– Single Doses of Investigational Zilebesiran Resulted in Sustained Serum Angiotensinogen and Blood Pressure Reductions Through Six Months, Supporting Quarterly and Potentially Biannual Dosing –

– Blood Pressure Response to Low-Salt Intake under the Peak Pharmacodynamic Effect of Zilebesiran was Consistent with Augmented Pharmacology, with No Hypotensive Adverse Events Reported –

– Coadministration with Irbesartan Resulted in Additional Blood Pressure Lowering without Signals of Renal Toxicity –

– Zilebesiran was Generally Well Tolerated, With No Treatment-Related Serious Adverse Events or Study Withdrawals, Supporting Continued Development –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive interim results from the ongoing Phase 1 study of zilebesiran (formerly known as ALN-AGT), an investigational subcutaneous RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension. Findings on the pharmacodynamic and antihypertensive effects of zilebesiran six months after a single dose were presented at the American Heart Association (AHA) Scientific Sessions 2021, taking place virtually from November 13-15, 2021. Additional results demonstrated that zilebesiran was safe and well tolerated in the Phase 1 study during salt restriction and when administered concomitantly with irbesartan, an oral renin-angiotensin-aldosterone system inhibitor (RAASi).

In the Phase 1 study, 84 patients with hypertension were randomized and enrolled in ascending single dose cohorts of zilebesiran up to 800 mg (N=12 per dose cohort; 2:1 randomization of zilebesiran:placebo). As of the May 28, 2021 data cut-off date, patients treated with single doses of zilebesiran at ≥100 mg experienced reductions in serum AGT of ≥90 percent from Week 3 and sustained to Week 12. In the 800 mg dose cohort, durable reductions in serum AGT of >90 percent were maintained through six months. Dose-dependent reductions in blood pressure (BP), assessed by ambulatory blood pressure monitoring (ABPM), were observed in conjunction with AGT knockdown. Mean reductions in 24-hour systolic blood pressure (SBP) of >10 mm Hg were observed at Week 8 after single doses of zilebesiran at ≥200 mg, with clinically meaningful reductions in BP maintained through six months. After a single dose of 800 mg, mean reductions in 24-hour SBP of >20 mm Hg were observed at Month 6. Patients treated with zilebesiran at ≥200 mg experienced consistent and sustained lowering of daytime and nighttime SBP through six months, and similar improvements were seen for diastolic blood pressure (DBP), indicating early evidence of the potential for tonic BP control to be achieved by zilebesiran for an extended period.

“Hypertension is the leading cause of cardiovascular disease worldwide, including heart attack, stroke and chronic kidney disease, and a major risk factor for premature mortality. Despite the availability of multiple antihypertensive therapies, rates of hypertension and poor blood pressure control are expected to increase for years to come. Patient adherence to daily oral antihypertensive medications remains a challenge, warranting the development of novel treatment approaches to improve patient adherence through infrequent dosing and help patients achieve tonic blood pressure control,” said Weinong Guo, M.D., Ph.D., Senior Vice President of Clinical Development at Alnylam. “We believe the preliminary efficacy and safety findings reported at the AHA Scientific Sessions warrant further evaluation of zilebesiran in larger clinical studies, including the two KARDIA Phase 2 studies, which are evaluating zilebesiran as monotherapy and when administered concomitantly with standard-of-care antihypertensive medications.”

Additional parts of the ongoing Phase 1 study assessed the safety and tolerability of zilebesiran during low-salt intake or when given in combination with irbesartan, an oral RAASi. In the controlled salt diet cohort, 12 patients were randomized 2:1 to receive zilebesiran at 800 mg or placebo, with controlled salt intake delivered through a two-week low-salt/high-salt dietary subprotocol to assess the tolerability of zilebesiran during volume depletion due to sodium loss induced by a low-salt diet. As expected, a reduction in 24-hour mean SBP/DBP was observed in the absence of zilebesiran treatment for all patients on a low-salt diet, with reversal upon switching to a high-salt diet. When assessed on a background of zilebesiran treatment, changes in BP due to a low-salt diet were more profound than seen in placebo patients, consistent with augmented pharmacology. There were no hypotensive events among patients being treated with zilebesiran during a low-salt diet. A high-salt diet was shown to modulate the BP lowering effect of zilebesiran, providing early evidence that this standard intervention could be used to treat potential hypotensive adverse events should they occur. In the irbesartan add-on cohort, 10 patients who received a single dose of open-label zilebesiran at 800 mg proceeded to receive irbesartan daily at 300 mg by oral administration for two weeks. Coadministration with irbesartan reduced 24-hour mean SBP/DBP by an additional 6.4/3.2 mm Hg, with no clinically significant changes in serum creatinine or potassium.

Across various cohorts in the Phase 1 study, zilebesiran was shown to be generally well tolerated with an acceptable safety profile that supports continued development. In the ascending single dose study, most adverse events (AEs) were mild or moderate in severity and resolved without intervention, with the most common AE consisting of mild and transient injection site reactions in 5 out of 56 patients (8.9 percent) receiving zilebesiran. In the salt depletion and irbesartan cohorts, all AEs were mild in severity and there were no AEs of concern for hypotensive events. Across all cohorts, there were no treatment-related serious AEs or clinically significant elevations in serum ALT, serum creatinine, or serum potassium, and no patients required intervention for low blood pressure.

To view the data presented by Alnylam at the AHA Scientific Sessions, please visit www.alnylam.com/capella.

About Zilebesiran Phase 1 Study

The Phase 1 study is a multi-center, randomized, double-blind, placebo-controlled, single dose (SD) and active comparator-controlled multiple dose (MD) trial designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of zilebesiran in patients with essential hypertension. The study is being conducted in four parts: single ascending dose (SAD) phase in hypertensive patients; SD phase in hypertensive patients with controlled salt intake; MD phase in hypertensive patients who are obese, with once daily oral doses of irbesartan as the active comparator; and open-label SD phase with co-administration of irbesartan in hypertensive patients. The planned enrollment for this study, including optional cohorts, is up to 160 patients.

About Zilebesiran

Formerly known as ALN-AGT, zilebesiran (pronounced “zile-BEE-siran”) 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 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

Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure (SBP) of above 140 mm Hg and/or a diastolic blood pressure (DBP) greater than 90 mm Hg, though AHA/ACC guidelines have a lower threshold of a SBP above 130 mm Hg and/or a DBP greater than 80 mm Hg. 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 and daily peak and trough effects, 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 (Nasdaq: ALNY) is leading 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 genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO^® (patisiran), GIVLAARI^® (givosiran), and OXLUMO^® (lumasiran), as well as Leqvio^® (inclisiran), which is being developed and commercialized by Alnylam’s partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six 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, or on Instagram.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam’s expectations, plans, aspirations, and goals, including those related to encouraging results from the Phase 1 study of zilebesiran (formerly known as ALN-AGT), early evidence of the potential for tonic BP control to be achieved by zilebesiran, Alnylam’s commitment to advancing zilebesiran as a potential treatment to help address uncontrolled hypertension through its continued development in the KARDIA-2 and KARDIA-1 Phase 2 studies of zilebesiran, the potential that inhibiting the synthesis of AGT in the liver leads to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II , Alnylam’s aspiration to become a leading biotech company, and the planned achievement of its “Alnylam P5x25” strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. 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; the potential impact of the planned leadership transition at year end on Alnylam’s ability to attract and retain talent and 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, including zilebesiran; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, including zilebesiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO (and potentially vutrisiran, if approved) 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, 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 most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) 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.

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

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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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