CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) today announced additional positive interim results for the ongoing single ascending dose portion of the Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA).

马萨诸塞州剑桥市-（BUSINESS WIRE）-Alnylam Pharmaceuticals，Inc。（纳斯达克股票代码：ALNY）今天宣布了ALN-APP第一阶段研究中正在进行的单次递增剂量部分的额外积极中期结果，ALN-APP是一项研究性RNAi治疗靶向淀粉样蛋白前体蛋白（APP）正在开发中用于治疗阿尔茨海默病和脑淀粉样血管病（CAA）。

The data were presented today in a late-breaker session at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference, being held October 24-27, 2023, in Boston, MA. ALN-APP is the first clinical-stage program using Alnylam's proprietary C16-siRNA conjugate platform for central nervous system (CNS) delivery and the first investigational RNAi therapeutic to demonstrate gene silencing in the human brain.

这些数据今天在2023年10月24日至27日在马萨诸塞州波士顿举行的第16届阿尔茨海默病临床试验（CTAD）会议的突破性会议上发表。ALN-APP是第一个使用Alnylam专有的C16 siRNA结合平台进行中枢神经系统（CNS）递送的临床阶段计划，也是第一个在人脑中展示基因沉默的研究性RNAi治疗药物。

ALN-APP is being developed in collaboration with Regeneron..

ALN-APP正在与Regeneron合作开发。。

“Today’s results showcase the exciting emerging profile of ALN-APP. This novel approach appears generally well-tolerated and is able to target the amyloid pathway successfully, robustly lowering target engagement biomarkers sAPPα and sAPPβ and maintaining a significant effect up to 10 months after administration,” said Dr.

“今天的结果展示了ALN-APP令人兴奋的新兴概况。这种新方法通常表现出良好的耐受性，能够成功靶向淀粉样蛋白途径，强有力地降低靶标参与生物标志物sAPPα和sAPPβ，并在给药后10个月内保持显着效果，”博士说。

Cath Mummery, Consultant Neurologist and Head of Clinical Trials, Dementia Research Centre, University College London. “For the first time, we also see that single doses of ALN-APP can reduce cerebral spinal fluid levels of Aβ42 and Aβ40, which are the amyloidogenic peptides that are the primary components of amyloid deposits in Alzheimer’s disease and CAA.

伦敦大学学院痴呆研究中心神经科顾问兼临床试验负责人Cath Mummery。“我们还首次看到单剂量的ALN-APP可以降低Aβ42和Aβ40的脑脊液水平，这是淀粉样蛋白生成肽，是阿尔茨海默病和CAA中淀粉样蛋白沉积的主要成分。

This approach warrants further study to evaluate whether it can potentially interrupt relentless progression of these two devastating diseases.”.

这种方法值得进一步研究，以评估它是否有可能中断这两种破坏性疾病的无情进展。”。

Twenty patients have been enrolled in three single-dose cohorts in Part A of the ongoing Phase 1 study in patients with early-onset Alzheimer’s disease. In this study to date, blinded single doses of ALN-APP, which are administered by intrathecal injection, have been well tolerated. All adverse events were mild or moderate in severity.

在正在进行的针对早发性阿尔茨海默氏病患者的1期研究的A部分中，有20名患者参加了三个单剂量队列研究。在迄今为止的这项研究中，通过鞘内注射给药的盲法单剂量ALN-APP具有良好的耐受性。所有不良事件的严重程度均为轻度或中度。

Cerebral spinal fluid (CSF) safety biomarkers, routine labs, and the exploratory biomarker neurofilament light chain (NfL) all continue to show no concerning trends. Patients treated with a single dose of 75mg ALN-APP experienced rapid and sustained reduction in CSF of both soluble APPα (sAPPα) and soluble APPβ (sAPPβ), biomarkers of target engagement, with maximum reductions of 84% and 90%, respectively.

脑脊液（CSF）安全性生物标志物，常规实验室和探索性生物标志物神经丝轻链（NfL）都继续显示没有相关趋势。用单剂量75mg ALN-APP治疗的患者经历了可溶性APPα（sAPPα）和可溶性APPβ（sAPPβ）（靶标接合的生物标志物）的CSF的快速和持续降低，最大降低分别为84%和90%。

These effects were highly durable, with mean reductions in sAPPα and sAPPβ of 33% and 39%, respectively, at 10 months after a single 75mg dose. Available data on exploratory disease-related biomarkers showed robust reductions in CSF of Aβ42 and Aβ40, the soluble forms of the amyloidogenic peptides that aggregate into amyloid deposits in AD and CAA.

这些作用非常持久，单次75mg剂量后10个月，sAPPα和sAPPβ的平均降低分别为33%和39%。有关探索性疾病相关生物标志物的可用数据显示，Aβ42和Aβ40（淀粉样蛋白生成肽的可溶形式，在AD和CAA中聚集成淀粉样蛋白沉积物）的CSF显着降低。

At two months after a single dose of 75mg ALN-APP, mean reductions in CSF Aβ42 and Aβ40 were 49% and 71%, respectively..

单剂量75mg ALN-APP两个月后，CSFAβ42和aβ40的平均降低分别为49%和71%。。

Further exploration of single doses of ALN-APP is ongoing in Part A. In addition, the first patient has now been dosed in Part B, the multiple-dose part of the study. Part B was previously initiated in Canada and has also now received all required approvals to proceed in the UK and the Netherlands. The multiple dose part of the study remains on partial clinical hold in the U.S.

A部分正在进一步探索单剂量ALN-APP。此外，第一名患者现已在B部分（研究的多剂量部分）给药。B部分先前在加拿大启动，现在还获得了在英国和荷兰进行的所有必需批准。该研究的多剂量部分在美国仍处于部分临床保留状态。

due to findings observed in non-clinical chronic toxicology studies..

由于在非临床慢性毒理学研究中观察到的发现。。

“These additional interim data further illustrate the potential for RNAi therapeutics to set a new standard for silencing disease-causing genes in the CNS, providing evidence that a single dose of ALN-APP can achieve deep target engagement, a long duration of action, and an encouraging early safety profile,” said Tim Mooney, Director, ALN-APP Program Leader at Alnylam.

“这些额外的中期数据进一步说明了RNAi疗法为沉默中枢神经系统致病基因设定新标准的潜力，提供了单剂量ALN-APP可以实现深度目标参与，长期作用和令人鼓舞的早期安全概况，“Alnylam ALN-APP项目负责人蒂姆·穆尼（Tim Mooney）说。

“The robust lowering we see in Aβ42 and Aβ40 shows that reducing APP protein production with RNAi can reduce these downstream disease-associated peptides and gives us confidence as we proceed with Part B of the Phase 1 study and further explore the opportunity for ALN-APP in both Alzheimer’s disease and CAA.”.

“我们在Aβ42和Aβ40中看到的强烈降低表明，用RNAi减少APP蛋白的产生可以减少这些下游疾病相关肽，并使我们有信心，因为我们继续进行1期研究的B部分，并进一步探索ALN-APP在阿尔茨海默病和CAA中的机会“。

Successful human translation of the C16-siRNA conjugate platform is unlocking a broader portfolio of CNS programs. In addition to ALN-APP, Alnylam and Regeneron have named 10 targets in the CNS as part of their exclusive collaboration established in 2019 to discover RNAi therapeutics for CNS and ocular diseases..

C16 siRNA结合平台的成功人类翻译正在解锁更广泛的CNS计划组合。除ALN-APP外，Alnylam和Regeneron还命名了CNS中的10个靶标，作为其2019年成立的独家合作的一部分，旨在发现用于CNS和眼部疾病的RNAi疗法。。

About the Phase 1 Study of ALN-APP

关于ALN-APP的第一阶段研究

The Phase 1 study is a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of ALN-APP in patients with early-onset Alzheimer’s disease (EOAD). The study is being conducted in two parts: single ascending dose phase (Part A) and multiple dose phase (Part B) in patients with EOAD.

第一阶段研究是一项多中心，随机，双盲，安慰剂对照试验，旨在评估ALN-APP在早发性阿尔茨海默病（EOAD）患者中的安全性，耐受性，药代动力学和药效学效应。该研究分为两部分进行：EOAD患者的单次递增剂量阶段（A部分）和多剂量阶段（B部分）。

The planned enrollment for this study is up to 60 patients..

这项研究的计划入学人数最多为60名患者。。

The interim readout of the Phase 1 study of ALN-APP is focused on assessing safety, tolerability and levels of target engagement biomarkers, sAPPα and sAPPβ.

ALN-APP的1期研究的临时读数集中于评估目标参与生物标志物sAPPα和sAPPβ的安全性，耐受性和水平。

About ALN-APP

关于ALN-APP

ALN-APP is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Genetic mutations that increase production of APP or alter its cleavage cause early-onset AD, early-onset CAA, or both.

ALN-APP是一种研究性鞘内注射RNAi治疗靶向淀粉样蛋白前体蛋白（APP），用于治疗阿尔茨海默病（AD）和脑淀粉样血管病（CAA）。增加APP产生或改变其裂解的基因突变会导致AD早发，CAA早发或两者兼而有之。

ALN-APP is designed to decrease APP mRNA in the central nervous system (CNS), to decrease synthesis of APP protein and all downstream intracellular and extracellular APP-derived cleavage products, including amyloid beta (Aβ). Reducing APP protein production is expected to reduce the secretion of Aβ peptides that aggregate into extracellular amyloid deposits and reduce the intraneuronal APP cleavage products that trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in Alzheimer’s disease.

ALN-APP旨在减少中枢神经系统（CNS）中的APP mRNA，减少APP蛋白以及所有下游细胞内和细胞外APP衍生的裂解产物（包括淀粉样β蛋白（Aβ））的合成。减少APP蛋白的产生有望减少聚集到细胞外淀粉样蛋白沉积物中的Aβ肽的分泌，并减少神经元内APP裂解产物，从而触发神经原纤维缠结的形成并引起阿尔茨海默氏病的神经元功能障碍。

ALN-APP is the first program utilizing Alnylam’s proprietary C16-siRNA conjugate technology, which enables enhanced delivery to cells in the CNS. This program is being developed in collaboration with Regeneron Pharmaceuticals. The safety and efficacy of ALN-APP have not been evaluated by the FDA, EMA, or any other health authority..

ALN-APP是第一个利用Alnylam专有的C16 siRNA结合技术的程序，该技术可增强向CNS细胞的递送。该计划正在与Regeneron Pharmaceuticals合作开发。ALN-APP的安全性和有效性尚未得到FDA，EMA或任何其他卫生部门的评估。。

About Alzheimer’s Disease

关于阿尔茨海默病

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the most common form of dementia, affecting over 30 million people worldwide. AD is characterized by progressive memory loss and cognitive decline, with neuropathological accumulation of amyloid plaques, neurofibrillary tangles, and neuroinflammation, ultimately resulting in significant brain atrophy.

阿尔茨海默病（AD）是最常见的神经退行性疾病和最常见的痴呆形式，影响全球3000多万人。AD的特征在于进行性记忆丧失和认知能力下降，伴有淀粉样斑块，神经原纤维缠结和神经炎症的神经病理学积累，最终导致显着的脑萎缩。

Disease progression results in progressive loss of independence, increased caregiver burden, institutionalization, and premature death. Early-onset Alzheimer’s disease (EOAD) refers to a subgroup of AD with symptom onset prior to the age of 65, representing approximately 4% to 6% of all AD. EOAD is the leading cause of dementia in younger individuals and is a significant cause of disability and early mortality.

疾病进展导致独立性逐渐丧失，看护者负担增加，机构化和过早死亡。早发性阿尔茨海默病（EOAD）是指在65岁之前出现症状的AD亚组，约占所有AD的4%至6%.EOAD是年轻人痴呆的主要原因，并且是一个重要原因残疾和早期死亡。

Available treatment options include symptomatic treatment and treatment to reduce amyloid deposits in the brain. There are currently no available treatments that have been shown to halt or reverse the progression of the disease..

可用的治疗选择包括对症治疗和减少脑内淀粉样蛋白沉积的治疗。目前还没有可用的治疗方法可以阻止或逆转疾病的进展。。

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）是基因沉默的天然细胞过程，代表了当今生物学和药物开发中最有前途和最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。

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（Small interfering RNA，siRNA）是介导RNAi并构成Alnylam RNAi治疗平台的分子，通过有效沉默信使RNA（mRNA）-遗传前体-编码致病或疾病途径蛋白，从而阻止它们成为当今药物的上游。

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，有可能改变遗传和其他疾病患者的护理。。

About Alnylam Pharmaceuticals

关于Alnylam制药公司

Alnylam Pharmaceuticals (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 Pharmaceuticals（纳斯达克股票代码：ALNY）已将RNA干扰（RNAi）翻译成全新一类创新药物，有可能改变患有罕见和流行疾病且需求未得到满足的人们的生活。基于诺贝尔奖获奖科学，RNAi therapeutics代表了一种强大的，临床验证的方法，可产生转化药物。

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’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis.

自2002年成立以来，Alnylam领导了RNAi革命，并继续以大胆的愿景将科学可能性变为现实。Alnylam的商业RNAi治疗产品是由Alnylam的合作伙伴开发和商业化的ONPATTRO®（patisiran），AMVUTTRA®（vutrisiran），GIVLAARI®（givosiran），OXLUMO®（lumasiran）和Leqvio®（inclisiran），诺华。

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拥有深入的研究药物管道，包括处于后期开发阶段的多种候选产品。Alnylam正在执行其“Alnylam P5x25”战略，通过可持续创新和卓越的财务绩效，为世界各地的患者提供罕见和常见疾病的转化药物，从而形成领先的生物技术知名度。

Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on X (formerly Twitter) at @Alnylam, on LinkedIn, or on Instagram..

Alnylam总部设在马萨诸塞州剑桥市。有关我们的人员，科学和管道的更多信息，请访问www.Alnylam.com并在X（以前的Twitter）上与我们联系@Alnylam，LinkedIn或Instagram。。

Alnylam Forward Looking Statements

Alnylam前瞻性声明

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, including ALN-APP, Alnylam’s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam’s projected commercial and financial performance, should be considered forward-looking statements.

本新闻稿包含1933年“证券法”第27A条和1934年“证券交易法”第21E条含义内的前瞻性陈述。除了关于Alnylam的期望，信念，目标，计划或前景的历史事实陈述之外的所有陈述，包括但不限于对Alnylam成为领先生物技术公司的愿望以及计划实现其“Alnylam P5x25”战略的期望，Alnylam有可能确定新的潜在药物开发候选药物并推进其研究和开发计划，包括ALN-APP，Alnylam获得新商业产品批准或现有产品其他适应症的能力，以及Alnylam预计的商业和财务业绩，应该是被视为前瞻性声明。

Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition; Alnylam’s ability to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and .

由于各种重要风险，不确定性和其他因素，实际结果和未来计划可能与这些前瞻性声明所表明的实质性结果和未来计划有很大差异，包括但不限于：COVID-19全球流行病或任何未来对Alnylam业务的大流行病，运营结果和财务状况；Alnylam能够成功执行其“Alnylam P5x25”策略；Alnylam能够发现和开发新的候选药物和递送方法，并成功证明其候选产品的有效性和安全性；Alnylam候选产品（包括vutrisiran）的临床前和临床结果；监管机构的行动或建议以及Alnylam获得和维持其候选产品（包括vutrisiran）的监管批准的能力，以及有利的定价和报销；成功启动，营销和。

This press release discusses investigational RNAi therapeutics and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics. There is no guarantee that any investigational therapeutics will successfully complete clinical development or gain health authority approval..

本新闻稿讨论了研究性RNAi疗法，并不打算传达有关这些研究性疗法的有效性或安全性的结论。不能保证任何研究性治疗药物能够成功完成临床开发或获得卫生部门的批准。。