Alnylam Pharmaceuticals has landed a long-awaited FDA decision that expands use of its drug, Amvuttra, to the treatment of a type of cardiomyopathy that’s growing in prevalence. It’s the second FDA approval in this indication in four months and the third overall, introducing new competition to the treatment of a disease that leads to heart failure and frequent hospitalizations, often becoming fatal within five years of diagnosis.
Amvuttra is now approved for treating adults who develop cardiomyopathy from transthyretin amyloidosis (ATTR), a disease in which abnormal versions of the liver protein transthyretin (TTR) lead to buildup of amyloid proteins in body tissue. The regulatory decision announced late Thursday covers ATTR cardiomyopathy that develops naturally as well as disease that is hereditary. Amvuttra is the third medication approved for ATTR cardiomyopathy, behind products from Pfizer that have become the standard of care and a BridgeBio Pharma drug approved last fall. But Amvuttra introduces a new mechanism of action to the disease.
Cambridge, Massachusetts-based Alnylam specializes in RNA interference drugs, therapies that deliver small pieces of RNA to “silence” a gene, knocking down production of a disease-causing protein. Amvuttra is designed to lower levels of the TTR proteins that drive ATTR. The drug, administered as an injection every three months, was first approved in 2022 as a treatment for polyneuropathy caused by the disease.
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FDA approval of Amvuttra in ATTR cardiomyopathy is based on data from a placebo-controlled Phase 3 study, HELIOS-B, whose main goal was measuring death from all causes and recurrent cardiovascular events. The results on this composite endpoint showed Amvuttra achieved the statistically significant 28% reduction during the treatment period of up to 36 months. On a secondary goal measuring mortality, results showed a 36% reduction through 42 months. Results were published last August in the New England Journal of Medicine.
“We believe Amvuttra has the potential to become a new standard of care in ATTR cardiomyopathy,” Alnylam CEO Yvonne Greenstreet said, speaking during a Thursday evening conference call. “Our confidence stems from the success of the HELIOS-B study, which demonstrated a therapeutic profile for Amvuttra that is supportive of first-line potential.”
Pfizer won the first FDA approvals in ATTR cardiomyopathy in 2019. Its drug, tafamidis, marketed as Vyndaqel (a four-times-a-day capsule) and Vyndamax (a once-daily capsule), binds to mutant TTR protein, stabilizing it in order to prevent the protein buildup characteristic of ATTR. Though this Pfizer small molecule is approved in other countries for treating ATTR polyneuropathy, its U.S. approval only covers cardiomyopathy caused by the disease. Pfizer reported $5.5 billion in global sales for the Vyndaqel family of products in 2024, a 65% increase over the prior year. Most of the product’s revenue comes from the U.S.
FDA approval of BridgeBio drug Attruby last November brings new cardiomyopathy competition. The twice-daily pill won European regulatory approval last month. Like the Pfizer drugs, Attruby is a TTR stabilizer. But BridgeBio contends its drug is the better stabilizer, with product label language stating the pill achieves “near-complete stabilization” of the target protein.
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Acknowledging the caveats that come with cross-trial comparisons, some differences could affect how prescribers and patients view these therapies. The reduction in cardiovascular hospitalizations and urgent heart failure visits with Amvuttra were well below what Attruby showed in its trial, Leerink Partners analyst Mani Foroohar wrote in a note sent to investors Friday. But William Blair’s Myles Minter highlights the Alnylam drug’s data on all-cause mortality as an edge over Attruby, which did not achieve statistical significance on this measure in its pivotal study. The label of Pfizer’s tafamidis includes a mortality benefit.
“Given [all-cause mortality] claims and the totality of data in Amvuttra’s label, which derives from a patient population of whom some were on background tafamidis treatment, we see Amvuttra as a best-in-class option for patients and healthcare providers,” Minter said.
Minter added that subgroup analyses show Amvuttra use was favored across patient populations, including younger and healthier patients that reflect the current disease population. William Blair believes the Alnylam drug is well positioned for first-line use in these patients.
One headwind for Amvuttra is its price. For ATTR cardiomyopathy, Alnylam said Amvuttra will carry the same wholesale price as it does in ATTR polyneuropathy, which is about $119,000 per injection or $476,000 annually. In an investor presentation, the company said the product’s net price will decrease over time as uptake of the drug increases. But for now, patients will have less expensive options with Pfizer’s ATTR cardiomyopathy drugs, which carry a $267,987 annual list price, and BridgeBio’s Attruby priced at $244,500 a year.
With a significantly higher list price, Leerink analysts expect challenges getting payers to cover Amvuttra in the new indication. But William Blair analysts see Amvuttra’s label as strong enough to secure broad payer coverage. The firm also sees quarterly injections as an advantage because this dosing regimen boosts compliance compared to needing to remember to take a pill every day.
Amvuttra’s approval in cardiomyopathy offers the opportunity to address a much bigger market than polyneuropathy, one that Alnylam estimates is 300,000 patients globally. Furthermore, most of these patients undiagnosed, offering opportunity the company the opportunity to reach new patients.
In 2024, Alnylam reported Amvuttra accounted for $970.5 million in revenue in the polyneuropathy indication. With the new approval, the company expects $1.6 billion to $1.725 billion in TTR product revenue this year. Though Amvuttra is already available for polyneuropathy, Alnylam is projecting a second-half 2025 launch for the drug as the company continues discussions with payers on value-based agreements for Amvuttra and secures formulary placement for the drug in its new indication.
Amvuttra is still under review in other countries. Alnylam expects a regulatory decision in Japan in the second quarter of this year; additional decisions in Europe, Brazil, and Canada are expected later this year. In the nearer term, Alnylam is set to present additional Amvuttra data during the American Cardiology Conference in Chicago at the end of March.
Photo by Alnylam Pharmaceuticals