Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced the presentation of new results from its Phase 1 study of nucresiran (formerly ALN-TTRsc04), a next-generation RNAi therapeutic in development for the treatment of transthyretin (ATTR) amyloidosis. The data were presented in an oral session at the American Heart Association Scientific Sessions 2024 in Chicago. .

领先的RNAi治疗公司Alnylam Pharmaceuticals，Inc.（纳斯达克股票代码：ALNY）今天宣布，其对nucresiran（原ALN-TTRsc04）的第一阶段研究的新结果将公布，nucresiran是正在开发的用于治疗甲状腺素转运蛋白（ATTR）淀粉样变性的下一代RNAi治疗剂。。。。

These new results demonstrated that a single dose of nucresiran at 300 mg or higher led to rapid knockdown of serum TTR with low inter-patient variability, with mean reductions of greater than 90% from baseline achieved at Day 15 and sustained through at least Day 180. At these doses, peak reduction of mean TTR levels of greater than 96% were achieved by Day 29.

这些新结果表明，单剂量300 mg或更高剂量的nucresiran可导致血清TTR的快速敲低，患者间变异性低，平均比第15天达到的基线降低90%以上，并持续至少180天。在这些剂量下，到第29天，平均TTR水平的峰值降低超过96%。

Furthermore, serum TTR levels remained substantially reduced at Day 360 with a mean reduction of greater than 70% after a single 300 mg dose. Day 360 results are not yet available for the 600 mg and 900 mg dose cohorts. All doses of nucresiran have been well tolerated to date. .

此外，在第360天，血清TTR水平仍然显着降低，单次300 mg剂量后平均降低超过70%。600 mg和900 mg剂量组尚未获得第360天的结果。迄今为止，所有剂量的nucresiran都具有良好的耐受性。。。

“We are very excited by these new Phase 1 data with nucresiran, our next-generation TTR-targeting RNAi therapeutic, which demonstrated that a single dose of ≥300 mg achieved rapid knockdown of TTR greater than 90% from Day 15 that was sustained to at least six months,” said Pushkal Garg, M.D., Chief Medical Officer, Alnylam.

Alnylam首席医疗官Pushkal Garg医学博士说：“我们对nucresiran（我们的下一代TTR靶向RNAi治疗剂）的这些新的第一阶段数据感到非常兴奋，这表明单剂量≥300 mg从第15天起，TTR的快速敲低率达到90%以上，持续至少六个月。”。

“Furthermore, we are encouraged by the potential of nucresiran to reduce interpatient variability in TTR lowering. Nucresiran utilizes 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.

“此外，我们对nucresiran减少TTR降低患者间差异的潜力感到鼓舞。nucresiran利用我们的IKARIA平台，该平台现已证明有可能实现支持两年或每年给药的耐久性，代表了治疗ATTR淀粉样变性的潜在新范例。

Importantly, nucresiran has been well tolerated at all dose levels tested to date. We look forward to sharing Phase 3 development plans in the first quarter of 2025.” .

重要的是，nucresiran在迄今为止测试的所有剂量水平上都具有良好的耐受性。我们期待着在2025年第一季度分享第三阶段的发展计划。”。。

The ongoing Phase 1 dose-finding study evaluated the safety, as well as pharmacodynamics and pharmacokinetics, of single doses of nucresiran in healthy subjects. As previously presented at Alnylam’s R&D Day in December 2023, a single dose of nucresiran led to rapid knockdown of serum TTR that was highly durable. .

正在进行的第一阶段剂量发现研究评估了健康受试者单剂量nucresiran的安全性，以及药效学和药代动力学。正如之前在2023年12月Alnylam的研发日上所介绍的那样，单剂量的nucresiran导致血清TTR的快速敲低，这是非常持久的。。。

In subjects receiving a single 300 mg dose of nucresiran, mean serum TTR reduction of 90.3% was observed at Day 15, 96.5% at Day 29, and 92.6% at Day 180. At Day 360, mean serum TTR Reduction was 71.12%. In subjects receiving a single 600 mg dose, mean serum TTR reduction of 95.0% was observed at Day 15, 97.8% at Day 29, and 96.0% at Day 180.

在接受单剂量300 mg nucresiran的受试者中，在第15天观察到平均血清TTR降低90.3%，在第29天观察到96.5%，在第180天观察到92.6%。在第360天，平均血清TTR降低为71.12%。在接受单次600 mg剂量的受试者中，在第15天观察到平均血清TTR降低95.0%，在第29天观察到97.8%，在第180天观察到96.0%。

In subjects receiving a single 900 mg dose, mean serum TTR reduction of 91.7% was observed at Day 15, 96.7% at Day 29, and 94.2% at Day 180. As of the data cutoff date, TTR knockdown levels at Day 360 were not available for either the 600 mg or 900 mg cohort. .

在接受单次900 mg剂量的受试者中，在第15天观察到平均血清TTR降低91.7%，在第29天观察到96.7%，在第180天观察到94.2%。截至数据截止日期，600 mg或900 mg队列均无法获得第360天的TTR敲低水平。。。

There has been low inter-patient variability in the TTR reduction observed; at Day 29, TTR reduction ranged from 96.0 – 96.7% in the 300 mg cohort, 96.6 – 98.6% in the 600 mg cohort, and 96.0 - 97.3% in the 900 mg cohort.

观察到的TTR降低的患者间差异很低；在第29天，300 mg组的TTR降低范围为96.0-96.7%，600 mg组为96.6-98.6%，900 mg组为96.0-97.3%。

In the study, nucresiran has been well tolerated at all tested doses. The majority of adverse events across doses have been mild and none have been considered to be related to treatment. There have been no injection site reactions and no safety signals identified, including no liver-related signals. .

在这项研究中，nucresiran在所有测试剂量下都具有良好的耐受性。各剂量的大多数不良事件都是轻微的，没有一个被认为与治疗有关。没有注射部位反应，也没有发现安全信号，包括没有肝脏相关信号。。。

Phase 1 Study Design

第一阶段研究设计

The Phase 1 trial is a randomized, double-blind, placebo-controlled, single ascending dose study designed to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of nucresiran in healthy adult subjects. The study enrolled 48 healthy adult subjects randomized 3:1 to receive a single ascending dose of 5, 25, 100, 300, 600, or 900 mg of nucresiran or placebo.

第一阶段试验是一项随机，双盲，安慰剂对照，单次递增剂量研究，旨在评估nucresiran在健康成人受试者中的安全性，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，以3:1的比例随机接受单次递增剂量的5、25、100、300、600或900毫克的nucresiran或安慰剂。

The primary endpoint of the study is safety and secondary endpoints include the change from baseline in serum TTR over time, as well as characterization of plasma and urine pharmacokinetics (PK) of nucresiran. .

该研究的主要终点是安全性，次要终点包括血清TTR随时间从基线的变化，以及nucresiran血浆和尿液药代动力学（PK）的表征。。。

About Nucresiran

关于Nucresiran

Nucresiran is an investigational RNAi therapeutic in development to deliver rapid knockdown of mutant and wild-type transthyretin (TTR) and address the underlying cause of transthyretin (ATTR) amyloidosis. As part of Alnylam’s proprietary IKARIA™ platform, nucresiran has the potential to achieve deeper and more durable rapid knockdown of TTR, allowing for less frequent dosing.

Nucresiran是一种正在开发的研究性RNAi治疗剂，可快速敲除突变型和野生型甲状腺素转运蛋白（TTR），并解决甲状腺素转运蛋白（ATTR）淀粉样变性的根本原因。作为Alnylam专有IKARIA™平台的一部分，nucresiran有可能实现更深入和更持久的TTR快速敲除，从而减少给药频率。

The safety and efficacy of nucresiran have not been established or evaluated by the FDA, EMA or any other health authority. .

美国食品和药物管理局（FDA）、欧洲药品管理局（EMA）或任何其他卫生部门尚未确定或评估nucresiran的安全性和有效性。。。

Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy or both manifestations of disease.

运甲状腺素蛋白淀粉样变性病（ATTR）是由错误折叠的运甲状腺素蛋白（TTR）蛋白引起的一种诊断不足，快速进展，衰弱和致命的疾病，该蛋白以淀粉样蛋白沉积物的形式积聚在身体的各个部位，包括神经，心脏和胃肠道。患者可能会出现多发性神经病，心肌病或两种疾病的表现。

There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000-300,000 people worldwide. .

有两种不同形式的ATTR–遗传性ATTR（hATTR），由TTR基因变异引起，影响全球约50000人；野生型ATTR（wtATTR），无TTR基因变异，影响全球约200000-300000人。。。

About RNAi

关于RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine.

RNAi（RNA干扰）是一种基因沉默的自然细胞过程，代表了当今生物学和药物开发中最有前途和快速发展的前沿之一。它的发现被誉为“每十年左右发生一次的重大科学突破”，并获得2006年诺贝尔生理学或医学奖的认可。

By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors that encode for disease-causing or disease pathway proteins – thus preventing them from being made.

通过利用我们细胞中发生的RNAi的自然生物学过程，一类被称为RNAi疗法的新型药物现已成为现实。小干扰RNA（siRNA）是介导RNAi并构成Alnylam RNAi治疗平台的分子，它通过有效沉默信使RNA（mRNA）（编码致病或疾病途径蛋白的遗传前体）而在当今药物的上游发挥作用，从而阻止了它们的产生。

This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. .

这是一种革命性的方法，有可能改变对遗传病和其他疾病患者的护理。。。

About Alnylam Pharmaceuticals

关于Alnylam Pharmaceuticals

Alnylam (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines.

Alnylam（纳斯达克股票代码：ALNY）领导将RNA干扰（RNAi）转化为一类全新的创新药物，有可能改变患有罕见和流行疾病且需求未得到满足的人的生活。基于诺贝尔奖获得者的科学，RNAi疗法代表了一种强大的，临床验证的方法，产生了转化药物。

Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile.

Alnylam拥有丰富的研究药物渠道，包括处于后期开发阶段的多种候选产品。Alnylam正在实施其“Alnylam P5x25”战略，通过可持续创新和卓越的财务表现，为世界各地的罕见病和常见病患者提供变革性药物，从而产生领先的生物技术概况。