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An expansion of Amvuttra’s label to include ATTR-cardiomyopathy "represents a major inflection point in our journey towards becoming a top-tier biopharma company," Alnylam CEO Yvonne Greenstreet said on a Monday conference call. In one of the most closely watched biotech trial readouts of the year, Alnylam Pharmaceuticals said its RNA interference drug reduced the risk of death or recurrent cardiovascular events in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). The result appears to be a best-case scenario for Alnylam, but analysts are still eager to see detailed data from Amvuttra’s combination with Pfizer’s tafamidis. In the go-big-or-go-home HELIOS-B trial, Alnylam’s Amvuttra (vutrisiran) reduced the risk of death or recurrent cardiovascular events by 28% compared with placebo in the overall ATTR-CM study population, including those who were on background treatment with Pfizer’s standard-of-care blockbuster tafamidis, up to 36 months. For the 60% of trial participants who weren’t on tafamidis—sold commercially as Vyndaqel or Vyndamax—the Alnylam med cut the risk of death or recurrent cardio events by 33%. Alnylam didn’t break down the specific data on patients taking Amvuttra and tafamidis together, as the company noted that the trial was not designed to pick apart that analysis. To further back Amvuttra’s case, the trial met statistical significance across several secondary endpoints across both the monotherapy and overall trial populations, too. The HELIOS-B readout is “the big-win scenario,” Alnylam CEO Yvonne Greenstreet said during a Monday conference call. Analysts agreed, even as they tried—largely in vain—to wrangle additional details from Alnlyalm management on the call. The win gave investors a major relief after a couple of last-minute trial design tweaks had unnerved some. Alnylam’s stock price jumped 36% in pre-market trading Monday. “This is impressive and shows vutrisiran is highly effective in both naïve and tafamidis-experienced patients (“consistent effects”) and supports broad use, in our view, which is in line with our best-case scenario,” William Blair analyst Myles Minter, Ph.D., said in a Monday note. If the FDA’s 2018 approval for the older-generation ATTR drug Onpattro established Alnylam as the leader in RNA interference therapy, then HELIOS-B could determine whether the Massachusetts biotech can stay in that position, especially after the FDA declined to approve Onpattro in ATTR-CM last year. Amvuttra is currently approved to treat hereditary ATTR-polyneuropathy, which affects the nervous system. By Alnylam’s estimate, ATTR-CM is about ten times more prevalent than hereditary ATTR-polyneuropathy. “We believe expansion of Amvuttra’s label to include ATTR-cardiomyopathy represents a major inflection point in our journey towards becoming a top-tier biopharma company,” Greenstreet said. “The results of HELIOS-B show the true power of the RNAi mechanism of action, supporting what we believe to be a highly differentiated therapeutic profile and positioning vutrisiran as a new standard of care in ATTR-cardiomyopathy,” Greenstreet added. The big question heading into the HELIOS-B readout was not whether Amvuttra could beat placebo as a monotherapy but whether it could add benefits on top of Pfizer’s tafamidis. The combination data are considered important because doctors have viewed tafamidis as tough to displace in the treatment paradigm. In 2023, the tafamidis family brought Pfizer $3.3 billion in global sales, a 36% increase from the prior year. While the HELIOS-B overall population hit statistical significance, the exact numbers in the tafamidis combo subgroup remain unknown. On the Monday conference call, Alnylam’s chief medical officer, Pushkal Garg, M.D., was only willing to say that the company saw “evidence of additive effects” in the combination group. Meanwhile, Alnylam also highlighted Amvuttra’s power as a single agent by pointing to its ability to reduce the risk of death. “For a disease where the median survival is two and a half to five and a half years, what patients and physicians really want is a clear impact on mortality,” Alnylam’s chief commercial officer, Tolga Tanguler, said on the call. Amvuttra showed similar benefits in the monotherapy and overall groups in cutting patients’ risk of death from any cause, posting reductions of 34.5% and 35.5%, respectively, up to month 42. Amvuttra’s overall treatment effects “manifest early,” and its separation from placebo on the mortality benefit “grows over time, just as you would expect,” Garg said. Because of different patient characteristics, Amvuttra’s death reduction data are difficult to compare to tafamidis’ analysis in the phase 3 ATTR-ACT trial, in which the Pfizer drug slashed the risk of death by 30% compared with placebo. The two trials were conducted years apart, and the supportive care for ATTR-CM has also evolved. In addition, no specifics about the actual number of deaths were shared from HELIOS-B, making the comparison even more difficult. Amvuttra works by reducing the circulating levels of the TTR protein and hence disease-causing amyloid deposition in the heart and nerves, whereas tafamidis stabilizes TTR. Alnylam has argued that Amvuttra’s RNA-silencing mechanism means its treatment effects may expand over time. Alnylam will need to emphasize Amvuttra’s single-agent activity because, as Tanguler noted, payers will likely only cover ATTR-CM monotherapy offerings for the next several years. Analysts and doctors have previously said it would be difficult for payers to reimburse a combination of tafamidis and Amvuttra, given both are pricey innovative drugs. Amvuttra is administered under the skin by a healthcare professional every three months, a schedule that Tanguler said aligns with patients’ frequency of doctor visits. The Vyndaqel drugs are taken orally once daily. That dosing method could give Amvuttra an advantage to lower out-of-pocket costs for patients, he added. The HELIOS-B study also showed statistically significant improvements for Amvuttra on all secondary endpoints. These measures included a six-minute walk test, the patient self-reported Kansas City Cardiomyopathy Questionnaire (KCCQ) and the New York Heart Association (NYHA) Class, a heart failure staging classification, at month 30. “These remarkable results of vutrisiran in a contemporary population of patients with ATTR-cardiomyopathy with clinical benefits seen on every single one of these rigorous set of endpoints highlight the power of RNAi mechanism of action, and suggest that vutrisiran has the potential to become the new standard of care,” Garg said. Alnylam has submitted the detailed HELIOS-B results as a late-breaking abstract to the European Society of Cardiology for presentation. The company plans to submit for regulatory approvals later this year, including using a priority review voucher for its FDA application.

− Achieved 28% and 33% Reduction in Composite of All-Cause Mortality and Recurrent Cardiovascular Events in the Overall and Monotherapy Populations, Respectively – − Reduced All-Cause Mortality by 36% and 35% in the Overall and Monotherapy Populations, Respectively, in a Pre-Specified Secondary Endpoint – − Demonstrated Clinically Significant Benefits on 6-Minute Walk Test, Kansas City Cardiomyopathy Questionnaire and NYHA Class – Key Measures of Disease Progression – − Observed Consistent Effects in All Key Subgroups, Including Baseline Tafamidis – − Demonstrated Encouraging Safety, Consistent with Established Profile – − Alnylam to File a U.S. Supplemental New Drug Application Using a Priority Review Voucher – − Alnylam to Host Conference Call Today at 8:00 am ET – CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive topline results from its HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM). The study met the primary endpoint, demonstrating a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular (CV) events during the double-blind period in both the overall population (HR 0.718, p-value 0.0118; n=654) and in the monotherapy population (patients not receiving tafamidis at baseline; HR 0.672, p-value 0.0162; n=395). The study also demonstrated statistically significant improvements across all secondary endpoints in both the overall and monotherapy populations. This includes key measures of disease progression: 6-minute walk test (6-MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ) and New York Heart Association (NYHA) Class at Month 30 (p<0.025 for all). Importantly, treatment with vutrisiran also reduced all-cause mortality in the overall population (HR 0.645, p<0.025) and in the monotherapy population (HR 0.655, p<0.05) up to Month 42. This was a pre-specified, intent-to-treat analysis that included up to six months of data from the open-label extension. “I’m thrilled by these overwhelmingly positive data from the HELIOS-B study, which suggest that vutrisiran has the potential to address the needs of patients with ATTR amyloidosis with cardiomyopathy, a steadily progressive, debilitating, and ultimately fatal disease,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “The results showed that vutrisiran improved cardiovascular outcomes, including survival, function and quality of life in all patient groups with ATTR cardiomyopathy. We are moving with urgency to compelling data with regulators to bring this medicine to patients around the world.” In addition, vutrisiran demonstrated consistent effects on the primary composite endpoint and all secondary endpoints across all key subgroups, including baseline tafamidis use, ATTR disease type and measures of disease severity. In the HELIOS-B study, vutrisiran demonstrated encouraging safety and tolerability, consistent with its established profile. Rates of adverse events (AEs), serious AEs and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. No AEs were seen ≥3% more frequently in the vutrisiran arm compared to the placebo arm. “I am overjoyed by the results of the HELIOS-B study, which suggest the potential for vutrisiran to be a transformative medicine for patients with ATTR amyloidosis with cardiomyopathy,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “Assuming favorable regulatory review, vutrisiran has the potential to become the new standard of care for the treatment of this disease, driving Alnylam’s next era of substantial growth.” HELIOS-B (NCT: NCT04153149) is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the efficacy and safety of vutrisiran on the reduction of all-cause mortality and recurrent cardiovascular events as a primary composite endpoint in patients with ATTR amyloidosis with cardiomyopathy in the overall and monotherapy populations. The study randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized 1:1 to receive vutrisiran 25mg or placebo subcutaneously once every three months during a double-blind treatment period of up to 36 months. After the double-blind period, all eligible patients remaining on the study may receive vutrisiran in an open-label extension period. Detailed results from the HELIOS-B study have been submitted as a late-breaking abstract to the European Society of Cardiology for presentation. The Company plans to proceed with global regulatory submissions starting later this year, including filing a supplemental New Drug Application with the U.S. Food and Drug Administration using a Priority Review Voucher. Investor Webcast Information Management will discuss the HELIOS-B topline results via conference call on Monday, June 24, 2024, at 8:00 am ET. To access the call, please register online at . Participants are requested to register at a minimum of 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live audio webcast of the call will be available on the Investors section of the Company’s website at . An archived webcast will be available on the Company’s website approximately two hours after the event. IMPORTANT SAFETY INFORMATION Reduced Serum Vitamin A Levels and Recommended Supplementation AMVUTTRA® (vutrisiran) treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). Adverse Reactions The most common adverse reactions that occurred in patients treated with AMVUTTRA for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) were arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). For additional information about AMVUTTRA, please see the full Prescribing Information. 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. About AMVUTTRA® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of mutant and wild‑type transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection, 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. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), which encompasses both wild-type and hereditary forms of the disease. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. 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) 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 and engage with us on X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram. Alnylam Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, Alnylam’s expectations regarding the safety and efficacy of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, including its potential to be a transformative medicine for patients with ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to become the new standard of care for the treatment of ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to obtain regulatory approval for the treatment of ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to drive Alnylam’s next era of substantial growth; the expected timing of the presentation of full data from the HELIOS-B clinical trial and the filing of a U.S. Supplemental New Drug Application for vutrisiran; Alnylam’s plans to use a Priority Review Voucher in connection with the Supplemental New Drug Application for vutrisiran; the potential for vutrisiran’s clinical pro support first-line positioning in newly diagnosed patients and in those patients who continue to experience disease progression with stabilizers; and the potential for Alnylam to achieve its Alnylam P5x25 vision of becoming a leading biopharma company should be considered forward-looking statements. 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, risks and uncertainties relating to: Alnylam’s ability to successfully execute on its “Alnylam P5x25” strategy; Alnylam’s ability to successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; and any delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2023 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q 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.