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Alnylam Reports Positive Interim Results from Ongoing Phase 1 Study of ALN-AGT, an Investigational RNAi Therapeutic for the Treatment of Hypertension

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today positive interim data 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 in a poster presentation at the American Heart Association (AHA) Scientific Sessions 2020, taking place virtually from November 13 – 17, 2020.

Data presented at the AHA Scientific Sessions are from the ongoing Phase 1 study of ALN-AGT with a data cut-off date of September 16, 2020. The study is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study, evaluating the safety, tolerability and preliminary pharmacokinetic and pharmacodynamic activity of ALN-AGT in patients with mild or moderate hypertension, who were either treatment naïve or had discontinued other anti-hypertensive medications. Patients (N=60) had a mean age of 52 years (range 35 – 65) and a mean baseline 24-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 139 (standard deviation [SD] +/- 8) millimeters of mercury (mm Hg) and 86 (SD +/- 7) mm Hg, respectively. Patients were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg or 200 mg ALN-AGT (N=12 per cohort; 2:1 randomization of ALN-AGT:placebo).

Compared to placebo, patients treated with ALN-AGT experienced dose-dependent reductions in serum AGT — the sole precursor of all angiotensin peptides, including the potent vasoconstrictor angiotensin (Ang) II. In the 200 mg dose cohort, the mean reduction (+/- standard error [SE]) of AGT at 8 weeks was 94.9 +/- 1.6 percent. Reductions of more than 90 percent persisting through 12 weeks after single doses of 100 or 200 mg were observed, with up to 97.6 percent AGT knockdown at 200 mg. The durability of AGT knockdown supports the potential for once quarterly dosing and possibly even less frequent dosing.

Suboptimal blood pressure (BP) control is the most common attributable risk factor for cardiovascular disease and cerebrovascular disease, and a leading cause of chronic kidney disease progression. In the Phase 1 study, lowering of BP was observed concomitantly with AGT knockdown, with a greater than 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 in cohorts receiving doses of 100 or 200 mg, as measured by ambulatory BP monitoring (ABPM). At 200 mg, mean BP reductions (+/- SE) at 8 weeks were 11.0 +/- 2.4 mm Hg for systolic and 7.7 +/- 1.1 mm Hg for diastolic BP. Maximum reductions up to 19.0 mm Hg and 12.3 mm Hg were observed in SBP and DBP, respectively.

“We believe these initial data for ALN-AGT support the potential for a fundamentally new approach in the management of hypertension, a disease where innovation has been lacking for decades. With approximately half of all hypertensive patients experiencing poor BP control, there is a significant need for new therapies that achieve improved patient adherence and sustained BP control between dosing intervals,” said Lauren Melton, Senior Director, Program Leader, ALN-AGT Program at Alnylam. “By blocking the source of all angiotensin peptides through RNAi-mediated AGT silencing, we believe ALN-AGT has the potential for prolonged pharmacodynamic effect, infrequent dosing administration and sustained BP reductions, which could help patients reach and maintain their BP goal, thereby reducing their risk for cardiovascular disease without the burden of multiple daily medications.”

ALN-AGT was shown to be generally well tolerated with an acceptable safety profile for continued development. 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 40 patients (12.5 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.

“Hypertension is recognized to be a modifiable risk factor for cardiovascular disease and a major contributor to death and disability worldwide. Despite the availability of effective antihypertensive therapy, treatment to guideline-recommended blood pressure targets remains suboptimal in clinical practice. While a number of factors are likely responsible for this treatment gap, high patient pill burden and inconsistent adherence to prescribed therapies may play an important role,” said Akshay Desai, M.D., M.P.H., Director of the Cardiomyopathy and Heart Failure Program in the Cardiovascular Division at Brigham and Women's Hospital and Associate Professor of Medicine at Harvard Medical School. “The interim Phase 1 study results of ALN-AGT suggesting a dose-dependent and sustained reduction in blood pressure persisting up to 3 months after a single subcutaneous dose are promising and may offer a novel path to securing better treatment adherence and improved blood pressure control. Further study to establish the safety and clinical efficacy of this approach seems warranted.”

To view the data presented by Alnylam at the AHA Scientific Sessions, please visit

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 subcutaneously administered ALN-AGT in patients with essential hypertension. The study will be 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 184 patients.


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 as a systolic blood pressure of above 130 mm Hg or a diastolic blood pressure of greater than 80 mm Hg. Approximately 47 percent of U.S. adults live with hypertension with more than half of patients on medication remaining above the blood pressure target level. Despite the availability of antihypertensive medications, there remains an unmet medical need, particularly 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 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), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI® (givosiran), approved in the U.S., EU, Brazil, and Canada. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its “Alnylam 2020” strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options and now expects to exceed its “Alnylam 2020” guidance. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit and engage with us on Twitter at @Alnylam or on LinkedIn.

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 safety and clinical activity of ALN-AGT and its potential for to be a fundamentally new approach in the management of hypertension, the potential for ALN-AGT to demonstrate prolonged pharmacodynamic effect, infrequent dosing administration and sustained BP reductions, expectations regarding the potential for a once quarterly or even less frequent dose regimen for ALN-AGT due to the durability of AGT knockdown, and expectations regarding the continued execution on and potential to exceed its “Alnylam 2020” guidance for the advancement and commercialization of RNAi therapeutics, 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, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylam’s business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylam’s ability to execute business continuity plans to address disruptions caused by the COVID-19 or any future 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, including ALN-AGT; the pre-clinical and clinical results for its product candidates, including ALN-AGT, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including ALN-AGT, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylam’s ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to establish and maintain strategic business alliances and new business initiatives; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; 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 Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. 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.


Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom
(Investors and Media)

Joshua Brodsky

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