phase 3 efficacy part of HIBISCUS will randomize approximately 380 patients with sickle cell disease 1:1 to receive the selected dose of etavopivat (400 mg) or placebo.10 Participants in HIBISCUS can continue for an additional 52 weeks of treatment in an open-label extension phase and have the option to participate in a long-term roll-over study.10

The primary endpoints of HIBISCUS are annualized VOC rate at week 52 and hemoglobin response rate at week 24, measured as an increase of >1 g/dL from baseline.10 Key secondary endpoints are time-to-first VOC, change in hemolysis biomarkers (absolute reticulocyte count, indirect bilirubin, and lactate dehydrogenase), and a patient-reported outcome measure (PROMIS Fatigue Scale).10

About etavopivat
Etavopivat is an investigational, oral, small-molecule activator of erythrocyte pyruvate kinase (PKR) in development for the treatment of sickle cell disease and other hemoglobinopathies.11 Etavopivat-mediated activation of PKR lowers levels of 2,3- diphosphoglycerate (2,3-DPG) and raises adenosine triphosphate (ATP) levels in red blood cells, which has the potential to increase oxygen affinity, reduce hemolysis, and decrease VOCs.11-13

About Novo Nordisk
Novo Nordisk is a leading global healthcare company, founded in 1923 and headquartered in Denmark. Our purpose is to drive change to defeat serious chronic diseases, built upon our heritage in diabetes. We do so by pioneering scientific breakthroughs, expanding access to our medicines, and working to prevent and ultimately cure disease. Novo Nordisk employs about 72,000 people in 80 countries and markets its products in around 170 countries. For more information, visit novonordisk.com, Facebook, Instagram, X, LinkedIn, and YouTube.

Contacts for further information

References

1. Jang T, Poplawska M, Cimpeanu E, et al. Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events. J. Transl. Med. 2021;19(1):397.

2. Delicou S, El Rassi F, et al. Etavopivat reduces incidence of vaso-occlusive crises in patients with sickle cell disease: HIBISCUS trial phase 2 results through 52 weeks. 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) 7-10 December 2024, San Diego, US. 179.

3. Novo Nordisk. Data on File.

4. American Society of Hematology. Sickle Cell Disease. Accessed December 2024. Available at .

5. Safo MK, Kato GJ. Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin. Hematol Oncol Clin North Am. 2014;28(2):217–231.

6. National Heart, Lung, and Blood Institute. What Is Sickle Cell Disease? Accessed December 2024. Available at .

7. Bailey M, Abioye A, Morgan G, et al. Relationship between Vaso-Occlusive Crises and Important Complications in Sickle Cell Disease Patients. Blood. 2019; 134 (Supplement_1):2167.

8. National Organization for Rare Disorders (NORD). Sickle cell disease. Rare Diseases. Accessed December 2024. Available at .

9. Thomson AM, et al. GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol. 2023;10(8):e585–e599.

10. Clinicaltrials.gov. A Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (HIBISCUS). Accessed December 2024. Available at .

11. Saraf SL, Hagar R, Idowu M, et al. Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease. Blood Adv. 2024;8(16):4459–4475.

12. Barros GDS, Leal CVF, Leite LAC, Fujimoto DE, Cançado RD. Real-world evidence of the burden of sickle cell disease: a 5-year longitudinal study at a Brazilian reference center. Hematol Transfus Cell Ther. 2024;46(2):161-166. doi:10.1016/j.htct.2023.10.001

13. Schroeder, P et al. Etavopivat for the treatment of sickle cell disease. J Pharmacol Exp. 2022; 380(3):210-219.

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