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.
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SOURCE Novo Nordisk
新澤西州普萊恩斯伯勒,2024年12月7日 /PRNewswire/ — 諾和諾德今天公佈了正在進行的針對鐮狀細胞病患者的Etavopivat的2/3期HIBISCUS研究計劃的第二階段52周結果。這些結果已在加利福尼亞州聖地亞哥舉行的美國血液學會(ASH)第66屆年會和博覽會上公佈。
這部分研究的結果已用於確定正在進行的3期HIBISCUS研究計劃的劑量。根據全部數據,在鐮狀細胞病中建立了依他沃匹瓦的概念驗證,這表明與安慰劑相比,在52周內血管閉塞危象(VOCs,即血管阻塞和組織缺氧時引起的劇烈疼痛)的發生率呈下降趨勢,第24周血紅蛋白反應增加的趨勢。1,2 結果將試圖在HIBISCUS的3期成分中得到證實審判。
「由於數十年的資金不足以及缺乏長期、持續的臨床登記制度,批准用於鐮狀細胞病患者的治療方法很少。結果,受影響的人往往終身面臨使人衰弱的痛苦和生活質量下降。」 生命綜合鐮狀細胞中心聯合主任、阿拉巴馬大學伯明翰分校血液學和腫瘤學系教授朱莉·坎特博士說。「急性疼痛危機是鐮狀細胞病的公認特徵,會導致嚴重的疼痛,從而導致器官損傷,以及急診室就診和住院。我們需要爲鐮狀細胞病患者提供更多的治療選擇,以幫助解決該社區未得到滿足的需求。Etavopivat是一種前景看好的鐮狀細胞病患者的研究性治療方法,我期待看到這將如何影響治療格局。」
在意向治療人群的第52周(n=60),依他沃匹瓦200 mg和400 mg組的年化揮發性有機化合物發生率分別爲1.07和1.06,安慰劑組的年化揮發性有機化合物發生率分別爲1.97和1.9周。2 在第24周,血紅蛋白反應(>1)依他沃匹瓦組的g/dL(較基線增加)更高,200 mg和400 mg組的反應分別爲38%和25%,而安慰劑組的這一比例爲10.5%。2 患者報告的結果使用PROMIS測量疲勞量表顯示,與接受安慰劑的參與者相比,接受依他沃匹瓦的參與者的數值有所改善。2
在每個方案的人群中(定義爲80%或更高的協議依從性且已結束雙盲期,沒有重大方案偏差),依他沃匹瓦200 mg和400 mg組的年化VOC率分別爲0.66(n = 13)和0.7(n = 12),安慰劑組的年化VOC率爲1.77(n = 15)。2 第24周的血紅蛋白反應爲46%(n=6/15)13) 在 200 mg 和 400 mg 組中爲 33%(n=4/12),安慰劑組爲 13%(n=2/15)。2
已確定兩種 SAE 可能/可能與藥物有關,依他沃匹瓦特 200 mg 組中有一名患者的肝酶升高,400 mg 組中有一名患者的血紅蛋白降低。2 在 etavopivat 200 mg 組中報告了兩個導致永久停藥的 SAE,肝酶升高和腦血管意外。2
Novo Nordisk執行副總裁兼開發主管Martin Holst Lange表示:「在諾和諾德,我們在血液學和罕見病領域擁有超過35年的歷史和專業知識,我們的目標是通過開發不僅能緩解症狀而且能改變病程的治療方法,改變鐮狀細胞病患者的護理標準。」 3 「儘管還需要更多的研究,HIBISCUS的新結果可能具有重大意義。向前邁出一步,實現這一雄心壯志,並有可能爲患者提供鐮狀細胞疾病的選擇可以幫助控制症狀和疾病進展。」
關於鐮狀細胞病
鐮狀細胞病是一組使人衰弱、危及生命的罕見遺傳性紅細胞疾病,由血紅蛋白基因突變引起。4 這種突變會導致紅細胞變硬並呈半月形或 「鐮狀」 形狀。4 鐮狀細胞攜帶氧氣的效果較差,持續時間不如健康細胞,並有可能卡在血管中,導致稱爲血管閉塞的阻塞 .1,5-8 鐮狀細胞病的特徵是急性和慢性疼痛、貧血、疲勞以及揮發性有機化合物,這可能需要住院治療並可能導致包括器官損傷在內的併發症。4,7,8 在全球範圍內,有將近800萬人患有鐮狀細胞病。9
關於 HIBISCUS
HIBISCUS(NCT04624659)是一項多中心、2/3期、隨機、雙盲、安慰劑對照的研究項目,旨在研究依他沃匹伐在鐮狀細胞病中的安全性和療效。10 第二階段劑量確定隊列招收了60名鐮狀細胞病患者,以 1:1:1 的隨機比例在52周內接受依他沃匹瓦200 mg、400 mg或安慰劑。10 三期療效 HIBISCUS 的一部分將對大約 380 名鐮狀細胞病患者進行隨機分配 1:1,接受選定劑量的依他沃匹瓦特(400 mg)或安慰劑。10 HIBISCUS 的參與者可以在開放標籤延期階段再繼續接受52周的治療,並可以選擇參與長期延期研究。10
HIBISCUS的主要終點是第52周的年化揮發性有機化合物含量和第24周的血紅蛋白反應率,測量值爲比基線增加>1 g/dL。10 關鍵次要終點是首次揮發性有機化合物的時間、溶血生物標誌物的變化(絕對網織紅細胞數量、間接膽紅素和乳酸脫氫酶)和患者報告的結果指標(PROMIS)疲勞量表).10
關於 etavopivat
Etavopivat 是一種研究性口服小分子激活紅細胞丙酮酸激酶 (PKR) 活化劑,正在開發中,用於治療鐮狀細胞病和其他血紅蛋白病。11 ETAVOPIVAT 介導的 PKR 激活可降低 2,3-二磷酸甘油酯 (2,3-DPG) 的水平,並提高紅色的三磷酸腺苷 (ATP) 水平血細胞,它有可能增加氧氣親和力、減少溶血和減少揮發性有機化合物。11-13
關於 Novo Nordisk
諾和諾德是一家全球領先的醫療保健公司,成立於1923年,總部位於丹麥。我們的目標是在我們在糖尿病領域的傳統基礎上推動變革,戰勝嚴重的慢性病。我們通過開創科學突破、擴大藥物供應渠道以及努力預防並最終治癒疾病來做到這一點。諾和諾德在80個國家擁有約72,000名員工,並在大約170個國家銷售其產品。欲了解更多信息,請訪問 novonordisk.com、Facebook、Instagram、X、LinkedIn 和 YouTube。
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參考文獻
Jang t、Poplawska m、Cimpeanu E 等。鐮狀細胞病的血管閉塞危機:次要事件的惡性循環。J. Transl。2021 年中學; 19 (1): 397。
Delicou S、El Rassi F 等。Etavopivat可降低鐮狀細胞病患者血管閉塞危象的發生率:HIBISCUS的2期試驗結果持續52周。美國血液學會(ASH)第66屆年會和博覽會,2024年12月7日至10日,美國聖地亞哥。179。
諾和諾德。文件中的數據。
美國血液學會。鐮狀細胞病。2024 年 12 月訪問。可在以下網址獲得。
Safo Mk、Kato GJ。改變鐮狀血紅蛋白氧氣親和力的治療策略。Hematol Oncol Clin North Am. 2014; 28 (2): 217—231。
國家心肺血液研究所。什麼是鐮狀細胞病?2024 年 12 月訪問。可在以下網址獲得。
Bailey m、Abioye A、Morgan G 等鐮狀細胞病患者血管閉塞危機與重要併發症之間的關係。Blood. 2019; 134 (Supplement_1): 2167。
全國罕見疾病組織(NORD)。鐮狀細胞病。罕見疾病。2024 年 12 月訪問。可在以下網址獲得。
Thomson Am 等人GBD 2021 鐮狀細胞病合作者。2000-2021年鐮狀細胞病的全球、區域和國家患病率和死亡負擔:來自2021年全球疾病負擔研究的系統分析。Lancet Haematol. 2023; 10 (8): e585—e599。
ClinicalTrials.gov。Etavopivat對患有鐮狀細胞病(HIBISCUS)的成人和青少年的研究。2024 年 12 月訪問。可在以下網址獲得。
Saraf SL、Hagar R、Idowu m 等。對鐮狀細胞病患者進行爲期長達12周的依他沃匹瓦特(Ft-4202)治療的多中心1期研究。Blood Adv.2024; 8 (16): 4459—4475。
Barros GDS、Leal CVF、Leite LAC、Fujimoto DE、CancRD。鐮狀細胞病負擔的真實證據:在巴西參考中心進行的一項爲期5年的縱向研究。Hematol Transfus Cell Ther. 2024;46 (2): 161-166. doi: 10.1016/j.htct.2023.10.001
施羅德,P 等Etavopivat 用於治療鐮狀細胞病。《藥學雜誌》,2022年;380(3):210-219。
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