Tafamidis Meglumine

After releasing pivotal trial data for Amvuttra in transthyretin amyloid cardiomyopy (ATTR-CM), Alnylam is ready to pursue a label expansion and play ball with Pfizer in a market showdown. 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. Later this year, Alnylam is kicking off a phase 3 study designed to show the value of Amvuttra and tafamidis as a combination treatment.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.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.

Alnylam Pharmaceuticals is continuing to make its case for vutrisiran to become the drug of choice for a heart muscle disease, and while the company reported positive results at a major medical meeting Friday, they still leave questions about vutrisiran’s potential place on the market. Vutrisiran is an siRNA drug that won FDA approval in 2022 for a rare neurological condition, and it’s sold under the brand name Amvuttra. Alnylam is looking to unlock the drug’s blockbuster potential through a label expansion for transthyretin amyloid cardiomyopathy (ATTR-CM), which affects more than 120,000 people in the US, according to ICER. Vutrisiran has a lot to prove in a market that’s been dominated solely by Pfizer’s transthyretin stabilizer Vyndaqel since 2019, with BridgeBio’s acoramidis following close behind. When the company unveiled topline data from the Phase 3 HELIOS-B trial in ATTR-CM in June, CEO Yvonne Greenstreet described them as “really, really tremendous data” and said the drug could become a new standard of care for the disease. But a closer look at patient outcomes and survival, particularly in the monotherapy arm, suggests that the door is still open for competition. “It’s going to be a very hard call” for doctors to choose between Alnylam and Pfizer’s drugs based on the latest data, Angela Dispenzieri, consultant in the division of hematology at Mayo Clinic, told Endpoints News in an interview. Alnylam shares $ALNY fell close to 7% at market open Friday, while BridgeBio $BBIO rose about 5%. At the European Society of Cardiology annual meeting in London, an investigator broke down the results of the composite co-primary endpoints of freedom from cardiovascular events and all-cause mortality in the overall population and vutrisiran monotherapy subgroups. In the monotherapy group, placebo patients fared slightly better than vutrisiran patients for around the first three months. The curves then start to separate in favor of vutrisiran. Dispenzieri said that although it’s likely that the curves will separate even more with time, the way they cross is unusual. In a key secondary endpoint, the subgroup of 395 patients who only took vutrisiran saw a 30% risk reduction relative to placebo in all-cause mortality at up to 36 months (p=0.1179). According to its label , Vyndaqel was linked with a 30% relative reduction in the risk of death at 30 months compared to placebo in its registrational trial. But the Pfizer study notably enrolled patients who were slightly sicker at baseline, Dispenzieri said. “If you have to choose [between the two drugs], it’s going to be cost,” Dispenzieri said. And as a small-molecule medicine, Vyndaqel will likely have a cost advantage over a siRNA like vutrisiran. Another major question has been whether there’s added benefit to using the treatments together — in other words, if vutrisiran adds enough to be worth the additional cost and complexity. Alnylam says the new data could offer an answer. An analysis of the 40% of patients in the 655-participant trial who were also taking Pfizer’s Vyndaqel at baseline showed a 41% reduction in all-cause mortality by 42 months. Alnylam has suggested they have the data to support combination treatments, even if payers may be less enthusiastic. “You’re seeing some evidence of additive efficacy, and I think that suggests [the transthyretin stabilizers] are not fully meeting the needs of patients,” Alnylam Chief Medical Officer Pushkal Garg told Endpoints in an interview ahead of the meeting. But there are likely to be questions about these results. The combination analysis wasn’t powered for statistical significance, which will likely raise at least some doubts about if the effect is as strong as the numbers suggest. While the subgroup data are “very interesting and promising,” they will need to be confirmed in a larger group of patients, Bianca Rocca, associate professor of pharmacology at the Catholic University of Rome, told Endpoints in an interview ahead of the meeting. Raj Dasgupta, chief medical advisor for Fortune Recommends Health, told Endpoints in an email statement that he thinks it’s unlikely many patients will take the drugs together in the real world because the efficacy of the combination is still “unclear” and “insurance companies would probably not cover both drugs at the same time.” In June, topline data from HELIOS-B released showed the trial met its co-primary endpoints , with vutrisiran slashing the risk of death, heart-related hospital visits and hospitalizations by 28% compared with placebo at 33 months. In the subgroup of 395 patients taking vutrisiran monotherapy, the drug cut the risk of these events by 33%. The monotherapy group’s role in the trial’s primary endpoint was a relatively new addition that Alnylam introduced in February as part of a broader package of protocol changes. It also added three months to the primary endpoint timeframe from the original 30-month period. The changes caused the stock to dip. In defending the decision later that month, Greenstreet told Endpoints that they would allow the company to show a greater difference between the effects of drug and placebo. Alnylam plans to file for label expansion for ATTR-CM in the US by the end of the year, with a potential approval expected in the first half of 2025, Alnylam’s Garg said. While many prescribers are already familiar with the drug from its current indication — polyneuropathy caused by hereditary transthyretin-mediated amyloidosis — the company will continue its disease education efforts to ensure a smooth rollout in ATTR-CM, he added. Last year, BridgeBio unveiled data from a Phase 3 test of its small molecule transthyretin stabilizer acoramidis in patients with ATTR-CM which showed the drug cut the rate of hospitalization in half. Acoramidis was also linked with a 25% relative risk reduction in mortality versus placebo at 30 months. In March, Bayer bought the European rights to BridgeBio’s drug for $310 million in upfront and near-term milestones. Acoramidis is currently under review in Europe with an approval anticipated next year while an FDA decision is expected by Nov. 29 . The asset could reach $3 billion in peak sales, TD Cowen analysts said earlier this month. Amvuttra made $230 million in the second quarter of the year, but Wall Street analysts say it has the potential to hit $2 billion to $4 billion in annual sales. Editor’s note: This story has been updated throughout to incorporate more data from the monotherapy subgroup of HELIOS-B and a doctor’s comments.