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Alnylam Presents New 18-Month Results from Exploratory Cardiac Endpoints in HELIOS-A Phase 3 Study of Investigational Vutrisiran

– New Exploratory Findings from 18-Month Analysis of HELIOS-A Suggest that Treatment with Investigational Vutrisiran May Benefit Patients with Hereditary ATTR (hATTR) Amyloidosis and Cardiac Involvement –

– Improvements in NT-proBNP and Echocardiographic Parameters Seen in Cardiac Subpopulation –

– Reductions in Technetium Uptake Observed in Patients with High Grade Uptake at Baseline –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced new positive results from an 18-month analysis of exploratory cardiac endpoints in the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis. The 18-month findings show that in a pre-defined cardiac subpopulation, treatment with vutrisiran was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of NT-proBNP, a measure of cardiac stress, and a trend towards improvement in echocardiographic parameters. Consistent beneficial effects on cardiac measures were observed in the modified intent-to-treat (mITT) group. Additionally, in a planned cohort of patients from the mITT population, vutrisiran treatment reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline in a majority of assessable patients, including those with Perugini grade ≥2 at baseline, suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefit from a TTR silencer.

The exploratory findings were presented in a late breaking oral session during the annual congress of the Heart Failure Association of the European Society of Cardiology (Heart Failure 2022; May 21-24, 2022). Alnylam previously announced that vutrisiran met its primary endpoint and all secondary endpoints at nine months in HELIOS-A, as well as all 18-month secondary endpoints in patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy, which were presented at the Société Francophone du Nerf Périphérique (SFNP) annual meeting earlier this year.

“While the full clinical significance of these findings requires further evaluation, the 18-month exploratory results from HELIOS-A continue to support the potential for vutrisiran to reduce amyloid burden in the heart and suggest that patients with a high degree of cardiac amyloid burden may benefit from this investigational RNAi therapeutic,” said Rena N. Denoncourt, Vice President, TTR Franchise Lead. “We look forward to seeing data from the APOLLO-B and HELIOS-B studies, which are investigating the efficacy and safety of patisiran and vutrisiran, respectively, to treat the cardiomyopathy of wild-type and hereditary ATTR amyloidosis. We are committed to bringing highly impactful therapeutic options to patients worldwide living with this progressive, multi-system and life-threatening disease.”

At 18 months, patients with pre-existing evidence of cardiac amyloid involvement (baseline LV wall thickness ≥1.3 cm and no aortic valve disease or hypertension in medical history; n=40/122 vutrisiran; n=36/77 external placebo group) treated with vutrisiran demonstrated improvement in NT-proBNP levels, with an adjusted geometric fold change of 0.95 compared to 1.93 in the external placebo group (p=0.0004). In the cardiac subpopulation, vutrisiran treatment was also associated with a trend towards improvement (nominal p values) in echocardiographic parameters at Month 18 relative to external placebo, including cardiac output (p=0.0426), LV end-diastolic volume (p=0.0607), global longitudinal strain (p=0.0781) and mean LV wall thickness (p=0.5397).

In a planned cohort of patients from the mITT population, vutrisiran also reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline. 96 percent of assessable patients maintained a stable grade or improved by one grade or greater in the Perugini grading scale at Month 18 relative to baseline. Among vutrisiran-treated patients with Perugini grade ≥1 at baseline, 50 percent showed a one grade or greater improvement at Month 18. Of patients with baseline Perugini grade ≥2 who represent those with evidence of the greatest degree of cardiac amyloid burden evaluated in the analysis, the proportion with improvement in normalized left ventricle total uptake and heart-to-contralateral lung ratio was 100 percent (25/25) and 77 percent (20/26), respectively.

“hATTR amyloidosis is a rapidly progressive disease that can affect multiple organs and tissues, including the heart, nerves and gastrointestinal tract, with potentially fatal outcomes,” said Julian D. Gillmore, M.D., Ph.D., University College London. “The exploratory cardiac findings from the HELIOS-A Phase 3 study are encouraging as they add to the growing body of data that suggest vutrisiran has the potential to help improve multiple aspects of the disease, including cardiac manifestations that can be life-threatening for these patients.”

The majority of adverse events reported in the vutrisiran arm of HELIOS-A were mild or moderate in severity. As previously reported, there were three study discontinuations in the vutrisiran arm (2.5 percent) by Month 18 due to adverse events, one due to a non-fatal event of heart failure and two due to deaths, none of which were considered related to the study drug. Vutrisiran demonstrated an acceptable cardiac safety profile through 18 months of treatment.

Vutrisiran is under review by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. In April, Alnylam announced a 3-month extension of the review period for the new drug application for vutrisiran in the U.S. with a new action date under the Prescription Drug User Fee Act (PDUFA) of July 14, 2022. The Company received Orphan Drug Designation in Japan for transthyretin type familial amyloidosis with polyneuropathy. A biannual 50mg dosing regimen is under evaluation within the ongoing randomized treatment extension (RTE) period in the HELIOS-A trial. Vutrisiran is also being evaluated in the HELIOS-B Phase 3 study for the treatment of patients with ATTR amyloidosis with cardiomyopathy, including both hATTR and wild-type ATTR (wtATTR) amyloidosis.

About Vutrisiran

Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency, or any other health authority.

About hATTR Amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

About HELIOS-A Phase 3 Study

HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 at 9 months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 months. Additional secondary endpoints at 18 months were evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point include NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients were eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.

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 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) 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 20 years ago, 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), 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 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, without limitation, those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with an encouraging safety profile for patients diagnosed with the polyneuropathy of hATTR amyloidosis, the 18-month exploratory results from HELIOS-A which support the potential for vutrisiran to reduce amyloid burden in the heart, the potential of patisiran and vutrisiran to treat the cardiomyopathy of wild-type and hereditary ATTR amyloidosis, the ongoing regulatory review of vutrisiran around the world, including the extended PDUFA date in the U.S., 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 recent leadership transition 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 vutrisiran and patisiran; 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 vutrisiran, 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, including vutrisiran; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for OXLUMO and ONPATTRO (and 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 uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.


Alnylam Pharmaceuticals, Inc.

Christine Regan Lindenboom

(Investors and Media)


Josh Brodsky



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