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− Novel Mechanism of Action Delivers Rapid Knockdown of Transthyretin, Addressing the Disease at its Source – − Proven Consistency of Effect on Cardiovascular Outcomes, Function, and Quality of Life in ATTR-CM Population Representative of Today’s Patients – – Only Therapeutic Approved in the U.S. to Address Both Cardiomyopathy and Polyneuropathy Manifestations of ATTR Amyloidosis − – Alnylam Offers Multiple Programs to Support Broad and Seamless Patient Access; Majority of Patients Expected to Pay $0 in Out-of-Pocket Costs for AMVUTTRA – CAMBRIDGE, MA, USA I March 20, 2025 I Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced the U.S. Food and Drug Administration (FDA) approval of the supplemental New Drug Application (sNDA) for its RNAi therapeutic, AMVUTTRA ® (vutrisiran), for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits. The approval expands the indication for AMVUTTRA, which now becomes the first and only therapeutic approved by the FDA for the treatment of ATTR-CM and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. ATTR-CM is a devastating, rapidly progressive, and ultimately fatal disease estimated to affect approximately 150,000 people in the U.S. and over 300,000 people worldwide. There is no cure for ATTR-CM, and the deposition of misfolded transthyretin (TTR) fibrils causes irreversible damage over time which can lead to premature death. Today, most patients remain undiagnosed and untreated, and a significant portion of those who are treated with commonly used therapies experience disease progression. “The FDA approval of AMVUTTRA for ATTR-CM marks a pivotal advancement for patients, providing a new and clinically differentiated treatment option that has been shown to improve outcomes, including cardiovascular mortality, and reduce progression for those living with this devastating disease,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “I would like to extend my deepest gratitude to the patients who participated in our clinical trials, their families and caregivers, the clinical researchers, regulators, and my colleagues at Alnylam who made this approval possible. Today represents a significant milestone in our nearly twenty years of partnership with the ATTR amyloidosis community, but we are not stopping here. We will continue to innovate for patients with ATTR amyloidosis so they can live longer, better, healthier lives.” AMVUTTRA is an RNAi therapeutic that works upstream to deliver rapid knockdown of TTR, addressing the disease at its source, with only four convenient subcutaneous doses per year. By rapidly knocking down TTR production, AMVUTTRA substantially decreases deposition of TTR fibrils, which form amyloid and cause irreversible cardiovascular damage and premature death in patients with ATTR-CM. “This FDA approval provides an opportunity to further transform ATTR-CM treatment with a new mechanism of action. The HELIOS-B clinical trial found that vutrisiran allowed patients to live longer, experience fewer hospitalizations, and improve how they function and feel,” said Ronald Witteles, M.D., HELIOS-B Investigator, Professor of Medicine at Stanford University School of Medicine and Co-Director of the Stanford Amyloid Center. “The trial enrolled patients who mirror the real-world population with this disease, and I am very encouraged by vutrisiran’s ability to demonstrate meaningful clinical benefits across both cardiovascular outcomes and multiple measures of disease progression. This is a very exciting day for patients with this challenging disease.” This approval is based on the HELIOS-B Phase 3 clinical trial which evaluated AMVUTTRA for the treatment of ATTR-CM. The trial achieved statistical significance compared to placebo on all 10 pre-specified primary and secondary endpoints. The results were presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine . In the overall population, AMVUTTRA reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events by 28% during the double-blind treatment period of up to 36 months. Mortality in this population was significantly reduced by 36% through 42 months in a pre-specified secondary endpoint analysis which included up to 36 months of the double-blind period plus six months of open-label extension. In the monotherapy population, AMVUTTRA significantly reduced the risk of ACM and recurrent CV events by 33% in the double-blind period and significantly reduced the risk of mortality by 35% through 42 months. As compared to patients treated with placebo, patients treated with AMVUTTRA also experienced preservation of functional capacity and quality of life, as well as early improvements in biomarkers NT-proBNP and troponin I, which are predictive of cardiovascular outcomes. The safety and tolerability of AMVUTTRA are well-established, as demonstrated in the positive HELIOS-A clinical trial for AMVUTTRA in hATTR-PN which resulted in FDA approval in 2022 and over 5,000 patient-years exposure to-date, globally. In that study, the most common adverse reactions in patients treated with AMVUTTRA were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). No new safety concerns were identified in the HELIOS-B clinical trial of patients with ATTR-CM. “Despite recent advances, there remains a significant need for patients living with ATTR-CM and I’ve witnessed, firsthand, the impact that ATTR amyloidosis can have on families, including diminished quality of life and the loss of loved ones,” said Muriel Finkel, President of the Amyloidosis Support Groups. “The availability of this groundbreaking treatment option is a significant moment for patients living with ATTR amyloidosis. It represents a beacon of hope for our community.” AMVUTTRA in hATTR-PN is covered by insurers for ~99% of patients with the majority paying $0 out-of-pocket. Similar broad coverage and out-of-pocket costs are expected in ATTR-CM given comparable payer dynamics and the clinical value demonstrated in the HELIOS-B clinical trial. Alnylam has a proven track record of working closely with payers to ensure broad patient access to our medicines, including pioneering innovative value-based agreements linked to clinical outcomes that ensure value and predictability for payers. Alnylam offers multiple support services and resources for patients prescribed its products through Alnylam Assist ® , the only in-house patient support program in ATTR-CM. Alnylam Assist ® is designed to provide one-on-one support for patients and their healthcare teams to help navigate the treatment journey, and includes a Quick Start program that provides eligible patients who encounter coverage delays or delays in treatment with an initial dose at no cost. In addition, Alnylam Assist ® offers support with insurance coverage, financial assistance, and disease and treatment education for a seamless start to the AMVUTTRA treatment experience. Physicians and patients can learn more about Alnylam’s patient support services by visiting AlnylamAssist.com/amvuttra or calling 1-833-256-2748. Marketing authorization applications based on HELIOS-B data are currently under review by several global health agencies including the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Alnylam remains on track to proceed with additional global regulatory submissions for vutrisiran in 2025. Visit AMVUTTRA.com/attr-cm for more information. Investor Webcast Information Alnylam management will discuss the FDA approval of AMVUTTRA for ATTR-CM via webcast today at 6:00 pmET. A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events . An archived webcast will be available on the Company’s website approximately two hours after the event. INDICATIONS AND IMPORTANT SAFETY INFORMATION Indications AMVUTTRA ® (vutrisiran) is indicated for the treatment of the: For additional information about AMVUTTRA, please see the full Prescribing Information . About AMVUTTRA® (vutrisiran) AMVUTTRA ® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection by a healthcare professional, AMVUTTRA is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults and is approved in the U.S. for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. About ATTR Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000 – 300,000 people worldwide. 1-4 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 X (formerly Twitter) at @Alnylam , or on LinkedIn , Facebook , or Instagram . 1 Hawkins PN, Ando Y, Dispenzeri A, et al. Ann Med . 2015;47(8):625-638. 2 Gertz MA. Am J Manag Care . 2017;23(7):S107-S112. 3 Conceicao I, Gonzalez-Duarte A, Obici L, et al. J Peripher Nerv Syst . 2016;21:5-9. 4 Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis . 2013;8:31. SOURCE: Alnylam Pharmaceuticals

The Food and Drug Administration on Thursday approved an Alnylam Pharmaceuticals medicine for a serious heart condition, a decision that should help the biotechnology firm secure its position as one of the sectors most valuable companies.The agency cleared the drug, called Amvuttra, for people with a cardiac form of the rare disease transthyretin amyloidosis. Alnylam already sells the therapy for individuals with a genetic type of the disease that causes progressive nerve damage.Transthyretin amyloidosis with cardiomyopathy is considered deadlier than the nerve type, and often leads to hospitalizations and heart failure. Its also thought to be more common, making it a target for drugmakers seeking a lucrative market opportunity.In testing, treatment with Amvuttra led to a 28% lower risk of recurrent cardiovascular events or death from any cause than placebo in people with the disease. The drug similarly reduced that risk versus placebo among people who werent receiving another medication for the condition, Pfizers tafamidis, at the studys start.Both measures were the studys main goals after statistical changes Alnylam made to the study a year ago.Amvuttra labeling specifies treatment can reduce hospitalizations or death resulting from heart complications, as well as urgent visits for heart failure. That indication could help the drugs commercial prospects, as tafamidis and the other available medication, BridgeBio Pharmas Attruby, are also cleared for that use.The approval provides a new and clinically differentiated treatment option that has been shown to improve outcomes, said CEO Yvonne Greenstreet, in a statement.Amvuttra will initially be priced in line with the cost in its other approved indication, for which a years supply has a roughly $476,000 list price,the company revealed on a conference call. Alnylam expects the drugs net price to then gradually decrease as patient uptake climbs. By comparison, tafamidis has a list price of over $250,000 while Attrubys yearly cost is about $244,000.Approval of Amvuttra in transthyretin amyloidosis, or ATTR, cardiomyopathy is important for the future of Alnylam, which pioneered a drugmaking method called RNA interference.Though the company has developed four other marketed medicines cementing itself as one of the industrys most prolific developers its still not profitable. Alnylam has accumulated a deficit of more than $7 billion since its 2002 founding, including $1.85 billion in combined net losses over the last three years, according to its most recent annual report.Wall Street analysts and investors view approval in ATTR cardiomyopathy as Alnylams best opportunity yet to turn a regular profit. Historically, the disease has been underdiagnosed as it can be mistaken for other conditions. But better awareness, diagnostic tools and the availability of tafamidis since 2019 have grown the market, leading analysts to forecast annual sales for drugs that treat the condition rising to $15 billion to $20 billion over time. Global sales of tafamidis surpassed $5 billion last year.Alnylam has sought to prove its medicines can deliver powerful benefits by silencing the misfolded protein implicated in the disease rather than stabilizing it like tafamidis does. The company came close to an approval with an earlier drug, Onpattro. But the FDA rejected it in 2023 after determining the supportive data werent meaningful enough to warrant an OK, and Alnylam abandoned seeking a clearance of Onpattro in cardiomyopathy.The company tried again with Amvuttra, which works similarly to Onpattro but is administered through an under-the-skin injection rather than an infusion. Alnylam also ran the main trial supporting its approval for long enough to assess whether treatment could extend lives the kind of evidence underlying tafamidis approval and detected a benefit that appears to have satisfied U.S. regulators.Amvuttras sales potential may not end up being as high as some on Wall Street predict, however. The drug will compete for market share tafamidis and Attruby, both of which are taken orally. The latter was approved last year and is off to a faster-than-expected start. Alnylams drug wasnt tested directly against either one and, while cross-trial comparisons can be misleading, its results dont appear strong enough to indicate vutrisiran is clearly superior. Physicians interviewed by BioPharma Dive last year said that deciding which drug to start new patients on, or switch to if one therapy stops working, will be difficult.Given the drugs costs, insurers may not approve use of Amvuttra alongside tafamidis or Attruby. Generic versions of tafamidis, which could arrive later this decade, will further shift the market balance. Ionis Pharmaceuticals and Intellia Therapeutics are advancing other medicines, meanwhile.In an interview ahead of the FDAs decision, Chief Commercial Officer Tolga Tanguler said Amvuttra can help grow the market. While diagnosis rates have climbed since tafamidis initial approval, the majority of patients arent on treatment, leaving room for new entrants to gain share, he said.Tanguler said Alnylam sees Amvuttra as well positioned to become the standard of care. He noted how adherence to the drug, which is injected four times a year, is very high in the neuropathy form of ATTR. You dont get that on an oral therapy, he added. Good results can only happen if you're actually taking your medicine.Alnylams therapy also was tested in people who were already on other background therapies, among them tafamidis, which set the bar very high. Amvuttra nevertheless succeeded, with benefit reported across different subgroups.“I have every confidence we'll be able to communicate that very effectively to both payers and prescribers, Tanguler said.The company projects Amvuttra and Onpattro will generate about $1.6 billion to $1.7 billion in combined revenue this year, versus just over $1.2 billion last year. Tanguler expects Amvuttras usage to grow over the second half of the year and accelerate after.Editors note: This story has been updated with Amvuttras list price. '