Alnylam Announces Publication of Phase 1 Study Results for Zilebesiran in the New England Journal of Medicine

— Dose-Dependent Reductions in Serum Angiotensinogen and 24-hour Ambulatory Blood Pressure Were Sustained for Six Months After Single Doses of Zilebesiran —

— Acceptable Safety Profile Supporting Further Development —

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that results from its Phase 1 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, were published in the New England Journal of Medicine (NEJM). The full manuscript is titled, “Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension,” and will appear in the July 20, 2023 issue of NEJM. The key data reported in the publication showed that in the Phase 1 study, compared to placebo, zilebesiran was associated with dose-dependent reductions in serum AGT, achieving tonic blood pressure control with consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after single doses of ≥200 mg of zilebesiran. Zilebesiran also demonstrated an acceptable safety profile supporting continued clinical development; the most frequent treatment-related adverse events were mild, transient injection-site reactions.

“Hypertension is the leading cause of premature death, cardiovascular disease, and chronic kidney disease worldwide, and the global prevalence is steadily increasing in parallel with population aging and secular trends in the prevalence of risk factors including obesity, physical inactivity, and unhealthy diet. Despite the availability of effective antihypertensive treatments, nearly half of patients with hypertension fail to achieve guideline-recommended blood pressure targets, leaving them at residual risk for myocardial infarction, stroke, kidney disease progression, and mortality. For clinicians, the challenge in optimizing treatment of hypertension is frequently compounded by poor adherence to prescribed medical therapy and substantial variability in blood pressure between office visits and over the 24-hour cycle,” said Akshay Desai, M.D., the lead author of the manuscript and Director of the Cardiomyopathy and Heart Failure Program in the Advanced Heart Disease Section of the Cardiovascular Division at Brigham and Women’s Hospital. “In this context, the data we have published in NEJM are exciting, suggesting the potential role for zilebesiran to treat hypertension in a novel way via a novel, subcutaneously administered gene silencing approach to hypertension. This novel approach may provide durable, tonic blood pressure control with infrequent, office-based dosing and a favorable safety profile. Additional clinical trials will provide further insights into the potential of this approach to improve clinical outcomes in the growing population of patients with hypertension.”

“The data published in NEJM suggest the potential for zilebesiran to be an effective and highly-differentiated treatment that may help people with hypertension achieve sustained blood pressure control,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam. “To that end, we are currently evaluating the safety and efficacy of zilebesiran in our KARDIA Phase 2 clinical program either as a monotherapy (KARDIA-1) or in combination with a standard-of-care antihypertensive medication (KARDIA-2), and we look forward to reporting results from these programs in mid- and late 2023, respectively.”

Summary of Published Results

The study was conducted in 107* patients (zilebesiran, N=80; placebo, N=32) with mild-to-moderate hypertension. In Part A, patients were randomized 2:1 to receive single ascending subcutaneous doses of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. Part B of the study assessed the effects of zilebesiran (800 mg) on blood pressure under low- and high-salt diet conditions and Part E assessed the effects of zilebesiran (800 mg) coadministration with irbesartan (an angiotensin II receptor blocker). The study primary endpoint was the frequency of adverse events (AEs). AEs were reported for 58 patients receiving zilebesiran (72 percent) and 28 receiving placebo (88 percent). The most frequent treatment-related adverse events were mild, transient injection-site reactions reported in five (6 percent) patients who received zilebesiran. No events of hypotension, hyperkalemia, or worsening renal function requiring intervention were observed. Secondary and exploratory endpoints included change from baseline in serum AGT, pharmacokinetics, and change from baseline in blood pressure. In Part A, versus placebo, zilebesiran was associated with dose-dependent reductions in serum AGT that were sustained for up to six months. Single doses of zilebesiran (≥200 mg) resulted in reductions in systolic (>10 mm Hg) and diastolic (>5 mm Hg) blood pressure by Week 8, which were consistent throughout the diurnal cycle and sustained to six months. At the 800 mg dose, zilebesiran treatment resulted in mean (± standard error) systolic and diastolic reductions of 22.5 ± 5.1 mm Hg and 10.8 ± 2.7 mm Hg at Month 6, respectively. In Parts B and E of the study, blood pressure changes following zilebesiran treatment could be attenuated through high dietary salt intake and were augmented by irbesartan coadministration.

*Five patients receiving placebo in Part A of the study re-enrolled into Part E of the study and thus transitioned from placebo to zilebesiran.

About Zilebesiran

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in Phase 2 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 subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority.

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 In the U.S. alone, approximately 47 percent of adults live with hypertension, with more than half of patients on medication remaining above the blood pressure (BP) target level. 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, difficult-to-treat and resistant hypertension, 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 Twitter at @Alnylam, on LinkedIn, on Instagram, or on Facebook at @AlnylamPharma.

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 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, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, 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. 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 Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; 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. https://doi.org/10.1016/j.jacc.2018.07.008

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