Patisiran sodium

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.

Pictured: Alnylam's headquarters building in Massachusetts/iStock, hapabapa Alnylam Pharmaceuticals on Monday revealed topline data from the Phase III HELIOS-B study, showing that its RNAi therapy Amuvttra (vutrisiran) can significantly lower the risk of death and recurrent cardiovascular events in transthyretin amyloidosis patients with cardiomyopathy. Alnylam CMO Pushkal Garg in a statement said the company is “thrilled” by the “overwhelmingly positive data” from HELIOS-B, which point to the potential of Amvuttra to be an effective treatment option for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). “The results showed that vutrisiran improved cardiovascular outcomes” as well as survival and quality of life in patients, according to Garg. “We are moving with urgency to compelling data with regulators,” Garg said. Alnylam is looking to submit its global regulatory applications—including a supplemental New Drug Application with the FDA—later this year. The company has also submitted these data as a late-breaking abstract to the European Society of Cardiology for presentation at its upcoming medical meeting. HELIOS-B is a randomized, double-blinded and placebo-controlled study that enrolled 655 ATTR-CM patients. During a double-blind period lasting up to 36 months, patients were given a 25-mg subcutaneous dose of Amvuttra or placebo once every three months. Eligible patients still on the study were then allowed to receive Amvuttra during an open-label extension period. At the study’s baseline, some of the patients were being treated with Pfizer’s Vyndamax (tafamidis), an FDA-approved oral therapy for ATTR-CM. In these patients, Amvuttra reduced the risk of all-cause mortality and recurrent cardiovascular events by 28%. In those who were being treated with only Amvuttra, risk reduction for the composite endpoint was 33%. Alnylam’s RNAi therapy also aced key secondary endpoints. Death from all causes was lowered by 36% in patients with Vyndamax exposure at baseline, and by 35% in patients treated with Amvuttra monotherapy. Amvuttra, whether as a monotherapy or in the overall patient population, also significantly improved six-minute walk distance and New York Heart Association classification, among other measures of disease progression. Designed to be administered as a subcutaneous injection, Amvuttra is a small-interfering RNA therapeutic that targets both mutant and wild-type transthyretin mRNA, tagging it for degradation. Amvuttra lowers serum levels of the transthyretin protein and counters the accumulation of its misfolded forms across the body, including the heart, helping to address the underlying pathological pathway in ATTR-CM. Stifel analysts in a Monday note to investors said they believe the topline HELIOS-B data “are highly positive and support vutrisiran becoming a blockbuster in TTR-cardiomyopathy,” adding that “what stands out the most is the highly robust benefit on top of tafamidis.” The FDA first approved Amvuttra in June 2022 for the treatment of ATTR amyloidosis with polyneuropathy—a similar condition where the misfolded transthyretin proteins afflict the nerves instead of the heart. If the FDA approves its label expansion, Amvuttra would help Alnylam recoup from the regulator’s rejection in October 2023 blocking the use of Onpattro (patisiran) in ATTR-CM. The regulator at the time said that Alnylam had not sufficiently established the benefit of the siRNA therapy in ATTR-CM. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.