Alnylam Presents Positive Late-Breaking Data from Ongoing Phase 1 Study of ALN-AGT, an Investigational RNAi Therapeutic for the Treatment of Hypertension

– Single Doses of Investigational ALN-AGT Achieved Sustained Reductions in Serum Angiotensinogen (AGT) at 12 Weeks Resulting in Reduced Blood Pressure –

– Durability of AGT Knockdown Supports the Potential of Once Quarterly or Biannual Dosing –

– ALN-AGT was Generally Well Tolerated, with No Serious Treatment-Related Adverse Events or Study Withdrawals –

– Data Confirm Potential for AGT Silencing as a Novel Approach for Treatment of Hypertension and Support Initiation of Phase 2 KARDIA Studies Mid-Year –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today positive interim results from the ongoing Phase 1 study of ALN-AGT, a subcutaneous investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) for the treatment of hypertension. Results were presented during a late-breaking oral presentation at the 2021 Joint Meeting of the European Society of Hypertension (ESH) and the International Society of Hypertension (ISH). ALN-AGT treatment was associated with dose-dependent knockdown of AGT and reductions in blood pressure (BP) with a durability that supports the potential for a once quarterly or biannual dosing regimen, and was found to be generally safe and well tolerated.

“We face an intractable challenge in controlling hypertension, which affects an estimated 1.13 billion people worldwide and is a major risk factor for cardiovascular disease morbidity and premature mortality.ⁱ Despite well-established treatments including lifestyle modifications and several classes of available anti-hypertensive medications, fewer than 20 percent of people with hypertension globally have it under control,”ⁱ said Reinhold Kreutz, M.D., Ph.D., Professor, Charité and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology and President, ESH. “While several factors contribute to the high rate of uncontrolled hypertension, inconsistent blood pressure control and medication adherence in those patients receiving treatment may play critical roles, and the encouraging early-stage results for ALN-AGT suggest its potential as a novel therapeutic approach to address long-standing treatment gaps.”

Eighty-four patients with hypertension were randomized in this double-blind, placebo-controlled, single ascending dose (SAD) study evaluating the safety, tolerability and preliminary pharmacokinetic and pharmacodynamic activity of ALN-AGT. Patients, who were either treatment naïve or had discontinued other anti-hypertensive medications prior to study entry, enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg ALN-AGT.

Patients treated with single doses of ALN-AGT at 100 mg or higher experienced durable reductions in serum AGT of more than 90 percent through 12 weeks. In the 800 mg dose cohort, all patients experienced reductions in serum AGT of 96 – 98 percent at Week 12. Concomitant reductions in BP were observed with AGT knockdown, with clinically meaningful mean reductions in 24-hour systolic blood pressure (SBP) of >10 mm Hg observed at Week 8 after single doses of 100 mg or higher. At 800 mg, mean reductions in 24-hour SBP of 17 mm Hg were observed at Week 8 (compared to a mean increase of 1 mm Hg in the placebo group) and sustained through Week 12. All data are as of a February 25, 2021 cut-off date.

Suboptimal BP control remains the most common attributable risk factor for cardiovascular disease and cerebrovascular disease, and a leading cause of chronic kidney disease progression. These durable pharmacologic effects of ALN-AGT may support tonic control of BP with once quarterly and potentially biannual dosing. Less frequent dosing than available with current treatment options may help achieve improved medication adherence, an important part of maintaining BP control.ⁱⁱ

ALN-AGT was shown to be generally well tolerated with an acceptable safety profile that supports advancement into Phase 2 studies. 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 ALN-AGT. There were no clinically significant elevations in serum alanine aminotransferase (ALT), serum creatinine or serum potassium, and no patient required intervention for hypotension. There were no treatment-related serious AEs, deaths or AEs leading to study withdrawal.

“We believe the results for ALN-AGT are highly encouraging and demonstrate the potential of an RNAi therapeutic to help people reach and maintain their blood pressure goals,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “We believe ALN-AGT has the potential to transform the way hypertension is managed, a disease that has been devoid of new therapeutic interventions for decades and remains a major contributing risk factor for stroke, heart attack and sudden death. Based on these findings, we look forward to advancing the clinical program for ALN-AGT with the initiation of Phase 2 KARDIA studies planned in mid-2021.”

To view the data presented at the ESH-ISH 2021 Joint Meeting, please visit www.alnylam.com/capella.

About ALN-AGT 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 ALN-AGT 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 (angiotensin II receptor blocker) used as the active comparator; and open-label SD phase with co-administration of irbesartan in hypertensive patients. Patients will be randomized 2:1 ALN-AGT to placebo or ALN-AGT to irbesartan. The planned enrollment for this study, including optional cohorts, is up to 160 patients.

About ALN-AGT

ALN-AGT 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 regulation and whose inhibition has well-established anti-hypertensive effects. ALN-AGT inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II. ALN-AGT 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 ALN-AGT have not been 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 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 or a DBP greater than 80 mm Hg. More than one billion people worldwide live with hypertension. 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 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 therapies and peak and trough effects. In particular, there are a number of high unmet need settings where novel approaches to hypertension are warranted, including resistant and refractory hypertension, chronic kidney disease, and heart failure.

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 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), OXLUMO™ (lumasiran), and Leqvio^® (inclisiran) 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 future expectations, plans and prospects, including, without limitation, Alnylam’s views with respect to the effects of treatment with ALN-AGT in knocking down AGT and reducing BP and the associated safety profile, the durability of ALN-AGT potentially supporting a once quarterly or biannual dosing regimen, the potential of ALN-AGT to transform the way hypertension is managed, expectations regarding the initiation of Phase 2 studies of ALN-AGT, and Alnylam’s ability to achieve 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; 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 its product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, 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 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 risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Annual Report on Form 10-K 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.

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

ⁱⁱ Improving Medication Adherence Among Patients with Hypertension. Million Hearts. https://millionhearts.hhs.gov/data-reports/factsheets/adherence.html. Published April 2020. Accessed April 2021.

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