- Zilebesiran Met Primary Endpoint Demonstrating Greater than 15 mmHg Reduction of Systolic Blood Pressure at Three Months of Treatment Compared to Placebo at Two Highest Single Doses Evaluated -

- Study Met Key Secondary Endpoints Showing Consistent and Sustained Reductions of Systolic Blood Pressure at Six Months, Supporting Quarterly or Biannual Dosing -

- Zilebesiran Demonstrated an Encouraging Safety and Tolerability Profile in Adult Patients with Mild-to-Moderate Hypertension -

- Full Study Results to be Presented at an Upcoming Scientific Conference -

Alnylam Pharmaceuticals, Inc. Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the KARDIA-1 Phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, met the primary endpoint demonstrating a dose-dependent, clinically significant reduction in 24-hour mean systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) at Month 3, achieving a placebo-subtracted reduction greater than 15 mmHg (p less than 0.0001) with both 300 mg and 600 mg doses. The study also met key secondary endpoints including significant change in 24-hour mean SBP as measured by ABPM at Month 6, as well as significant change in office SBP at Month 3 and Month 6, for all zilebesiran arms, compared to placebo. The study results indicate zilebesiran was associated with dose-dependent, potent and durable knockdown of serum AGT levels through Month 6. Zilebesiran also demonstrated an encouraging safety and tolerability profile that the company believes supports continued development. These findings of robust and tonic blood pressure control will help determine the optimal dose and regimen of zilebesiran for future studies.

“Hypertension is a growing global health crisis responsible for around 10 million deaths worldwide each year. Despite the availability of several classes of oral anti-hypertensive treatments, up to 80% of individuals globally remain uncontrolled, leaving them at an increased risk of cardiovascular, cerebrovascular and renal disease, which is further exacerbated by blood pressure variability, lack of nighttime blood pressure control and poor adherence,” said Professor George L. Bakris, M.D., Board-Certified Hypertension Specialist and Director of the American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine. “As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic blood pressure of greater than 15 mmHg, along with the ability to achieve durable tonic blood pressure control, provide hope that we may one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events.”

Zilebesiran demonstrated an encouraging safety and tolerability profile. There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to study drug. Serious adverse events were reported in 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated patients. None were considered related to study drug. Adverse events occurring in 5% or more of zilebesiran-treated patients in any dose arm included COVID-19, injection site reaction (ISR), hyperkalemia, hypertension, upper respiratory tract infection, arthralgia and headache.

The KARDIA-1 Phase 2 trial is a randomized, double-blind (DB), placebo-controlled, multi-center global dose-ranging study designed to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. The study enrolled 394 adults representing a diverse patient population with untreated hypertension or who were on stable therapy with one or more anti-hypertensive medications. Any patients taking prior anti-hypertensive medications completed at least a two- to four-week wash-out before randomization. Patients were randomized to one of five treatment arms during a 12-month DB period and DB extension period: 150 mg zilebesiran subcutaneously once every six months; 300 mg zilebesiran subcutaneously once every six months; 300 mg zilebesiran subcutaneously once every three months; 600 mg zilebesiran subcutaneously once every six months; or placebo. Patients who received placebo were randomized to one of the four initial zilebesiran dose regimens beginning at Month 6.

The primary endpoint is the change from baseline in SBP at Month 3, assessed by 24-hour ABPM. Key secondary and exploratory endpoints in this study include additional measures of blood pressure reduction at six months, time-adjusted change in blood pressure, and change in daytime average and night-time average blood pressure.

“We are thrilled that the KARDIA-1 Phase 2 results show zilebesiran’s ability to achieve sustained blood pressure reductions of greater than 15 mmHg, as well as long-term efficacy out to six months with infrequent dosing. We believe these results further validate the differentiated profile we observed in Phase 1. Moreover, they reinforce the potential for zilebesiran to be a transformative therapy to reduce cardiovascular risk in patients with hypertension and to offer new possibilities in a field of medicine that has seen limited innovation in nearly 20 years,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam. “We look forward to sharing the full KARDIA-1 results at an upcoming scientific conference and to reporting topline results from our KARDIA-2 Phase 2 study of zilebesiran in combination with one of three standard classes of anti-hypertensive medications in patients with mild-to-moderate hypertension in early 2024. It is a very exciting time for Alnylam, as these results build on the momentum from the recent strategic agreement to co-develop and co-commercialize zilebesiran with our collaboration partner, Roche, to potentially transform the landscape for patients with cardiovascular diseases.”

The KARDIA-2 Phase 2 study of zilebesiran used in combination with one of three standard classes of anti-hypertensive medications completed enrollment in June 2023. Topline results are expected in early 2024.

About 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 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. 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.

About Hypertension

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. 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.

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

About Alnylam Pharmaceuticals

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. 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. 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 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 Forward Looking Statements

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. 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 and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; 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 patisiran and vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including patisiran and vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam’s research and development programs, including as may arise from recent disruptions in the supply of non-human primates; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO or AMVUTTRA in the future; Alnylam’s ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products, including Roche, Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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

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.

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