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
Media: | | |
Ambre James-Brown
+45 3079 9289
[email protected] | Liz Skrbkova (US)
+1 609 917 0632
[email protected] | |
References
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.
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.
Novo Nordisk. Data on File.
American Society of Hematology. Sickle Cell Disease. Accessed December 2024. Available at .
Safo MK, Kato GJ. Therapeutic strategies to alter the oxygen affinity of sickle hemoglobin. Hematol Oncol Clin North Am. 2014;28(2):217–231.
National Heart, Lung, and Blood Institute. What Is Sickle Cell Disease? Accessed December 2024. Available at .
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.
National Organization for Rare Disorders (NORD). Sickle cell disease. Rare Diseases. Accessed December 2024. Available at .
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.
Clinicaltrials.gov. A Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (HIBISCUS). Accessed December 2024. Available at .
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.
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
Schroeder, P et al. Etavopivat for the treatment of sickle cell disease. J Pharmacol Exp. 2022; 380(3):210-219.
Novo Nordisk is a registered trademark of Novo Nordisk A/S.
2024 Novo Nordisk All rights reserved. US24SCD00030 December 2024
SOURCE Novo Nordisk
新泽西州普林斯堡，2024年12月7日 /PRNewswire/ -- 诺和诺德今天宣布关于正在进行的第二/第三阶段HIBISCUS研究项目对镰状细胞病患者的实验性etavopivat的52周结果。这些结果在加利福尼亚州圣地亚哥举行的美国血液学会（ASH）第66届年会上进行了发布。
这部分研究的结果已被用于判断正在进行的第三阶段HIBISCUS研究项目的剂量。根据所有数据的总和，etavopivat在镰状细胞病中的概念验证已建立，显示出52周内血管闭塞危机（VOCs - 由于血管阻塞而导致的严重疼痛，导致组织缺氧）的发生率有降低的趋势，且与安慰剂相比，24周时的血红蛋白反应增加。1,2 这些结果将试图在HIBISCUS试验的第三阶段部分得到确认。
“由于几十年的资金不足和缺乏长期的、持续的临床登记，获批的镰状细胞病治疗方法寥寥无几。因此，受影响的个体往往面临着一生的虚弱疼痛和减少的生活质量，” 阿拉巴马大学巴irmingham分校血液学与肿瘤学系联合主任Julie Kanter博士说道。“急性疼痛危机是镰状细胞病的一大标志，导致显著的疼痛，并可能导致器官损伤以及急诊就诊和住院。我们需要更多的治疗选项来帮助解决这个社区未满足的需求。Etavopivat是对镰状细胞病患者的一种有前景的实验性治疗，我期待看到这将如何影响治疗领域。”
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."
关于镰状细胞病
镰状细胞病是一种致残且危及生命的罕见遗传性红细胞疾病，以血红蛋白基因的突变为特征。4 这种突变导致红细胞变得僵硬，呈半月形或“镰刀”形。4 镰状细胞在运送氧气方面的效率较低，存活时间不如健康细胞，并且容易陷入血管中，导致称为血管闭塞的阻塞现象。1,5-8 镰状细胞病的特点是急性和慢性疼痛、贫血和疲乏，同时伴随血管闭塞（VOC），可能需要住院治疗并导致并发症，包括器官损伤。4,7,8 全球约有800万名患者生活在镰状细胞病中。9
关于HIBISCUS
HIBISCUS（NCT04624659）是一个多中心、2/3期、随机、双盲、安慰剂对照的研究计划，旨在调查etavopivat在镰状细胞病中的安全性和有效性。10 2期剂量判断组招募了60名镰状细胞病患者，随机分组1:1:1接受200 mg、400 mg或安慰剂治疗，持续52周。10 HIBISCUS的3期有效性部分将大约随机380名镰状细胞病患者1:1接受选择的etavopivat剂量（400 mg）或安慰剂。10 HIBISCUS的参与者可以在公开标签的延伸阶段继续接受额外52周的治疗，并具有参与长期延续研究的选项。10
HIBISCUS的主要终点是第52周的年度血管闭塞率和第24周的血红蛋白反应率，测量基线增加超过1 g/dL。10 关键次要终点为首次血管闭塞的时间、溶血生物标志物的变化（绝对网织红细胞计数、间接胆红素和乳酸脱氢酶）以及患者报告的结果衡量（PROMIS疲劳量表）。10
关于etavopivat
Etavopivat是一种实验性口服小分子红细胞丙酮酸激酶（PKR）的激活剂，正在开发用于镰状细胞病及其他血红蛋白病的治疗。11 Etavopivat介导的PKR激活降低了红细胞中2,3-二磷酸甘油酸（2,3-DPG）的水平，并提高了三磷酸腺苷（ATP）的水平，可能有助于增加氧亲和力，减少溶血，降低血管闭塞的发生。11-13
关于诺和诺德
诺和诺德是一家领先的全球医疗保健公司，成立于1923年，总部位于丹麦。我们的使命是推动变革，以战胜严重的慢性疾病，建立在我们在糖尿病领域的传统基础上。我们通过开创科学突破、扩大药物的可及性以及努力预防并最终治愈疾病来实现这一目标。诺和诺德在80个国家雇佣约72,000名员工，并在约170个国家销售其产品。如需更多信息，请访问novonordisk.com、Facebook、Instagram、X、LinkedIn和YouTube。
联系方式以获取更多信息
媒体： | | |
安布雷·詹姆斯-布朗
+45 3079 9289
[email protected] | 莉兹·斯克尔博娃（美国）
+1 609 917 0632
[email protected] | |
参考文献
Jang t, Poplawska m, Cimpeanu E, 等. 镰状细胞病中的血管闭塞危机：二次事件的恶性循环. J. Transl. Med. 2021;19(1):397.
Delicou S, El Rassi F, 等. Etavopivat减少镰状细胞病患者血管闭塞危机的发生率：HIBISCUS试验第二阶段在52周内的结果. 第66届美国血液学会年会和展览会（ASH）2024年12月7-10日，美国圣地亚哥. 179.
诺和诺德. 文件数据.
美国血液学会. 镰状细胞病. 访问于2024年12月. 可在此获取.
Safo Mk, Kato GJ. 改变镰状血红蛋白氧亲和力的治疗策略. Hematol Oncol Clin North Am. 2014;28(2):217–231.
国家心脏、肺和血液研究所。镰状细胞疾病是什么？访问时间：2024年12月。可在以下网址获取。
Bailey m，Abioye A，Morgan G等。镰状细胞疾病患者血管堵塞危机与重要并发症之间的关系。《血液》。2019；134（补充_1）：2167。
国家罕见疾病组织（NORD）。镰状细胞疾病。罕见疾病。访问时间：2024年12月。可在以下网址获取。
Thomson Am等。GBD 2021镰状细胞疾病合作组。2000-2021年镰状细胞疾病的全球、区域和国家流行率及死亡负担：来自2021年全球疾病负担研究的系统分析。《柳叶刀血液学》。2023；10（8）：e585–e599。
Clinicaltrials.gov。一项关于Etavopivat在镰状细胞疾病成年人与青少年中的应用的研究（HIBISCUS）。访问时间：2024年12月。可在以下网址获取。
Saraf SL，Hagar R，Idowu m等。关于Etavopivat（Ft-4202）治疗镰状细胞疾病患者的多中心1期研究，持续时间可达12周。《血液进展》。2024；8（16）：4459–4475。
Barros GDS，Leal CVF，Leite LAC，Fujimoto DE，Cançado RD。镰状细胞疾病负担的真实世界证据：在巴西一个参考中心的五年纵向研究。《血液学转输细胞治疗》。2024；46（2）：161-166。doi:10.1016/j.htct.2023.10.001
Schroeder，P等。Etavopivat治疗镰状细胞疾病。《药理学实验》。2022；380（3）：210-219。
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