Alnylam is circling the bases after walloping—in the words of chief medical officer Pushkal Garg M.D.—a “grand slam” with data that position its RNA silencer Amvuttra (vutrisiran) to potentially become a standard-of-care treatment for the rare heart disease transthyretin amyloid cardiomyopathy (ATTR-CM).
Alnylam on Friday provided detailed results from the phase 3 HELIOS-B study, which met all 10 of its primary and secondary endpoints in both its overall and monotherapy populations, bolstering the company's claim that Amvuttra will challenge Pfizer’s Vyndaqel (tafamidis) franchise. Alnylam shared the results at the European Society of Cardiology conference in London.
While Alnylam hailed the results, some analysts and investors took issue with the study findings. Mid-morning Friday, the company's shares were down about 7% as the results apparently failed to live up to expectations.
"Objectively this data appears to be short of the aforementioned investor bar," wrote Myles Minter, Ph.D., an analyst with William Blair.
In June, Alnylam made waves when it released top-line data from the trial. On Friday, the company filled in the blanks with mortality and cardiovascular hospitalization endpoint curves, additional data on subgroups, as well as complete results from a 6-minute walk test. Also presented were findings from the patient-reported Kansas City Cardiomyopathy Questionnaire (KCCQ), plus the New York Heart Association (NYHA) heart failure classification survey.
In the overall study group of 654 patients, including those who were on Pfizer's tafamadis, Amvuttra reduced the risk of death or recurrent cardiovascular events by 28% versus placebo. Of those in the monotherapy group—which comprised 60% of the patients in the trial—Amvuttra reduced the risk of death or recurrent cardiovascular events by 33% compared to placebo.
In one crucial dataset that analysts have been waiting for, Amvuttra reduced the risk of death or recurrent cardiovascular events by 22% in patients who were taking tafamidis at the start of the study. The siRNA therapy also led to a 41% reduction in all-cause mortality among tafamadis takers through 42 months versus placebo.
"It suggests that, while not head-to-head, that you're seeing very compelling efficacy from this agent," Garg said in an interview earlier this week.
"With the level of benefit, we think vutrisiran is well positioned both as monotherapy as well as add on to tafamidis, boding well for market uptake after generic tafamidis entry in 2028," analysts at Evercore ISI wrote in a note to clients.
Amvuttra started to show a survival benefit—as the all-cause mortality curves separated—in the overall study population at 18 months, which was in line with Pfizer's ATTR-ACT trial for tafamidis. For the group of patients in HELIOS-B who were using tafamidis at baseline, the curves separated at 24 months.
The study was statistically powered to measure Amvuttra as a monotherapy and in the overall trial population, but not specifically on the subgroup of patients who received both tafamidis and the Alnylam drug.
Still, the company believes that the results are overwhelming evidence that Amvuttra is transformative in the indication.
“We think this represents the potential for this drug to become the new standard of care for this disease, something that can be used front line in patients but also in those who are not optimally managed with current medicines as a switch therapy or even as an add-on over time,” Garg added.
Subgroup analyses also showed all-cause mortality reductions of up to 65% in newly diagnosed patients.
“We see disproportionate benefits in patients with earlier disease—those who are younger or have (less severe forms of the disease)—which really highlights the importance of getting the most effective treatment as early as possible,” Garg added.
In an additional endpoint, which was revealed in June, in the overall patient population there was a 36% reduction in the risk of death up to month 42, while in the Amvuttra monotherapy group, there was a 35% reduction in the risk of death over the same period.
Analysts at UBS continue to believe that Amvuttra has "first-line, best-in-class potential," and pointed out that its trial performance, versus that of tafamidis, came in a "healthier patient population" and "are highly supportive of vutrisiran's activity."
To this point, in addition to the 40% of patients on tafamidis at the baseline of HELIOS-B, 22% more of the participants began taking Pfizer’s drug during the course of the trial. On top of that, 30% of the patients were on an SGLT2 inhibitor.
“This was a pretty heady gauntlet for this drug to have to show a benefit on top of,” Garg said. “It really showed a remarkable benefit across the full spectrum of patients on some very, very hard endpoints.”
Alnylam plans to file for FDA approval of Amvuttra in ATTR-CM later this year and will use a priority review voucher, which will slice by four months the regulator’s standard 10-month appraisal period.
Amvuttra was approved in June of 2022 for ATTR-polyneuropathy, a condition which has roughly one-tenth the population size of ATTR-CM. Amvuttra generated sales of $558 million in 2023.
Meanwhile, Pfizer’s group of tafamidis drugs—which include Vydaqel, Vyndamax and Vynmac (outside the U.S.)—rang up (PDF) sales of $3.3 billion in 2023, which were up 36% in their fourth full year on the market.
As an RNA interference drug, Amvuttra may have a mechanism of action edge on tafamidis. While it reduces the circulating levels of the transthyretin (TTR) protein and hence the amyloid clumps in the heart, tafamidis works by stabilizing the TTR. Alnylam contends that Amvuttra’s treatment effects may expand over time.
"What we do is work upstream transthyretin and turn off production in the liver," Garg said. "We're stopping the disease-causing protein from being formed in the first place."
Still, challenging Pfizer’s entrenched, first-of-its-kind treatment will not be easy, according to a note two months ago from analysts at Leerink Partners, who cited the “ease of use, pristine safety and accumulated real-world data,” of tafamidis.
As for the ease of use, while vutrisiran is administered once every three months by way of injection, tafamidis is a daily pill.
Among other companies pursuing the emerging class of RNA interference drugs, Intellia and Ionis have what analysts viewed as one of the most promising investigative treatments. Alnylam’s first RNA silencer, Onpattro (patirisan), was approved for ATTR-polyneuropathy in 2018 but the FDA rejected it last year for ATTR-CM, overruling an advisory panel that recommended it for approval by a 9-3 vote.
While tafamidis remains the only drug on the market for ATTR-CM, competition is likely on its way in the indication from BridgeBio as the FDA is reviewing its application for TTR stabilizer acoramidis.
Friday, analysts at ISI Evercore said that while the data on Amvuttra were "obviously positive," the idea that the drug "would emerge the undisputed best-in-class therapy appears to be fading." Likewise, Mizuho's Salim Syed wrote in a note he'd seen "nothing suggestive that vutrisiran is better" than acoramidis. BridgeBio's shares jumped 10% in the wake of Alnylam's data release.