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.
Angela Dispenzieri“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.
Added benefit on combination
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.
Pushkal Garg“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.”
BridgeBio ahead in regulatory journey
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%.
Yvonne GreenstreetThe 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.