CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive results from the KARDIA-1 Phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of patients with hypertension and high cardiovascular risk.

马萨诸塞州剑桥市-领先的RNAi治疗公司Alnylam Pharmaceuticals，Inc。（纳斯达克股票代码：ALNY）今天宣布了针对肝脏的研究性RNAi治疗药物zilebesiran的KARDIA-1 2期研究的积极成果。表达血管紧张素原（AGT）用于治疗高血压和高心血管风险患者。

The study results were presented during the American Heart Association (AHA) Scientific Sessions being held in Philadelphia, Pennsylvania from November 11-13, 2023. The Company previously announced positive topline results from the KARDIA-1 study in September 2023..

研究结果在2023年11月11日至13日在宾夕法尼亚州费城举行的美国心脏协会（AHA）科学会议上发表。该公司之前于2023年9月宣布了KARDIA-1研究的积极成果。。

The KARDIA-1 study achieved its primary endpoint, with single doses of zilebesiran demonstrating clinically significant reductions in 24-hour mean systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) at Month 3 across all doses, with the 150 mg, 300 mg, and 600 mg doses achieving placebo-adjusted reductions of 14.1 mmHg, 16.7 mmHg, and 15.7 mmHg, respectively (all p-values less than 0.0001).

KARDIA-1研究达到了其主要终点，单次剂量的zilebesiran显示在所有剂量的第3个月通过动态血压监测（ABPM）测量的24小时平均收缩压（SBP）的临床显着降低，150mg，300mg和600mg剂量实现安慰剂调整的14.1mmHg，16.7mmHg和15.7mmHg的减少，（所有p值均小于0.0001）。

The study also met key secondary endpoints across all doses, including demonstration of durable efficacy out to 6 months. At the 150 mg Q6M, 300 mg Q6M, 300 mg Q3M, and 600 mg Q6M doses, zilebesiran showed placebo-adjusted reductions in 24-hour mean SBP measured by ABPM of 11.1 mmHg, 14.5 mmHg, 14.1 mmHg, and 14.2 mmHg, respectively, at Month 6 (all p-values less than 0.0001).

该研究还满足了所有剂量的关键次要终点，包括证明长达6个月的持久疗效。在150mg Q6M，300mg Q6M，300mg Q3M和600mg Q6M剂量下，zilebesiran显示安慰剂调整的24小时平均SBP降低，通过ABPM测量为11.1mmHg，14.5mmHg，14.1mmHg和14.2mmHg，分别在第6个月（所有p值均小于0.0001）。

Zilebesiran demonstrated an encouraging safety and tolerability profile that the Company believes supports continued development..

Zilebesiran展示了公司认为支持持续发展的令人鼓舞的安全性和耐受性。。

“These KARDIA-1 results are impressive, showing that in a diverse group of patients with mild-to-moderate hypertension, zilebesiran can safely achieve clinically significant reductions in systolic blood pressure and tonic blood pressure control administered subcutaneously with either quarterly or bi-annual dosing,” said Professor George L.

“这些KARDIA-1结果令人印象深刻，表明在轻度至中度高血压患者的不同群体中，zilebesiran可以安全地实现临床上显着降低收缩压和强直性血压控制，每季度或每两年一次皮下给药，”乔治L.教授说。

Bakris, M.D., Board-Certified Hypertension Specialist and Director of the American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine. “I continue to be encouraged and optimistic that zilebesiran has the potential to become not only a novel treatment for hypertension but also a transformative therapy to lower cardiovascular and renal risk in patients with hypertension, an area where new and innovative therapies are desperately needed.”.

Bakris，M.D.，董事会认证的高血压专家和芝加哥大学美国心脏协会综合高血压中心主任。“我继续受到鼓励和乐观地认为，zilebesiran不仅有可能成为高血压的新型治疗方法，而且还有可能成为降低高血压患者心血管和肾脏风险的变革性治疗方法，这是一个迫切需要新的创新疗法的领域。”。

KARDIA-1 Study Results

KARDIA-1研究结果

The KARDIA-1 Phase 2 study is a randomized, double-blind, placebo-controlled, multi-center global dose-ranging study designed to evaluate the efficacy and safety of subcutaneously administered zilebesiran as monotherapy in adults with mild-to-moderate hypertension.

KARDIA-1 2期研究是一项随机，双盲，安慰剂对照，多中心全球剂量范围研究，旨在评估皮下注射齐来贝兰作为单药治疗轻度至中度高血压成人的疗效和安全性。

The study enrolled 394 adults representing a diverse patient population, of which more than 40% were female and nearly 25% were Black, with untreated hypertension or who were on stable therapy with one or more anti-hypertensive medications. Any patients taking prior antihypertensive medications completed at least a two- to four-week wash-out before randomization.

该研究招募了394名代表不同患者人群的成年人，其中40%以上为女性，近25%为黑人，未经治疗的高血压或使用一种或多种抗高血压药物进行稳定治疗。任何服用过抗高血压药物的患者在随机分组前至少完成2至4周的冲洗。

Patients were randomized to one of five treatment arms: 150 mg zilebesiran once every six months (Q6M); 300 mg zilebesiran Q6M; 300 mg zilebesiran once every three months (Q3M); 600 mg zilebesiran Q6M; or placebo..

患者被随机分配到五个治疗组之一：每六个月一次150 mg zilebesiran（Q6M）；300毫克zilebesiran Q6M；每三个月一次300毫克zilebesiran（Q3M）；600毫克zilebesiran Q6M；或安慰剂。。

The primary endpoint was the change from baseline in 24-hour mean SBP at Month 3, assessed by ABPM. Key secondary endpoints in this study include additional measures of blood pressure reduction at Month 3 and Month 6, and the proportion of patients achieving treatment response criteria at Month 6, defined as 24-hour mean ambulatory SBP <130 mmHg and/or reduction ≥20 mmHg without additional antihypertensive medications..

主要终点是ABPM评估的第3个月24小时平均SBP与基线的变化。本研究的关键次要终点包括第3个月和第6个月的血压降低的其他措施，以及第6个月达到治疗反应标准的患者比例，定义为24小时平均动态收缩压<130 mmHg和/或降低≥20 mmHg，无需额外的抗高血压药物。。

At six months, the study met its primary endpoint and all key secondary endpoints. The placebo-adjusted study results presented today are as follows:

在六个月时，该研究达到了其主要终点和所有关键次要终点。今天提出的安慰剂调整研究结果如下：

Key Endpoints

关键终点

150 mg Q6M

150毫克Q6M

300 mg Q6M

300毫克Q6M

300 mg Q3M

300毫克Q3M

600 mg Q6M

600毫克Q6M

Primary Endpoint

主要终点

Change from Baseline to Month 3 in 24-Hour Mean Ambulatory SBP

24小时平均动态收缩压从基线到第3个月的变化

-14.1 mmHg

-14.1毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-16.7 mmHg

-16.7毫米汞柱

(p less than 0.0001) *

（p小于0.0001）*

-15.7 mmHg

-15.7毫米汞柱

(p less than 0.0001)

（p小于0.0001）

Key Secondary Endpoints

关键次要终点

Change from Baseline to Month 6 in 24-Hour Mean Ambulatory SBP

24小时平均动态收缩压从基线到第6个月的变化

-11.1 mmHg

-11.1毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-14.5 mmHg

-14.5毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-14.1 mmHg

-14.1毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-14.2 mmHg

-14.2毫米汞柱

(p less than 0.0001)

（p小于0.0001）

Change from Baseline to Month 3 in Office SBP

从基线到第3个月的办公室SBP变化

-9.6 mmHg

-9.6毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-12.0 mmHg

-12.0毫米汞柱

(p less than 0.0001) *

（p小于0.0001）*

-9.1 mmHg

-9.1毫米汞柱

(p less than 0.0001)

（p小于0.0001）

Change from Baseline to Month 6 in Office SBP

从基线到第6个月的办公室SBP变化

-7.5 mmHg

-7.5毫米汞柱

(p=0.0025)

（p=0.0025）

-10.5 mmHg

-10.5毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-12.1 mmHg

-12.1毫米汞柱

(p less than 0.0001)

（p小于0.0001）

-10.2 mmHg

-10.2毫米汞柱

(p less than 0.0001)

（p小于0.0001）

* 300 mg Q6M and Q3M groups were pooled for Month 3 endpoints

*300mg Q6M和Q3M组在第3个月终点汇集

The final key secondary endpoint evaluating the proportion of patients achieving treatment response criteria at Month 6 was also met, with the odds of meeting response criteria being significantly higher across all zilebesiran regimens compared to placebo (p less than 0.001).

评估第6个月达到治疗反应标准的患者比例的最终关键次要终点也得到了满足，与安慰剂相比，所有zilebesiran方案符合反应标准的几率显着更高（p<0.001）。

Reductions in 24-hour mean blood pressure, measured by ABPM, were maintained over the full diurnal cycle, with consistently lower hourly, daytime, and nighttime blood pressure across all zilebesiran regimens compared to placebo through Month 6.

通过ABPM测量的24小时平均血压降低在整个昼夜周期中保持不变，与安慰剂相比，在第6个月时，所有zilebesiran方案的小时，白天和夜间血压始终较低。

Zilebesiran demonstrated an encouraging safety profile through Month 6. Serious adverse events were reported in 6.7% of patients in the placebo group and 3.6% of patients in the zilebesiran groups. There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to study drug.

Zilebesiran在第6个月展示了令人鼓舞的安全性。安慰剂组6.7%的患者和zilebesiran组3.6%的患者报告了严重不良事件。在zilebesiran治疗的患者中，由于心肺骤停导致一例死亡，这被认为与研究药物无关。

Drug-related adverse events (AEs) reported in more than 5% of patients in any zilebesiran arm were injection site reaction (ISR) occurring in 6.3% of patients and hyperkalemia in 5.3% of patients. No drug-related AEs were classified as serious or severe. ISR and hyperkalemia AEs were mostly mild and transient.

在任何zilebesiran组中超过5%的患者报告的药物相关不良事件（AE）是6.3%的患者发生注射部位反应（ISR），5.3%的患者发生高钾血症。没有与药物有关的AE被分类为严重或严重。ISR和高钾血症AE大多是轻度和短暂的。

No hyperkalemia events were associated with acute kidney injury or led to study drug discontinuation. Four patients had drug-related AEs leading to an investigator decision to discontinue zilebesiran. These AEs included orthostatic hypotension (n=2), blood pressure elevation (n=1), and ISR (n=1). Hypotension AEs were mild or moderate, non-serious, and transient.

没有高钾血症事件与急性肾损伤相关或导致研究药物停药。4名患者有药物相关的AE，导致研究者决定停用zilebesiran。这些AE包括体位性低血压（n=2），血压升高（n=1）和ISR（n=1）。低血压AE为轻度或中度，非严重和短暂。

A single event in the zilebesiran 300 mg Q3M group was treated with normal saline. Clinically relevant AEs of acute renal failure, hepatic AEs, hypotension, and hyperkalemia of any relatedness were reported in 1.3%, 3.0%, 4.3%, and 6.3% of patients receiving zilebesiran, and 0%, 1.3%, 1.3%, and 2.7% of patients receiving placebo..

用生理盐水处理zilebesiran 300mg Q3M组中的单个事件。接受zilebesiran治疗的患者中有1.3%，3.0%，4.3%和6.3%报告了急性肾功能衰竭，肝脏AE，低血压和任何相关性的高钾血症的临床相关AE，分别为0%，1.3%，1.3%和2.7%接受安慰剂的患者。。

“The totality of the data presented at the American Heart Association Scientific Sessions gives us confidence in zilebesiran’s potentially differentiated profile and its ability to transform the treatment landscape for patients with uncontrolled hypertension who are at high risk of future cardiovascular events,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam.

Simon Fox说：“美国心脏协会科学会议上提供的全部数据使我们对zilebesiran潜在的差异化特征及其改变未来心血管事件高风险未控制高血压患者治疗情况的能力充满信心。”Alnylam的zilebesiran项目负责人副总裁博士。

“We look forward to sharing topline results from the KARDIA-2 Phase 2 study, designed to evaluate the efficacy and safety of zilebesiran when used in combination with one other antihypertensive medication in patients with mild-to-moderate hypertension, in early 2024.”.

“我们期待在2024年初分享KARDIA-2 2期研究的顶级结果，该研究旨在评估齐来贝兰与其他抗高血压药物联合用于轻度至中度高血压患者的疗效和安全性。”。

To view the KARDIA-1 Phase 2 results presented at AHA, please visit Capella.

要查看AHA提供的KARDIA-1第二阶段结果，请访问Capella。

About Zilebesiran

关于Zilebesiran

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a demonstrated role in blood pressure (BP) regulation and its inhibition has well-established anti-hypertensive effects.

Zilebesiran是一种研究性皮下注射RNAi治疗靶向血管紧张素原（AGT），用于治疗高需求人群的高血压。AGT是肾素-血管紧张素-醛固酮系统（RAAS）中最上游的前体，RAAS是一种级联反应，在血压（BP）调节中具有明显的作用，其抑制作用具有公认的抗高血压作用。

Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II. Zilebesiran utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables infrequent subcutaneous dosing with increased selectivity and the potential to achieve tonic blood pressure control demonstrating consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after a single dose of zilebesiran.

Zilebesiran抑制肝脏中AGT的合成，可能导致AGT蛋白的持久减少，并最终导致血管收缩剂血管紧张素（Ang）II的持续减少。Zilebesiran利用Alnylam的增强稳定化学加（ESC+）GalNAc结合技术，实现罕见的皮下给药，具有更高的选择性，并有可能实现强直性血压控制，在24小时内表现出一致和持久的血压降低，持续至单剂量齐来贝兰后六个月。

The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche..

zilebesiran的安全性和有效性尚未由FDA，EMA或任何其他卫生部门建立或评估。Zilebesiran正在由Alnylam和Roche共同开发和共同商业化。。

About Hypertension

关于高血压

Uncontrolled hypertension is the chronic elevation of blood pressure (BP), defined by the 2017 ACC/AHA guidelines as ≥130 mmHg systolic blood pressure (SBP) and ≥80 mmHg diastolic blood pressure (DBP). More than one billion people worldwide live with hypertension.i Approximately one in three adults are living with hypertension worldwide, with up to 80% of individuals remaining uncontrolled despite the availability of several classes of oral anti-hypertensive treatments.

不受控制的高血压是血压的慢性升高（BP），由2017 ACC/AHA指南定义为收缩压≥130mmHg（SBP）和舒张压≥80mmHg（DBP）。全世界有超过10亿人患有高血压。我全世界大约有三分之一的成年人患有高血压，尽管有几类口服抗高血压治疗，但高达80%的人仍然无法控制。

Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing daily oral medications, resulting in inconsistent BP control and an increased risk for stroke, heart attack and premature death.ii In particular, there are a number of high unmet need settings where novel approaches to hypertension warrant additional development focus, including patients with poor medication adherence and in patients with high cardiovascular risk..

尽管可以使用抗高血压药物，但仍然存在大量未满足的医疗需求，特别是考虑到对现有日常口服药物的依从性较差，导致血压控制不一致，中风，心脏病发作和过早死亡的风险增加.ii特别是，有许多高度未满足的需求环境，其中高血压的新方法需要额外的发展重点，包括药物依从性差的患者和心血管风险高的患者。。

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, or on LinkedIn, Facebook, or 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@Alnylam的X（以前的Twitter）或LinkedIn，Facebook或Instagram上与我们联系。。

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, Alnylam’s views with respect to the results of the KARDIA-1 Phase 2 dose-ranging study of zilebesiran, Alnylam’s views with respect to the potential role for zilebesiran as a novel, subcutaneously administered gene silencing approach to hypertension, its views that zilebesiran has the potential to be an effective and highly-differentiated treatment; its expectations regarding its aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, 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Alnylam对zilebesiran的KARDIA-1阶段2剂量范围研究结果的看法，Alnylam对zilebesiran作为小说的潜在作用，皮下注射基因沉默治疗高血压，其观点认为zilebesiran有可能成为一种有效和高度分化的治疗方法；它对有望成为领先的生物技术公司的期望以及计划实现其“Alnylam P5x25”战略的期望应被视为前瞻性声明。

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 launc.

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；成功推出。

i Hypertension. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/hypertension. Published September 2019. Accessed November 2021.

我高血压。世界卫生组织。https://www.who.int/news-room/fact-sheets/detail/hypertension.发布于2019年9月。访问时间：2021年11月。

ii Carey, R. M., Muntner, P., Bosworth, H. B., & Whelton, P. K. (2018). Prevention and Control of Hypertension: JACC Health Promotion Series. Journal of the American College of Cardiology, 72(11), 1278–1293.

ii Carey，R。M.，Muntner，P.，Bosworth，H。B.，＆Whelton，P。K.（2018）。预防和控制高血压：JACC健康促进系列。美国心脏病学会杂志，72（11），1278-1293。