Preliminary data from a late-stage trial of Alnylam’s RNAi therapy for ATTR amyloidosis with cardiomyopathy appear strong but details expected later this summer are critical.
Unveiled late last month, topline results from a Phase III trial of Alnylam’s RNAi therapy Amvuttra in ATTR amyloidosis with cardiomyopathy are turning some heads. The treatment showed a statistically significant reduction in all-cause mortality and recurrent cardiovascular events.
“I expected this readout to be positive, but this was extremely positive,” said Kostas Biliouris, director and equity research analyst at Bank of Montreal Capital Markets. “I think the results reflect the best-case scenario.”
The initial results appear promising, but a clearer picture will emerge when the full data come out later this summer. Further details of the HELIOS-B study will be presented as an abstract at the European Society of Cardiology’s congress in London, taking place Aug. 30 to Sept. 2.
Paul Matteis, head of the therapeutics research team at Stifel, told BioSpace that not having those details is one of the biggest open questions at the moment. Amvuttra will have to face competition from Pfizer, whose ATTR-CM oral drugs Vyndamax and Vyndaqel were approved in 2019. The Vyndaqel family of drugs has earned blockbuster status, bringing in $1.1 billion in sales in the first quarter of 2024, a 66% boost from Q1 2023.
Research Outlook and the ATTR-CM Space
In the HELIOS-B trial, Amvuttra reduced the risk of mortality and recurrent cardiovascular events by 28% in patients also taking Pfizer’s Vyndamax compared to a placebo. Those only taking Amvuttra saw the risk drop by 33%. The risk of death from all causes, one of the secondary endpoints, was lowered by 36% in patients also taking Vyndamax, while it was reduced by 35% in those on Amvuttra monotherapy. Patients on Amvuttra also showed statistically significant improvements in other metrics, such as the six-minute walk test.
“Given the data we have right now, the totality of the data and the limited information . . . I believe this is potentially the best profile in ATTR cardiomyopathy,” Biliouris told BioSpace.
Matteis said Amvuttra is at least “tied at the top” based on the topline data but noted that the most significant caveat in comparing Amvuttra to Vyndamax or BridgeBio’s investigational drug acoramidis is that the duration of Alnylam’s study is longer, and the interest will be in what the data at 30 months look like. However, he noted it is unlikely that the 30-month data will suggest Amvuttra is worse than its competition.
“[Alnylam is] probably tied for first, in terms of the overall product offering and how compelling it is under the impetus to prescribe it,” he said.
Some experts have reservations about whether Amvuttra can challenge Pfizer, however. Myles Minter, a research analyst at William Blair, told BioSpace that Alnylam has “more work to do” as it is going up against Vyndamax, a safe drug with an “impressive” hazard ratio that has benefits in cardiovascular outcomes. He also claims that the “knock” on Amvuttra is that the clinical trials were done in patients who had much more severe cardiovascular events, which differs from when the drug would actually be prescribed.
“That’s not how the diagnosis is done today. So, we don’t have control data, like proper industry-standard control data against placebo in the patient population that we’re currently treating, which is early on in the treatment course,” Minter said.
He noted that the detailed data expected at the European Society of Cardiology’s congress later this summer will also help determine whether Amvuttra is competitive against the industry standard.
Amvuttra’s Financial Outlook
Minter said that right now, Amvuttra, which is only approved in polyneuropathy, is generating over $900 million in sales and growing 18% year over year from a patient population of between 30,000 and 60,000. The cardiomyopathy opportunity may allow Amvuttra’s population to expand 10-fold as more noninvasive diagnosis techniques are available for ATTR-CM, he said.
Minter estimates that the combined polyneuropathy and ATTR-CM peak sales of Amvuttra would be $3.7 billion in the U.S. and $1.8 billion in the European Union. Matteis projected peak drug sales of around $5 billion to $6 billion, but noted that the competition with Vyndamax will remain and said Pfizer’s drug will maintain its blockbuster status.
Another element of the financial equation is pricing. Amvuttra is currently priced much higher than Vyndamax, but Matteis said there is a “general expectation” that it will be lowered to some degree. He also added that there may be other “economic drivers” to Amvuttra, as a practice could make more money prescribing the drug because it is an in-office injection.
“There’s a chance where [Alnylam is] in pole position,” Matteis said. “But it is a little bit premature to draw that conclusion without seeing the full data.”
