This study will examine the clinical effectiveness of Tafamidis in patients with Mixed Phenotype Transthyretin Amyloidosis using data that already exist in patients' medical records

开始日期2024-05-19

申办/合作机构

Pfizer Inc.

NCT06086353 / RecruitingN/A

A Prospective, Single-arm, Multicenter, Observational Safety Surveillance Study of VyndaMx® (Tafamidis Capsule 61 mg) in Patients With Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in India

The purpose of this study is to learn about the safety of Tafamidis for the treatment of Transthyretin amyloid cardiomyopathy (ATTR-CM) in India.
ATTR-CM is a condition that affects people's hearts. Transthyretin is a protein that is made in the liver. In some people this protein stops working and forms clumps called as amyloid. Transthyretin amyloid builds up in heart and stops the heart from pumping properly.
This study is seeking for participants who are:
confirmed with ATTR-CM.
given Tafamidis capsules to be taken by mouth.
The safety of Tafamidis capsules will be checked based on side effects. These side effects can happen within 6 months after taking Tafamidis. A side effect is something (expected or unexpected) that you feel was caused by a medicine or treatment you take. The study doctor will collect side effect information and put the information on patient's case form.
Follow-up of the patient's will be performed via clinic re-visit or over a call. It is not a rule for the participants to visit the clinic in this study.
This study will help to see if Tafamidis is safe.

开始日期2024-03-25

申办/合作机构

Pfizer Inc.

NCT06321523 / Active, not recruitingN/A

Clinical Benefit of Tafamidis 61mg for Transthyretin Amyloid Cardiomyopathy (ATTR-CM) Patients in Korean Population in the Real-world Setting, Multicenter, Non-interventional Study

The purpose of this clinical trial is to learn about the effects of the study medicine (called Tafamidis 61milligrams (mg)) for the potential treatment of Transthyretin amyloid cardiomyopathy (ATTR-CM).
This study is seeking participants who were prescribed Tafamidis 61mg after being diagnosed with ATTR-CM and have taken Tafamidis 61mg at least once.
We will examine the experiences of people receiving the study medicine. This will help us determine if the study medicine is safe and effective.

开始日期2024-03-19

申办/合作机构

Pfizer Inc.

100 项与氯苯唑酸相关的临床结果

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100 项与氯苯唑酸相关的转化医学

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100 项与氯苯唑酸相关的专利（医药）

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457

项与氯苯唑酸相关的文献（医药）

2024-10-01·The American Journal of Cardiology

Impact of Anemia on Mortality and Morbidity in Transthyretin Amyloid Cardiomyopathy

Article

作者: Guadalupe, Samantha ; Weinsaft, Ariel Y ; Bampatsias, Dimitrios ; Mirabal-Santos, Alfonsina ; Maurer, Mathew S ; Santos, Jeffeny De Los ; Smiley, Dia A ; Teruya, Sergio ; Wardhere, Abdirahman

Anemia is prevalent in transthyretin amyloid cardiomyopathy (ATTR-CM), but its prognostic significance remains uncertain because of conflicting data mainly in patients not receiving disease-modifying therapy. Additionally, the effect of anemia on morbidity in this population has not been studied. This retrospective study included 270 patients diagnosed with ATTR-CM, receiving disease-modifying treatment (tafamidis), of which 30% (n = 80) were anemic (defined as a hemoglobin level <13 g/100 ml for males and <12 g/100 ml for females according to the World Health Organization). At baseline, patients with anemia were on average older (mean age 79 vs 77 years), more likely to be female (21% vs 12%), and exhibited higher symptom severity based on the New York Heart Association class (42% in class III vs 27%) compared with those without anemia. Additionally, they had a worse Columbia score (mean score 3 vs 5) and Columbia stage (12% in late-stage vs 7.1%) than those without anemia. Kaplan-Meier analysis indicates that anemia was associated with a higher likelihood of mortality, all-cause, and cardiovascular (CV) hospitalizations (p <0.05). However, in the Cox regression analysis, after adjusting for baseline age, ATTR genotype, and Columbia score, anemia was only associated with a higher risk of all-cause hospitalizations (hazard ratio 1.9 (1.3 to 2.7), p <0.001) and CV-related hospitalizations (hazard ratio 1.9 (1.2 to 2.9), p = 0.006). In conclusion, this study indicates that anemic patients with ATTR-CM have higher risks of CV and all-cause hospitalizations compared with nonanemic ATTR-CM patients. Further research is needed to understand how treating anemia may improve outcomes in this high-risk patient population.

2024-09-01·European Journal of Neurology

Effectiveness of patisiran after switching from tafamidis for the treatment of hereditary transthyretin‐mediated amyloidosis with polyneuropathy

Article

作者: Merkel, Madeline ; Adams, David ; Labeyrie, Celine ; Sweetser, Marianne T. ; Popadic, Lyuba ; Sethi, Sakshi ; Yang, Hongbo ; Lin, Hollis

AbstractBackground and purposeHereditary transthyretin‐mediated amyloidosis with polyneuropathy (ATTRv‐PN [v for variant]) is a rare, progressive disease associated with multisystemic impairments. This study assessed the real‐world outcomes of patients with ATTRv‐PN who switched from tafamidis to patisiran, as well as the reasons for the treatment switch.MethodsThis was a retrospective chart review study at a large expert referral center. Data were extracted from medical charts of patients with ATTRv‐PN who switched from tafamidis to patisiran on or before 30 August 2019. Data elements included demographic and clinical characteristics, rationale for switch, and disease measures evaluated from tafamidis initiation through the 12‐month patisiran treatment period.ResultsAmong the 24 patients with ATTRv‐PN included in the study, 50.0% had a V30M variant, and the mean (SD) age was 67.3 (8.0) years. During tafamidis treatment (mean [SD] = 30.1 [17.5] months) before switching to patisiran, patients worsened across multiple polyneuropathy measures, including walking ability, Neuropathy Impairment Score, and autonomic function. Neuropathic disease progression on tafamidis was the principal reason for switching to patisiran. After 12 months on patisiran (mean [SD] = 11.7 [1.4] months), patients experienced attenuated disease progression or improvement in the aforementioned measures of polyneuropathy.ConclusionsSwitching from tafamidis to patisiran attenuated the rate of functional decline, and most patients experienced stabilization or improvement of at least one polyneuropathy measure within 12 months of patisiran treatment. Timely switch from tafamidis to patisiran can be beneficial to avoid rapid disease progression in patients with ATTRv‐PN.

2024-09-01·Heart and Vessels

Effect of tafamidis on left atrial function of patients with transthyretin amyloid cardiomyopathy

Article

作者: Hisamatsu, Eriko ; Takeuchi, Kimikazu ; Ichikawa, Yasushi ; Nishihara, Yu ; Fukuda, Terunobu ; Todo, Saki ; Odajima, Susumu ; Tanaka, Hidekazu ; Nagai, Shun ; Kintsu, Masayuki ; Uemura, Koya ; Hirata, Ken-Ichi ; Oota, Eri

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural effects of amyloid infiltration, predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in the left atrium in ATTR-CM patients, but the association of left atrial (LA) myocardial function with cardiovascular events and of changes in LA myocardial function with tafamidis administration have not yet been clarified. Our aim was, therefore, to use speckle-tracking strain for investigating LA myocardial function in patients with ATTR-CM treated with tafamidis. We studied 55 patients with biopsy-proven ATTR-CM who had been treated with tafamidis (age: 76 ± 2 years, male: 93%). For speckle-tracking analysis of LA myocardial function, the systolic LA strain (LA reservoir function) was defined for this study as LA myocardial function from the apical 4-chamber view. The primary endpoint was defined as a composite comprising cardiovascular death and/or heart failure hospitalization after tafamidis administration over a median follow-up period of 28 ± 4 months. Patients with baseline LA strain < 8.6% (median value) experienced significantly more cardiovascular events than those without (log-rank P = 0.002). Moreover, LA strain in 26 patients worsened after tafamidis administration, and multivariate logistic regression analysis showed age, global longitudinal strain and relative apical longitudinal strain index were identified as independent determinants of deterioration of LA strain after tafamidis administration. In conclusion, baseline LA reservoir function is closely associated with cardiovascular events after tafamidis administration, and could be an additional parameter for the management of patients with ATTR-CM.

125

项与氯苯唑酸相关的新闻（医药）

2024-09-04

·BiG生物创新社

Alnylam vs.辉瑞，决战ATTR-CM，这家RNAi明星Biotech有何优势？

作者｜与安 RNAi明星Biotech-Alnylam正在多个治疗领域推进基于RNAi的创新药物深度管线，包括TTR、罕见病、心血管疾病、代谢疾病、神经系统等。其中，转甲状腺素淀粉样变心肌病（Transthyretin Amyloid Cardiomyopathy，ATTR-CM）是一种罕见、致死性疾病，主要表现为错误折叠的转甲状腺素（TTR）蛋白在心肌中沉积，心肌壁变硬，导致心脏泵血功能受损，最终可能引发心力衰竭。因疾病认知度低、临床症状缺乏特异性，常被误诊为原因不明性心力衰竭或肥厚型心肌病。针对ATTR-CM治疗，当前以辉瑞为市场主力，拿下全球首个获批的孤儿药，市场表现尤为亮眼。今年6月，Alnylam公布了HELIOS-B Ⅲ期试验的主要数据，引起一时轰动。上月，该司进一步公布了该研究的详细结果，并在于伦敦举行的欧洲心脏病学会会议上进行了分享，结果见刊于The New England Journal of Medicine。数据显示，该研究在总体人群和单药人群中满足了所有10个主要和次要终点，在降低全因死亡率和复发性心血管事件上呈现显著疗效，显示出成为ATTR-CM的标准治疗药物的深厚潜力。如此背景下，Anylam作为黑马，来势汹汹。本文以此展开分享！ 01 ATTR-CM：主要分类及其现状根据有无TTR基因突变 , ATTR-CM可分为遗传型/突变型(ATTRm) 和野生型（ATTRwt）两种类型。前者是由转甲状腺素基因突变引起的遗传性疾病，而后者则与年龄相关，随着年龄增长，正常的 TTR 蛋白变得不再稳定，最终因在心脏中沉积导致患病。作为一种罕见疾病，ATTR-CM的患病率存在显著的地域差别。据2016年大型多中心ATTR调查研究THAOS的注册数据显示，美国野生型占49%，欧洲野生型仅有5%。根据2022年发表在Clinical Cardiology上的综述文章Clinical recommendations to diagnose and monitor patients with transthyretin amyloid cardiomyopathy in Asia，从亚洲的有限数据及经验来看，遗传型报告的平均年龄，在韩国约为50岁，在日本则为40岁（含）以上；野生型则常见于70岁（含）以上的老年患者。由于ATTR-CM临床表现缺乏特异性，误诊率、漏诊率较高，加之以往缺乏有效的治疗手段，常导致患者预后不佳。如今，得益于诊断技术持续发展，更多的有效药物得以研发上市，ATTR-CM的治疗取得了显著进展，更多患者的诊疗和预后得以改善。然而，哥伦比亚大学欧文医学中心（Columbia University Irving Medical Center）心脏病学教授马修·毛雷尔（Mathew Maurer）指出，虽然辉瑞的tafamidis减缓了疾病进展，但无法实现逆转，对早期到中期的患者更加有效，“仍然有很高的剩余死亡率和发病率，因此研发人员正在积极开发新疗法”。 02 Alnylam Pharmaceuticals 奋起直追的新入局者今年6月，Alnylam公布了HELIOS-B Ⅲ期试验的主要数据，引起一时轰动。上月，该司进一步公布了该研究的详细结果，并在于伦敦举行的欧洲心脏病学会会议上进行了分享，结果见刊于The New England Journal of Medicine。数据显示，该研究在总体人群和单药人群中满足了所有10个主要和次要终点，在降低全因死亡率和复发性心血管事件上呈现显著疗效，显示出成为ATTR-CM的标准治疗药物的深厚潜力。图1 Alnylam披露的HELIOS-B Ⅲ期试验结果在总体人群中，与安慰剂相比，vutrisiran将全因死亡率和复发性心血管事件风险降低了28％，该人群的死亡率在42个月后显著降低36％。在单药人群中，与安慰剂相比，vutrisiran将全因死亡率和复发性心血管事件风险降低了33％，及至42个月后，该人群死亡率显著降低35％。在次要终点中，vutrisiran在6分钟步行试验（6MWT）、堪萨斯城心肌病问卷-总体总结评分（KCCQ-OSS）和纽约心脏协会分级方面，也显示出了显著的临床疗效，所有关键亚组中观察到的疗效一致，同时安全性表现良好。同时，在早期患者（即年轻患者和基线NT-proBNP较低的患者）中，还可以观察到疗效更佳的趋势。此外，在进入研究时正在服用tafamidis的患者中，与安慰剂相比，在42个月后，vutrisiran将全因死亡率风险降低了41％，由全因死亡率和复发性心血管事件组成的主要复合终点则下降22％。Evercore ISI的分析师在给客户的一份报告中写道：“鉴于其疗效水平，我们认为vutrisiran既适合作为单药治疗，也适合作为作为tafamidis的补充药物，2028年非专利tafamidis进入市场后，或将进一步推动市场良好发展。”然而，值得注意的是，二者尚不具备统计学意义，名义p值分别为0.0983和0.2701，联合用药的设想尚无定论。不可否认地，HELIOS-B的研究结果仍然强有力地展现出vutrisiran在ATTR-CM适应症上的喜人进展。“（这些结果）表明vutrisiran有可能成为ATTR-CM的新标准疗法。”Alnylam首席医疗官Pushkal Garg表示，“我们正在加紧向监管机构提交相关数据，尽快将其带给世界各地的患者。”Alnylam计划在2024年底前向FDA提交Vutrisiran用于ATTR-CM的适应症扩展申请，预计最早可能在2025年上半年获得批准。 03 Alnylam技术平台&管线介绍除vutrisiran外，作为RNAi领跑者的Alnylam还在siRNA领域开发出了多款商业化产品，技术平台与领域管线丰富。表1 Alnylam研发的上市小核酸药物 3.1 Alnylam的平台技术：主流小核酸平台LNP和GalNAc共轭偶联技术 ①LNP技术：脂质纳米颗粒（LNP）是化学合成的多组分脂质配方（~100 nm），包封siRNA递送到靶组织。在到达目的地的途中，LNP保护siRNA免受无处不在的核酸酶降解。图 2 LNP递送 ②GalNAc共轭偶联技术：修饰后的siRNA与靶向配体偶联，帮助siRNA找到途径进入体内特定细胞或组织。这像是一种“钥匙和锁”系统，其中锁是靶细胞上的受体，钥匙是附着在siRNA上的配体。整体可以分为3部分：GalNAc靶头、连接臂、小核酸分子。GalNAc是ASGPR的高亲和力靶向配体，可以快速被细胞吞入，而ASGPR主要在肝实质细胞表面高表达，实现siRNA的肝靶向。图3 GalNAc递送 ③C16偶联平台：2’-O-十六烷基（C16）是一种连接到siRNA的短脂质链，其亲脂性得以与细胞膜或膜蛋白相互作用，被多种细胞吸收，包括中枢神经系统（CNS）、肺和眼睛细胞。基于此平台研发的ALN-APP针对淀粉样蛋白前体蛋白，用于治疗阿尔兹海默症（AD）和脑淀粉样血管病（CAA）。图4 ALN-APP示意图 ④siRNA设计平台：IKARIA可以实现年度给药；Reversir能够迅速并且特异性逆转RNAi的基因沉默效果；GEMINI可以同时靶向两个基因；Rheostat用于可滴定的AAV基因治疗。图5 Alnylam siRNA设计平台 3.2 Alnylam的管线及其商业布局：多领域推进与“Alnylam p5×25”战略 Alnylam正在多个治疗领域推进基于RNAi的创新药物深度管线，包括TTR、罕见病、心血管疾病、代谢疾病、神经系统等。借助RNAi治疗平台和药物开发方法，该司正持续扩大管线，进行新适应症的临床试验。图6 Alnylam开发管线商业版图方面，2021年初，Alnylam制定并启动了“Alnylam p5×25”战略，重点计划在2025年底前成为市值排名前五的生物技术（Biotech）公司。通过可持续的创新和出色的财务表现，在罕见疾病和常见疾病领域提供变革性药物，使全球患者受益，从而打造顶级生物技术公司。具体来说，Alnylam打算在2025年结束时实现以下目标：表2 Alnylam目标一览其专利资产包括世界主要制药市场（美国、欧盟、日本以及世界其他国家）的大量已发布专利和正在申请的专利。这一广泛的产品组合涵盖寡核苷酸，包括修饰和未修饰的合成RNA分子，针对各种递送方式（例如基于脂质和缀合物的系统）进行了优化，及其合成和用途，包括用作治疗、诊断和研究的试剂。同时，Alnylam与其合作伙伴加速推进临床前和临床开发方面的项目，以及开展多种上市产品适应症扩大研究，呈现喜人的共赢局面。通过让其他公司在自家知识产权和相关专有技术的许可下推进 RNAi 疗法，Alnylam有望牢牢坐稳RNAi疗法的第一把交椅，并稳步地从小适应症向大适应症领域拓展。写在最后随着Alnylam Pharmaceuticals在RNAi领域的不断创新和突破，其在ATTR-CM治疗领域的进展不仅为治愈疾病增添新的助力，也为整个医学界注入了新的活力与研究方向。Alnylam的vutrisiran在HELIOS-B Ⅲ期试验中展现出的显著疗效，尤其是其在降低全因死亡率和复发性心血管事件方面的潜力，标志着ATTR-CM治疗迎来又一关键进展，同时也成为Alnylam保持行业领军地位的重要体现。这种疗法的成功，不仅有助于改善患者预后，还有利于进一步降低成本，扩大普惠范畴，既证明了RNAi技术在治疗遗传性疾病方面的巨大潜力，也为未来可能出现的新入局者和他们的创新疗法奠定了基础。主要参考文献 1.Weiqin Lin , Pairoj Chattranukulchai，et al. Clinical recommendations to diagnose and monitor patients with transthyretin amyloid cardiomyopathy in Asia. Clin Cardiol. 2022 Sep;45(9):898-907. doi: 10.1002/clc.23882. 2.BISTOLA V, et al.Practical recommendations for the diagnosis and management of transthyretin cardiac amyloidosis［J］. Heart Fail Rev, 2021, 26(4): 861-879. 3.Writing Committee Members; ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Card Fail. 2022 May;28(5):e1-e167. 4.Alnylam Presents Detailed Results from the Positive HELIOS-B Phase 3 Study of Vutrisiran in Patients with ATTR Amyloidosis with Cardiomyopathy at the European Society of Cardiology Congress https://investors.alnylam.com/press-release?id=28411 5.ATTR-CM Space Heats Up as RNA Therapies Show Promise https://biospace.com/drug-development/attr-cm-space-heats-up-as-rna-therapies-show-promise 6.Alnylam's Amvuttra turns in 'grand slam' showing in ATTR-CM, but leaves a window open for rivals https://fiercepharma.com/pharma/esc-2024-alnylam-touts-grand-slam-data-amvuttra-transthyretin-amyloid-cardiomyopathy 共建Biomedical创新生态圈！如何加入BiG会员？ ▼

孤儿药临床3期

2024-09-02

·PMLiVE

Alnylam shares positive phase 3 results for vutrisiran in ATTR with cardiomyopathy

Alnylam Pharmaceuticals has shared positive results from a late-stage study of its investigational RNAi therapeutic, vutrisiran, in transthyretin amyloidosis (ATTR) with cardiomyopathy. The phase 3 HELIOS-B trial randomised 655 adults with the heart condition to receive vutrisiran or placebo subcutaneously once every three months for up to three years, after which all eligible patients were given the therapy in an open-label extension period. Detailed results presented at this year’s European Society of Cardiology Congress showed that vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28% in the overall study population, which included patients receiving vutrisiran as a monotherapy and those using the therapy alongside standard treatments such as SGLT2 inhibitors and Pfizer’s Vyndaqel/Vyndamax (tafamidis). In the monotherapy population, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 33% and the risk of mortality by 35% at month 42. Mortality in the overall population was reduced by 31% during the double-blind period and by 36% at month 42. Vutrisiran was also associated with benefits across multiple clinical measures of disease progression, including the six-minute walk test, and subgroup analyses demonstrated consistent benefits across all key patient groups. ATTR amyloidosis is an underdiagnosed and rapidly progressive disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the heart and nerves. Patients may present with polyneuropathy, cardiomyopathy or both. Alnylam’s vutrisiran is designed to works with your body’s natural system to rapidly knock down TTR and already holds approvals under the brand name Amvuttra to treat polyneuropathy caused by ATTR in adults. The company’s chief medical officer, Pushkal Garg, said: “With this study, we have demonstrated that the rapid knockdown of toxic TTR seen with vutrisiran improves survival, and reduces cardiovascular hospitalisations and disease progression versus placebo, with benefits consistently observed across populations and regardless of background stabiliser use. “While the results have not yet been reviewed by a regulatory authority, the data we have shared… suggests that vutrisiran has the potential to become a new standard of care treatment for ATTR with cardiomyopathy, a progressive and ultimately fatal disease with limited treatment options.” Alnylam said it “remains on track” to proceed with global regulatory submissions for vutrisiran starting later this year.

临床结果临床3期AHA会议上市批准

2024-08-31

·药明康德

创新siRNA疗法3期结果登《新英格兰医学杂志》，监管申请递交在即

▎药明康德内容团队编辑今天，Alnylam Pharmaceuticals公布了其HELIOS-B临床3期研究的积极成果。分析结果显示，与安慰剂相比，皮下注射的siRNA疗法Amvuttra（vutrisiran）显著降低了伴有心肌病的转甲状腺素蛋白淀粉样变性（ATTR-CM）患者因任何原因死亡或复发性心血管事件的风险，同时维持了患者的身体功能和生活质量。这些数据在2024年欧洲心脏病学会（ESC）年会上公布，并同步发表于《新英格兰医学杂志》。基于这一积极结果，Alnylam计划在今年晚些时候使用优先审评券（PRV）向美国FDA递交补充新药申请（sNDA）。转甲状腺素蛋白淀粉样变性（ATTR）是一种进展迅速的致命性疾病，会导致患者衰弱不堪。该病由错误折叠的转甲状腺素蛋白（TTR）引起，这些错误折叠的蛋白质以淀粉样沉积物的形式在身体的多个部位堆积，包括神经、心脏和胃肠道等组织。患者可能会表现出多发性神经病、心肌病或两者的症状。ATTR主要有两种形式：遗传性ATTR（hATTR），由TTR基因变异引起，影响全球约5万人；以及野生型ATTR（wtATTR），不伴有TTR基因变异，影响全球约20至30万人。 HELIOS-B是一项全球多中心、随机、双盲、安慰剂对照的3期研究，旨在评估vutrisiran在ATTR-CM患者中减少全因死亡率和复发性心血管事件的效果和安全性（主要终点）。研究共招募了655名包含遗传性或野生型的成人ATTR-CM患者，按照1：1的比例随机接受每三个月一次25 mg的vutrisiran或安慰剂皮下注射，双盲治疗期最长达36个月。双盲期结束后，所有符合条件的患者可在开放标签扩展期接受vutrisiran治疗。受试者主要为纽约心脏病协会（NYHA）评分为I或II级的野生型疾病患者。大多数患者接受了当前标准治疗，如tafamidis和SGLT2抑制剂，这反映了目前ATTR-CM患者的治疗现状。此前公布的结果显示，HELIOS-B试验在总体患者和单药治疗患者中达到了所有10项的主要和次要终点。在研究中，vutrisiran相较于安慰剂显著降低了全因死亡率和复发心血管事件的风险。在总体患者中，vutrisiran将全因死亡率和复发性心血管事件的风险降低了28%（HR=0.72，95% CI：0.56-0.93，P=0.01），并且在死亡率和心血管事件这两个组成部分中，患者均表现出类似的下降趋势。在双盲期内，总体患者的死亡率降低了31%，而在长达42个月的随访中，死亡率降低了36%。 ▲Vutrisiran显著降低总体患者（左）与单药治疗患者（右）的全因死亡率和复发心血管事件的风险（图片来源：参考资料[2]）在接受vutrisiran单药治疗的患者中，vutrisiran将全因死亡率和复发心血管事件的风险显著降低了33%（HR=0.67，95% CI：0.49-0.93，P=0.02），并将死亡率显著降低了35%（HR=0.65，95% CI：0.46-0.90，P=0.01）。 ▲HELIOS-B试验主要与次要终点结果摘要（图片来源：参考资料[2]）此外，vutrisiran相较于安慰剂在多个疾病进展临床指标上皆表现出优效性，包括6分钟步行测试、堪萨斯城心肌病问卷总体概述（KCCQ-OS）、NYHA评分，以及心脏生物标志物NT-proBNP等。在总体患者中，与安慰剂相比，vutrisiran组在6分钟步行测试中的步行距离下降更少（最小二乘均差为26.5米；95% CI：13.4-39.6；P<0.001），KCCQ-OS评分的下降也更少（最小二乘均差为5.8分；95% CI：2.4-9.2；P<0.001）。而在单药治疗患者中也观察到了类似的益处。此外亚组分析显示，无论患者是否接受背景治疗（如tafamidis），vutrisiran在所有关键患者亚群中均显示出一致的益处。在早期疾病患者（如年轻患者和基线NT-proBNP较低者）中，疗效趋势更为明显。在HELIOS-B研究中，vutrisiran的安全性和耐受性与之前临床研究中的结果一致。两组的不良事件发生率相似（vutrisiran组为99%，安慰剂组为98%）；vutrisiran组的严重不良事件发生率为62%，而安慰剂组为67%。 Vutrisiran是一款皮下给药的RNAi疗法，正在开发用于治疗ATTR淀粉样变性，包括hATTR和wtATTR淀粉样变性。它通过靶向和沉默特定的mRNA，阻断野生型和变体转甲状腺素蛋白的产生。Vutrisiran基于Alnylam的增强稳定化学（ESC）-GalNAc偶联递送平台设计，增加了效力和代谢稳定性，可允许不频繁的皮下注射。此前研究数据表明，每季度给予患者vutrisiran可能有助于减少组织中的沉积，促进TTR淀粉样沉积物的清除，并有望恢复这些组织的功能。2022年6月，美国FDA批准vutrisiran上市（商品名Amvuttra），用于治疗hATTR淀粉样变性成人患者的多发性神经病（polyneuropathy）。目前产业界有多款针对ATTR-CM的在研疗法处于临床阶段。BridgeBio Pharma已向美国FDA递交其所研发的新一代、口服、高效TTR小分子稳定剂acoramidis的新药申请（NDA）。此前公布的3期试验数据显示，acoramidis组治疗期间的生存率为81%（安慰剂组为74%），该值开始接近无ATTR-CM人群的预期寿命估算（根据历史记录，该人群的生存率为85%）。而今天公布的最新数据则显示，在该试验中从活性对照组和安慰剂组在开放标签扩展研究中转为接受acoramidis治疗的参与者中，转换治疗第1个月时血清TTR平均增加3.0 mg/dL（n=21，p=0.01），第6个月时平均增加3.4 mg/dL（n=18，p=0.01）。阿斯利康（AstraZeneca）与Ionis Pharmaceuticals合作开发的反义寡核苷酸（ASO）疗法eplontersen，目前正在进行治疗转甲状腺素蛋白介导的心肌病（ATTR-CM）的临床3期试验，该疗法在去年12月获批用以治疗TTR介导的淀粉样变性的多发性神经病成人患者。2022年，阿斯利康与Neurimmune就一款用以治疗ATTR-CM的人源化单抗NI006达成超7亿美元的合作。去年公布的1期临床试验结果显示，在至少10 mg/kg的剂量下，患者心脏淀粉样蛋白沉积在12个月内显著减少。此外，患者NT-proBNP的水平也有所降低，这是一种用于测量心脏压力和心肌细胞死亡的生物标志物。锐正基因（Accuredit）在今年5月公布其基因编辑药物ART001用以治疗ATTR患者的最新24周临床研究数据。结果显示，给药后4周，高剂量组受试者外周TTR蛋白较基线即可平均下降90%以上，并初步显示出一次性给药即可获得长期持续药效的潜力。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Alnylam Presents Detailed Results from the Positive HELIOS-B Phase 3 Study of Vutrisiran▼ in Patients with ATTR Amyloidosis with Cardiomyopathy at the European Society of Cardiology Congress. Retrieved August 30, 2024 from https://www.businesswire.com/news/home/20240830554303/en/Alnylam-Presents-Detailed-Results-from-the-Positive-HELIOS-B-Phase-3-Study-of-Vutrisiran%E2%96%BC-in-Patients-with-ATTR-Amyloidosis-with-Cardiomyopathy-at-the-European-Society-of-Cardiology-Congress [2] Fontana M. “Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy” (2024) NEJM. DOI: 10.1056/NEJMoa2409134 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果siRNA优先审批临床3期

100 项与氯苯唑酸相关的药物交易

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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
甲状腺素运载蛋白淀粉样变心肌病	美国	FoldRx Pharmaceuticals LLC	2019-05-03

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	临床3期	意大利	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	瑞典	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	捷克	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	西班牙	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	加拿大	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	英国	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	巴西	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	法国	Pfizer Inc.	2013-12-09
甲状腺素运载蛋白淀粉样变心肌病	临床3期	比利时	Pfizer Inc.	2013-12-09
家族性淀粉样神经病	药物发现	日本	Pfizer Inc.	2011-11-01

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临床结果

适应症

分期

评价

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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


NCT01994889 (ATTR-ACT, Pubmed)	临床3期	甲状腺素运载蛋白淀粉样变心肌病 eGFR	-	Tafamidis 20 mg and 80 mg	選築窪鏇簾構遞繭糧積(壓顧網廠淵積獵願窪淵) = 糧蓋蓋構築艱廠醖鹽繭構築衊蓋鹽醖製窪餘廠 (鏇糧襯齋淵壓窪餘範簾 ) 更多	积极	2024-04-01
				Placebo	選築窪鏇簾構遞繭糧積(壓顧網廠淵積獵願窪淵) = 製壓鹹艱獵遞網蓋窪壓構築衊蓋鹽醖製窪餘廠 (鏇糧襯齋淵壓窪餘範簾 ) 更多
NCT02791230 (ATTR-ACT, Pubmed \| JACC Heart Fail)	临床3期	N-terminal pro-B-type natriuretic peptide (NT-proBNP)	-	Tafamidis	遞憲餘艱網遞廠築艱壓(顧夢鹽衊鑰願遞願廠膚) = 醖繭鹹築遞衊構鏇鹹繭憲積淵網鑰顧顧簾簾選 (窪鏇衊顧膚鬱顧鬱選築 )	积极	2024-01-01
				Placebo	遞憲餘艱網遞廠築艱壓(顧夢鹽衊鑰願遞願廠膚) = 膚蓋餘願憲廠糧積網餘憲積淵網鑰顧顧簾簾選 (窪鏇衊顧膚鬱顧鬱選築 )
ESC2023	N/A	甲状腺素运载蛋白淀粉样变心肌病	-	wtATTR patients receiving tafamidis	選鬱積簾遞獵醖選鹹鹽(鹽構積壓獵憲觸壓憲顧) = 蓋憲顧壓簾簾網餘繭願積夢製範遞遞網廠簾窪 (衊鹹憲膚膚繭選廠醖願 )	-	2023-08-27
				tafamidis	選鬱積簾遞獵醖選鹹鹽(鹽構積壓獵憲觸壓憲顧) = 願夢構艱觸網蓋衊選蓋積夢製範遞遞網廠簾窪 (衊鹹憲膚膚繭選廠醖願 )
ESC2023	N/A	老年性心脏淀粉样变性	75	Tafamidis	(製獵鹽鹹鹽鑰餘壓網繭): OR = 0.24 (95% CI, 0.12 ~ 0.47)	积极	2023-08-26
				tafamidis
ESC2023	N/A	转甲状腺素运载蛋白淀粉样变性	-	Acoramidis	艱壓壓衊遞顧觸積餘遞(網構艱遞繭糧憲獵鬱廠) = 積糧醖願齋鏇鬱鑰襯壓獵遞餘憲獵壓膚衊餘糧 (構鏇餘繭積淵選鬱範廠 ) 更多	-	2023-08-26
				Tafamidis	艱壓壓衊遞顧觸積餘遞(網構艱遞繭糧憲獵鬱廠) = 衊遞淵鬱鏇製醖網淵衊獵遞餘憲獵壓膚衊餘糧 (構鏇餘繭積淵選鬱範廠 ) 更多
NCT01994889 \| NCT02791230 (ATTR-ACT, Pubmed)	N/A	甲状腺素运载蛋白淀粉样变心肌病	-	Tafamidis 80mg	(鬱夢鬱顧願製築鹹糧夢): hazard ratio = 0.64 (95% CI, 0.41 ~ 0.99)	-	2023-07-11
				Placebo
ESC2023	N/A	转甲状腺素蛋白心脏淀粉样变 TTR \| RBP4 \| creatinine ... 更多	26	Tafamidis	(築製壓網窪餘襯製構餘) = 衊築簾淵蓋鏇構窪鬱築鏇膚鬱餘鑰獵淵範鑰衊 (齋鑰網遞齋夢鑰選鏇壓 ) 更多	-	2023-05-20
NCT01994889 (ATTR-ACT, Pubmed)	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 concentration	-	Tafamidis 80 mg	-	积极	2022-12-01
				Tafamidis 20 mg
ESC2022	N/A	甲状腺素运载蛋白淀粉样变心肌病	-	Tafamidis 61mg QD	網選壓襯觸淵糧積願壓(窪蓋膚夢夢窪構齋鹽糧) = 鹽艱繭糧鏇構膚夢製衊鑰鬱鬱繭觸遞範憲壓襯 (憲壓鏇艱鬱築鬱壓膚鹹 )	-	2022-08-29
				Tafamidis 20mg QD	網選壓襯觸淵糧積願壓(窪蓋膚夢夢窪構齋鹽糧) = 餘構襯淵遞鬱製淵鬱襯鑰鬱鬱繭觸遞範憲壓襯 (憲壓鏇艱鬱築鬱壓膚鹹 )
Pubmed 人工标引	N/A	转甲状腺素蛋白心脏淀粉样变	107	Tafamidis	(鬱襯鬱淵壓網觸餘範積) = 蓋夢鬱餘觸鏇範衊艱鬱醖鬱積範艱衊積衊鹹範 (網醖膚鬱構窪獵窪醖選 )	积极	2022-08-19
				not tafamidis	(鬱襯鬱淵壓網觸餘範積) = 糧鬱夢憲製獵憲獵鬱鬱醖鬱積範艱衊積衊鹹範 (網醖膚鬱構窪獵窪醖選 )