Full study data back Alnylam heart drug’s benefit, but leave doctors with tough choices

Two months ago, Alnylam Pharmaceuticals revealed that a medicine it’s been developing for people with a deadly heart condition succeeded in a closely watched clinical trial.

On Friday, the biotechnology company is presenting fuller study findings its leaders claim are evidence the drug should become the new standard of care for the disease, called transthyretin amyloidosis cardiomyopathy.

But doctors interviewed by BioPharma Dive, while impressed with the benefits shown in the study, aren’t sure such a shift will play out as readily as Alnylam hopes. They highlighted questions that could still leave them with difficult treatment decisions.

The results are from a study named Helios-B that tested Alnylam’s drug, vutrisiran, against a placebo over several years. In June, Alnylam said trial participants who received vutrisiran had a 28% lower risk of a recurrent cardiovascular event or death from any cause than those given placebo. Treatment was also associated with a 33% risk reduction among people who weren’t on the only available drug for the condition, Pfizer’s tafamidis, at the study’s start. Investigators recorded benefits on multiple secondary measures of heart health, Alnylam said at the time.

But the summary data didn’t include details that would have allowed doctors and analysts to comprehensively assess vutrisiran’s performance.

They’ve been anticipating such data since then and, on Friday, full results were published in The New England Journal of Medicine. Alnylam is simultaneously presenting them at the European Society of Cardiology’s annual meeting. The NEJM paper includes granular details on the study’s main and secondary study measures, and charts the time in which vutrisiran made an impact on patients’ survival and heart health.

Multiple doctors who reviewed the data at BioPharma Dive’s request had a positive view of the findings. “These are pretty remarkable results,” said Mazen Hanna, a cardiologist at the Cleveland Clinic, who wasn’t involved with the trial. Hanna has previously consulted with Alnylam and Pfizer.

“It’s a clearly positive, clinically meaningful trial in a contemporary [group of patients],” added Kevin Alexander, an assistant professor of cardiovascular medicine at Stanford Health Care. Alexander has also consulted with drugmakers in the past, among them Alnylam.

Hanna noted how about 40% of the people in Alnylam’s trial were already taking tafamidis and how, overall, participants were generally less sick than those involved in a key 2018 trial of Pfizer’s drug.

“From the get-go, the bar to try to show a benefit was going to be more difficult,” making it more impressive that Alnylam did, he said.

The results, and physicians’ view of them, are important to Alnylam’s future. The company is counting on vutrisiran to help it finally become consistently profitable after years of financial losses.

There are broader implications, too. Transthyretin amyloidosis cardiomyopathy — a disease in which the buildup of a toxic protein leads to heart failure and death — has become a crowded area of pharmaceutical research. Tafamidis, which Pfizer sells as Vyndamax and Vyndaqel, generated $3.3 billion in sales last year and may surpass that total in 2024. Another drug, called acoramidis and from BridgeBio Pharma, could be approved later this year. Multiple other treatments are in advanced testing.

Among the new information from Helios-B disclosed Friday was a more detailed accounting of how vutrisiran’s benefit evolved over time. The data show treatment reduced the relative risk of death by 31% up through 36 months — during the “double-blind” period during which the study’s primary objective was tabulated — and by 36% after 42 months.

Among participants not on tafamidis, investigators calculated a 30% reduction in the relative risk of death up through three years among the participants, but that difference versus placebo was not statistically significant.

At 30 months, people treated with Alnylam’s drug performed better on a walking test correlated with heart health. Participants on vutrisiran walked about 7.5 meters less at the study’s end than they did at the start, compared to a roughly 31-meter decline for those on placebo. Drug recipients scored an average of about six points better than the placebo group on a questionnaire evaluating their quality of life, while levels of a marker tied to disease progression were relatively stable versus placebo.

Rates of adverse events, serious adverse events and side effects leading to study discontinuation were similar between drug and placebo arms. Cardiac side effects with vutrisiran were also similar or lower than placebo, according to Alnylam.

Alnylam views the results as a “grand slam,” said Chief Medical Officer Pushkal Garg, in an interview. Vutrisiran hit all ten of its prespecified study objectives and, in doing so displayed “really clear and unequivocal benefits,” he said.

The study wasn’t powered to show statistical differences across patient subgroups. Still, investigators reported favorable trends across each one, including signs that adding vutrisiran to tafamidis could improve outcomes.

“It’s clear that there’s efficacy being left on the table” with tafamidis alone, said Garg.

Yet Alnylam’s drug hasn’t been directly compared to tafamidis or acoramidis, which stabilize the misfolded protein that causes the disease instead of silencing its molecular blueprint as vutrisiran does. Acoramidis was also recently tested in a group of people who more closely reflect those currently being diagnosed with the disease. It had a meaningful impact on survival and hospitalizations in its Phase 3 trial as well.

“We are hopeful that [vutrisiran] is going to be a significant game changer,” but “I don’t think I can say right now” whether it’s superior to other medicines, said Jose Alvarez-Cardona, a cardiologist and assistant professor at New York University Langone’s department of medicine.

Wall Street analysts have focused on how quickly vutrisiran’s survival benefit became apparent in the trial as an important clue as to what doctors will ultimately decide. Ahead of the meeting, Stifel analyst Paul Matteis wrote that a clear, early effect on survival would confirm a “best-in-disease profile” for Alnylam’s drug, possibly opening up broad commercial use as the preferred option for newly diagnosed patients.

But the study groups in each trial are so different that such comparisons may be an “overinterpretation,” according to Alexander.

“The trial wasn’t designed to answer that question,” he said, which is why he and others are bracing for tough discussions about who gets treated with which drug.

“Should you start both medicines at the same time? Should you just start this medicine? Tafamidis? I don’t know what the right answer is, to be honest,” said Mohammad Abuannadi, an associate professor of cardiology at UVA Health.

Abuannadi noted how cost will be an important factor, as tafamidis costs over $250,000 per year at list price and vutrisiran, which is already approved for another form of the disease, has a wholesale cost of more than $460,000.

Doctors will also have to figure out whether there’s a clear rationale for giving somebody a silencer therapy alongside a stabilizer, Alvarez-Cardona said. It’s unclear when a patient should switch from one therapy to another or what type of label the Food and Drug Administration might give, if it grants an approval.

“It’s going to be hard for us clinicians,” said Hanna. “The experts in the amyloidosis community are going to be left with tough decisions to make, without clear data to support our decisionmaking.”

Alnylam expects to file for vutrisiran’s approval in transthyretin amyloidosis cardiomyopathy this year and to potentially bring the drug to the U.S. market in 2025.

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