An Open-Label Extension Study to Assess the Safety and Efficacy of Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)

The purpose of this study is to obtain safety, efficacy, and pharmacodynamic data on the use of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy who continued on extended use of vutrisiran, or switched from patisiran.

开始日期2024-11-22

申办/合作机构

Alnylam Pharmaceuticals, Inc.

NCT04153149 / Active, not recruiting临床3期

HELIOS-B: A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)

This study will evaluate the efficacy and safety of vutrisiran 25 mg administered subcutaneously (SC) once every 3 months (q3M) compared to placebo in patients with ATTR amyloidosis with cardiomyopathy.

开始日期2019-11-26

申办/合作机构

Alnylam Pharmaceuticals, Inc.

NCT03759379 / Active, not recruiting临床3期

HELIOS-A: A Phase 3 Global, Randomized, Open-label Study to Evaluate the Efficacy and Safety of ALN-TTRSC02 in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis)

The purpose of this study is to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in participants with hereditary transthyretin amyloidosis (hATTR amyloidosis). Participants will receive vutrisiran subcutaneous (SC) injection once every 3 months (q3M) or the reference comparator patisiran intravenous (IV) injection once every 3 weeks (q3w) during the 18 month Treatment Period. This study will use the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the primary and most other efficacy endpoints during the 18 Month Treatment Period. Following the 18 Month Treatment Period, all participants will be randomized to receive vutrisiran 50 mg SC injection once every 6 months (q6M) or vutrisiran 25 mg q3M in the Randomized Treatment Extension (RTE) Period. Upon implementation of Amendment 6, participants receiving vutrisiran SC 50 mg q6M will transition to vutrisiran SC 25 mg q3M at their next scheduled dosing.

开始日期2019-02-14

申办/合作机构

Alnylam Pharmaceuticals, Inc.

100 项与 Vutrisiran Sodium 相关的临床结果

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100 项与 Vutrisiran Sodium 相关的转化医学

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100 项与 Vutrisiran Sodium 相关的专利（医药）

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项与 Vutrisiran Sodium 相关的文献（医药）

2024-11-01·Nature Reviews Cardiology

Benefit of vutrisiran in transthyretin amyloidosis with cardiomyopathy.

Article

作者: Lim, Gregory B

Data from the HELIOS-B trial show that RNA interference with vutrisiran reduces the risk of death and recurrent cardiovascular events in patients with transthyretin amyloidosis with cardiomyopathy.

2024-10-01·JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION

Use of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography in monitoring therapeutic changes of RNA interference therapeutics in patients with hereditary transthyretin amyloid cardiomyopathy

Article

作者: Ko, Chi-Lun ; Lee, Ming-Jen ; Jyh-Ming Juang, Jimmy ; Hung, Yi-Hsin ; Su, Mao-Yuan ; Hsu, Chia-Hua ; Chen, Yi-Chieh ; Cheng, Mei-Fang ; Lin, Kon-Ping ; Hsieh, Sung-Tsang ; Chao, Chi-Chao ; Lin, Yen-Hung ; Hsueh, Hsueh-Wen ; Yu, Wen-Chung ; Shun, Chia-Tung ; Tseng, Ping-Huei ; Tsai, Cheng-Hsuan ; Yu, An-Li

BACKGROUND:

RNA interference therapeutics reduce transthyretin production; however, their effect on hereditary transthyretin amyloid cardiomyopathy (ATTR-CA) remains unclear. We aimed to investigate alterations in technetium-99 m (^99mTc)-pyrophosphate (PYP) single-photon emission computed tomography/computed tomography (SPECT/CT) outcomes in patients receiving patisiran or vutrisiran.

METHODS:

We retrospectively identified individuals with hereditary ATTR-CA who received patisiran or vutrisiran. First and second ^99mTc-PYP SPECT/CT data, including visual grading, planar heart to contralateral lung (H/CL) ratio, and volumetric heart to lung (H/L) ratio were assessed.

RESULTS:

Eight patients with hereditary ATTR-CA were enrolled. Cohort A included four patients who underwent their first ^99mTc-PYP SPECT/CT imaging at the initiation of small interfering RNA (siRNA) treatment, while cohort B comprised four patients who had been receiving siRNA treatment before their first ^99mTc-PYP SPECT/CT imaging (median duration 1281 days). Overall, there were numerical reductions in planar H/CL ratio (1.7 ± 0.2 to 1.6 ± 0.1, p = 0.050) and a significant improvement in volumetric H/L ratio (4.0 ± 0.9 to 3.5 ± 0.4, p = 0.035). Although without significance, subgroup analysis showed more pronounced changes in cohort A for both planar H/CL ratio and volumetric H/L ratio (-20.1 ± 12.6% and -17.1 ± 11.4%) compared to cohort B (-3.3 ± 11.2% and -4.3 ± 12.7%).

CONCLUSION:

Our results demonstrated a significant decrease in volumetric H/L ratio in hereditary ATTR-CA patients receiving RNA interference therapeutics.

2024-08-01·Cardiology Research

Advances in the Diagnosis and Management of Cardiac Amyloidosis: A Literature Review

Review

作者: Llerena-Velastegui, Jordan ; Zumbana-Podaneva, Kristina

Cardiac amyloidosis, increasingly recognized for its significant impact on global heart health and patient survival, demands a thorough review to understand its complexity and the urgency of improved management strategies. As a cause of cardiomyopathy and heart failure, particularly in patients with aortic stenosis and atrial fibrillation, this condition also relates to higher incidences of dementia in the affected populations. The objective of this review was to integrate and discuss the latest advancements in diagnostics and therapeutics for cardiac amyloidosis, emphasizing the implications for patient prognosis. We evaluated the latest literature from major medical databases such as PubMed and Scopus, focusing on research from 2020 to 2024, to gather comprehensive insights into the current landscape of this condition. Insights from our review highlight the complex pathophysiology of cardiac amyloidosis and the diagnostic challenges it presents. We detail the effectiveness of emerging treatments, notably gene silencing therapies like patisiran and vutrisiran, which offer transformative potential by targeting the production of amyloidogenic proteins. Additionally, the stabilization therapy acoramidis shows promise in modifying disease progression and improving clinical outcomes. This review underscores the critical need for updated clinical guidelines and further research to expand access to groundbreaking therapies and enhance disease management. Advocating for continued research and policy support, we emphasize the importance of advancing diagnostic precision and treatment effectiveness, which are vital for improving patient outcomes and addressing this debilitating disease globally.

318

项与 Vutrisiran Sodium 相关的新闻（医药）

2024-11-18

·Endpoints

As cardiomyopathy market expands, Alnylam offers look at Phase 1 data in healthy volunteers

Alnylam’s experimental RNAi treatment for a rare form of cardiomyopathy has shown signs of efficacy in an early-stage trial of healthy volunteers, but analysts said development could be challenging as new treatments near the market. The Phase 1 study tested six doses of Alnylam’s nucresiran versus placebo in 48 healthy volunteers. The 300 mg dose achieved an average of 90.3% serum TTR reduction at 15 days, changing to 92.6% at 180 days. The 600 mg dose achieved a 95% serum TTR reduction at 15 days, changing to 96% at 180 days, according to data presented Sunday at the American Heart Association’s (AHA) scientific sessions in Chicago. Nucresiran was well tolerated at all doses, and the majority of side effects were mild to moderate, according to Alnylam. The drugmaker expects to share registrational development plans for the treatment early next year, with the trial’s initiation set to follow in the second half of 2025, the company said in the release. The only FDA-approved treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) is Pfizer’s Vyndaqel/Vyndamax, but competition is looming. Alnylam submitted Amvuttra to the regulator last month, and the FDA is expected to decide whether to approve BridgeBio’s acoramidis within weeks. The Phase 1 data suggest that nucresiran has the potential for “superior durability” to Amvuttra, Leerink analysts said Sunday. Nucresiran could be dosed twice or even once each year compared with once every three months for Amvuttra, TD Cowen analysts wrote Monday. But being able to enroll enough participants in a Phase 3 trial could be a difficult task, according to the Leerink analysts. “We see a cardiovascular outcomes trial as likely necessary, a study that would be quite challenging to enroll in a market with multiple approved agents,” they wrote. Nonetheless, the Leerink analysts noted that the Phase 1 data for nucresiran compare well with Intellia Therapeutics’ CRISPR gene-editing ATTR candidate, nex-z. Intellia’s therapy achieved an average of 90% reduction in serum TTR at 12 months in a Phase 1 trial, according to results presented Saturday at the AHA sessions.

临床结果上市批准AHA会议临床1期

2024-11-18

·凯莱英药闻

药效持续近一年！Alnylam公布第三代TTR siRNA药物最新数据

欢迎关注凯莱英药闻 2024年11月17日，Alnylam Pharmaceuticals在芝加哥举行的 2024 年美国心脏协会科学会议上，口头报告了旗下药物nucresiran（ALN-TTRsc04）的最新研究数据。Nucresiran是公司开发的第三代靶向TTR的RNAi 治疗药物，正开发用于治疗转甲状腺素蛋白淀粉样变性（ATTR）。关于最新研究数据本次披露的1期研究是一项随机、双盲、安慰剂对照、单次递增剂量试验，旨在评估nucresiran对健康成年受试者的安全性、耐受性、药代动力学 (PK) 和药效学 (PD) 作用。该研究招募了 48 名健康成年受试者，按 3:1 的比例随机分配接受单次递增剂量的nucresiran或安慰剂，剂量分别为 5、25、100、300、600 或 900 mg。研究的主要终点是安全性，次要终点包括血清转甲状腺素蛋白 (TTR)随时间的变化，以及使用nucresiran后的血浆和尿液药代动力学 (PK) 特征。结果显示：采用单剂量 300 mg或更高剂量的 nucresiran 可快速降低血清 TTR，且患者间差异较小；第 15 天平均降低幅度超过基线的 90%，并持续到至少第 180 天。在这些剂量下，第 29 天平均 TTR 水平的峰值降低幅度超过 96% 。在第 360 天血清TTR 水平仍然大幅降低；其中，单剂量300 mg后平均降低幅度超过 70%。患者在所有测试剂量下均具有良好的耐受性；剂量间大多数不良事件都很轻微，且均未被认为与治疗相关。未发现注射部位反应，也未发现包括肝脏相关的安全信号。关于Nucresiran Nucresiran 是一种临床在研的RNAi 疗法，可快速抑制突变型和野生型TTR，从根本上解决ATTR。该药物由Alnylam 专有IKARIA™ 平台开发，可能实现更深层次、更持久的 TTR 快速抑制，减少给药频次。上述数据支持nucresiran一年两次或一年一次皮下给药，公司计划将于2025 年第一季度公开该药物的III期开发计划。此前的临床前研究中，IKARIA 平台显示出了长效潜力和高特异性，或许可以实现每年给药一次。关于转甲状腺素蛋白淀粉样变性 ATTR是一种累及多系统的致死性疾病，患者在遗传、肿瘤或者感染等不同因素的作用下会产生由异常蛋白质分子折叠形成的淀粉样纤维，这些纤维可沉积至全身多个组织和器官，并最终导致其结构和功能损伤。心脏可为受累器官之一，表现为浸润性心肌病（即心肌增厚）、舒张功能明显受限及传导阻滞等，称为心脏淀粉样变（CM）。有30余种异常蛋白质会导致淀粉样变，其中最常见的两种为轻链型淀粉样变性（AL）和转甲状腺素蛋白（TTR）。 TTR由肝脏合成，是在血中负责转运视甲状腺素和黄醇结合蛋白-维生素A复合物的蛋白，正常情况下为四聚体，当解离成单体并错误折叠为淀粉样物质并沉积于心肌间质时，会导致心肌病变，即ATTR-CM。ATTR-CM患者生活质量差、生存率低，野生型（wtATTR）患者的中位生存期为诊断后43~57个月，而由遗传导致的突变型（hATTR或mATTR）患者的生存期则取决于突变基因，其中Val122Ile突变型患者的中位生存期仅为诊断后31个月。ATTR-CM患者死亡原因多为心原性因素，包括猝死和心衰。由于ATTR为罕见疾病，因此，医师对此疾病的临床认识不足、疾病的临床表现缺乏特异性以及既往缺乏治疗手段等因素，最终导致了此病导致误诊率高、诊断延迟、预后差。目前，全球约有5万名hATTR患者，20-30万名wtATTR患者。以ATTR-CM为例：根据一项法国的全国范围流行病学数据，2011年至2017年间，法国ATTR-CM患者发病率涨幅超6倍，从2011年的0.6/100,000人每年增至2017年的3.6/100,000人每年。患者的性别比（男/女）从2011年的1.52上升至2019年的2.23，确诊时的中位年龄为82.0岁。据统计，全球约有80%的ATTR-CM患者并没有得到治疗，约有75%的患者对目前的标准治疗没有应答或者仅有部分应答。因此，ATTR-CM治疗领域存在巨大的未满足临床需求。目前，有许多改善ATTR淀粉样变性的策略正在开发中，包括：1）TTR mRNA敲除和/或沉默；2）TTR稳定；3）TTR淀粉样纤维断裂和/或提取。药物类型主要以靶向TTR RNAi/ASO，单抗、小分子药物、基因编辑疗法为主。关于靶向TTR RNAi 据不完全统计，目前在研的靶向TTR RNAi药物约5种。以Alnylam领衔，公司曾用ALN-TTR01和ALN-TTRsc这两个失败候选药物来铺垫，目前已开发出三代TTR RNAi药物，即Onpattron (patisiran)、Amcuttra(vutrisiran)以及在研的ALN-TTRsc04。 Patisiran是一种包裹在脂质纳米颗粒中的siRNA，通过输注直接递送至肝脏，与编码异常TTR的mRNA相结合，阻止TTR的产生。有研究显示，patisiran治疗能够明显改善hATTR多发性神经病患者的神经功能，该药物已于2018年8月获FDA批准。 Vutrisiran是一种皮下给药的siRNA，是基于Alnylam公司的增强稳定化学（ESC）-GalNAc偶联递送平台设计而成的，与patisiran相比增加了效力和代谢稳定性，可以每3-6个月进行皮下注射，该药物于2022年6月获FDA批准。除此以外，国内公司圣诺医药（STP152G）和舶望制药（TTR RNAi）亦在该领域进行布局，研发均处于临床前的在研阶段。参考资料 1、公司官网 2、华创证券、招商证券、国金证券感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

siRNA临床3期临床1期临床结果

2024-11-18

·Firstwordpharma

AHA24: Alnylam, Intellia showcase upbeat early-stage data for ATTR therapies

Encouraging early clinical data from Alnylam Pharmaceuticals and Intellia Therapeutics presented at the American Heart Association’s (AHA) scientific sessions over the weekend hinted at significant progress in developing novel treatments for transthyretin amyloidosis (ATTR).While Alnylam’s next-generation siRNA therapeutic, nucresiran, demonstrated rapid and durable reduction of serum transthyretin (TTR) in healthy participants, a one-time administration of Intellia’s Regeneron-partnered CRISPR-based gene editing therapy, nexiguran ziclumeran (nex-z), showed disease stabilisation or improvement, alongside TTR lowering in a cohort of ATTR amyloidosis with cardiomyopathy (ATTR-CM).Robust siRNA-induced TTR knockdownIn one ongoing Phase I study, 48 healthy participants were randomised to receive a single ascending dose of nucresiran in the range of 5 mg to 900 mg, or placebo. Results showed that a ≥300-mg nucresiran dose achieved rapid and consistent knockdown of serum TTR, with mean reductions >90% by day 15, peaking >96% by day 29, and sustained through day 180. For the 300-mg dose, TTR reductions remained >70% at day 360. Moreover, nucresiran demonstrated low inter-patient variability in TTR reductions at all doses by day 29. Safety remained favourable across all doses, with no injection site reactions or liver-related signals identified. “Nucresiran utilises our IKARIA platform, which has now demonstrated the potential to achieve durability supportive of biannual or annual dosing, representing a potential new paradigm in the treatment of ATTR amyloidosis,” remarked Pushkal Garg, chief medical officer of Alnylam.Garg noted that the company will unveil Phase III development plans for the drug early next year. Subject to successful late-stage testing and approval, nucresiran would become the third addition to Alnylam’s siRNA portfolio for ATTR, which includes Onpattro (patisiran) and Amvuttra (vutrisiran), approved by the FDA in 2018 and 2022, respectively.CRISPR therapy alters ATTR-CM progressionMeanwhile, Intellia’s Phase I study is investigating nex-z in two cohorts: a 36-participant ATTR-CM arm and a 33-participant ATTR with polyneuropathy (ATTRv-PN) arm. Results for the ATTR-CM arm at the August 21 data-off showed that a single dose of nex-z led to a 90% reduction in serum TTR by month 12, which was sustained in 11 participants reaching the 24-month follow-up. Notably, the treatment also demonstrated disease-modifying effects, with 81%, 94% and 77% of participants achieving significant improvements on cardiac markers such as NT-proBNP, high sensitivity Troponin T and 6-minute walk test, respectively. On the safety front, nex-z was well tolerated, with no instances of treatment-related discontinuation.“The stability or improvement…in multiple markers of cardiac disease progression is remarkable, especially considering the high proportion of patients with cardiomyopathy who had advanced heart failure,” explained John Leonard, chief executive of Intellia. The company also noted positive and consistent trends, reflecting a disease-modifying effect in the ATTRv-PN cohort. Intellia is currently recruiting for the Phase III MAGNITUDE study of nex-z for ATTR-CM and is set to commence the MAGNITUDE-2 study for ATTRv-PN. The latest findings for nex-z could spell good news for the biotech, whose stock tumbled over 20% last month after investor concerns persisted despite positive mid-stage results of another CRISPR-based therapy, NTLA-2002, for hereditary angioedema.

临床结果临床3期上市批准AHA会议临床1期

100 项与 Vutrisiran Sodium 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11916 D11917	-	-	DB16699

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
转甲状腺素蛋白介导的淀粉样变性	澳大利亚	Medison Pharma Australia Pty Ltd.	2024-06-21
转甲状腺素运载蛋白淀粉样变性	美国	Alnylam Pharmaceuticals, Inc.	2022-06-13

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
甲状腺素运载蛋白淀粉样变心肌病	申请上市	美国	Alnylam Pharmaceuticals, Inc.	2024-10-09
斯塔加特病	临床2期	美国	Alnylam Pharmaceuticals, Inc.	2022-10-08

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04153149 (HELIOS-B, BusinessWire) 人工标引	临床3期	甲状腺素运载蛋白淀粉样变心肌病 N-terminal pro-B-type Natriuretic peptide \| Cardiac Troponin I	655	Vutrisiran 25mg	淵淵遞鹽觸鬱選積蓋鬱(醖觸築壓夢襯鑰簾鑰積) = 範繭繭淵夢鬱醖簾鑰網選簾蓋築齋夢醖網製製 (積襯鏇憲齋繭壓鹹醖繭 ) 更多	积极	2024-09-29
NCT04153149 (HELIOS-B, Pubmed \| N Engl J Med) 人工标引	临床3期	甲状腺素运载蛋白淀粉样变心肌病	655	Vutrisiran 25 mg	構齋夢觸齋觸構範積鑰(鏇憲簾鬱網醖構鹹齋簾): HR = 0.72 (95% CI, 0.56 ~ 0.93), P-Value = 0.01 更多	积极	2024-08-30
				Placebo
NCT04153149 (HELIOS-B, Company_Website) 人工标引	临床3期	甲状腺素运载蛋白淀粉样变心肌病	655	Vutrisiran (overall population)	齋壓蓋築壓醖網鹽鏇製(蓋製遞艱醖膚鬱顧積衊) = Rates of adverse events (AEs), serious AEs and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. No AEs were seen ≥3% more frequently in the vutrisiran arm compared to the placebo arm. 憲積醖壓衊鹽餘壓鹽艱 (選餘觸衊網積鬱鏇構衊 )	积极	2024-06-24
				Vutrisiran (not receiving tafamidis at baseline)
NCT03759379 (HELIOS-A, Pubmed)	临床3期	家族性淀粉样神经病	164	Vutrisiran	築選鬱遞鏇淵壓鬱鏇鬱(繭顧網鏇壓膚壓壓壓襯) = 膚衊範憲鹹廠憲鬱願廠鹽顧淵顧廠艱願淵構衊 (餘選齋觸構選夢廠顧膚 )	-	2023-07-31
NCT01960348 \| NCT03759379 (APOLLO, ANA2022)	临床3期	多发性神经病 NfL	-	Patisiran	選壓觸艱鏇艱觸壓獵願(範廠顧齋鏇衊觸糧鏇網) = 鹹糧齋鹽願簾廠廠顧鹹獵鹹願壓齋壓憲淵鏇膚 (獵餘鑰鹹廠觸選願製顧 )	积极	2022-09-14
				Vutrisiran	選壓觸艱鏇艱觸壓獵願(範廠顧齋鏇衊觸糧鏇網) = 夢艱淵醖遞衊製餘觸鏇獵鹹願壓齋壓憲淵鏇膚 (獵餘鑰鹹廠觸選願製顧 )
NCT03759379 (HELIOS-A, Corporate Publications) 人工标引	临床3期	心肌疾病	199	vutrisiran	齋鹹壓鬱簾構選製鏇淵(獵醖獵艱鹽餘憲衊鬱壓) = 糧淵顧簾網糧膚夢網獵鏇衊遞積廠鏇廠壓鏇遞 (鏇餘膚糧構衊獵遞選膚 )	积极	2022-05-23
				Placebo	齋鹹壓鬱簾構選製鏇淵(獵醖獵艱鹽餘憲衊鬱壓) = 選糧鏇壓選鬱遞膚齋憲鏇衊遞積廠鏇廠壓鏇遞 (鏇餘膚糧構衊獵遞選膚 )
NCT03759379 (HELIOS-A, Corporate Publications) 人工标引	临床3期	淀粉样神经病	199	Vutrisiran	範糧顧齋窪壓鑰觸淵選(顧衊鬱簾繭選糧鹽願蓋) = 範窪蓋憲簾鹹積糧淵憲選窪餘衊糧遞鏇鹽構鑰 (觸壓齋構壓鬱壓積願構 ) 更多	积极	2022-01-21
				Placebo	範糧顧齋窪壓鑰觸淵選(顧衊鬱簾繭選糧鹽願蓋) = 齋築鹹觸網艱製構夢範選窪餘衊糧遞鏇鹽構鑰 (觸壓齋構壓鬱壓積願構 ) 更多