FDA panel backs Alnylam drug despite doubts over benefit

Advisers to the Food and Drug Administration on Wednesday endorsed Alnylam Pharmaceuticals’ drug Onpattro for a rare heart condition, despite questions from agency scientists over the degree of benefit offered by the RNA-based therapy.

The advisory committee’s 9-3 vote sets up a decision by the regulator on the drug’s approval for the condition, which is caused by buildup of a misfolded protein that damages the heart and other organs. In 2018, the FDA approved Onpattro to treat nervous system damage caused by the same toxic buildup of the protein, called transthyretin or TTR.

Onpattro is designed to stop production of the mutated protein by interfering with the RNA messages that instruct cells to make TTR.

In a trial called APOLLO-B, Alnylam sought to prove that Onpattro could help people who had cardiomyopathy caused by the mutated TTR. Participants in the study completed a walking test for six minutes. At the end of the study, researchers detected a statistically significant difference of 15 meters between people given Onpattro and those who received a placebo.

But, at Thursday’s meeting, FDA officials and some of the assembled experts questioned whether that difference was actually meaningful to patients.

The study also involved a questionnaire that asked participants to assess how the disease affects their functioning and quality of life. There, too, treatment was associated with a statistically significant benefit for Onpattro, which FDA staff and a few advisers challenged.

Another drug called tafamidis — sold by Pfizer as Vyndaqel and Vyndamax — is also approved for cardiomyopathy from TTR amyloidosis, and has shown a heart and survival benefit in testing. The APOLLO-B trial, by comparison, hasn’t run for long enough to definitively measure survival.

Alnylam executives noted how patients also care about measures like walking endurance. “Patients say that quality of life is their most important goal of therapy and what they’re most afraid to lose,” said Ronald Witteles, a Stanford University cardiologist who spoke on behalf of Alnylam at the meeting. “I see clear evidence that [Onpattro] fundamentally alters the progression of disease.”

Broadly, results from APOLLO-B show the drug worked in study participants. But in female participants there was no difference on the walking test and questionnaire between patients taking Onpattro versus placebo, while in Black trial volunteers there was no comparative difference in questionnaire scores. Additionally, the study didn’t show a clear benefit on the walking test among patients already taking tafamidis at the trial’s start.

However, all of those subgroups were small compared to the study’s overall enrollment of 359 volunteers, meaning there was not enough people to formally test for a statistical advantage.

The FDA only asked advisers to judge whether the benefits of Onpattro outweigh the risk in the TTR-driven cardiomyopathy. The three members who voted against pointed to the drug’s relatively small benefit and warned that, if approved, patients might choose Onpattro over tafamadis, which is backed by data showing it prevents heart complications and death.

“I did not feel that there was benefit. Using existing clinically relevant thresholds, none of them met what we would typically use in cardiology,” said C. Noel Bairey Merz, a cardiologist at Cedars-Sinai Medical Center and a panel member. Bairey Merz said the risk-benefit balance “was upset not by risks but by potential harm” for patients who might benefit from tafamadis instead.

The majority who supported Onpattro pointed to the low occurrence of side effects, as well as the small differences on the quality-of-life tests. “There is a light wind for benefit, and no wind for risk,” said Edward Kasper, a Johns Hopkins University cardiologist, who voted yes. “So if you’re asking if the benefits outweigh the risk, the answer is yes.”

The FDA has set a deadline of Oct. 8 to decide on approval. The FDA doesn’t have to follow the recommendations of its advisory committees, but it often does.

Approval of Onpattro in a new indication could help Alnylam reach profitability, a metric which has eluded it despite the company winning approval for four drugs. The company lost more than $1 billion in 2022 and recorded losses of $450 million through the first six months of 2023.

The FDA’s discussion at the advisory committees was “consistently negative,” Stifel analyst Paul Matteis wrote in a post-meeting note to clients, indicating he believed an FDA rejection could be in the cards.

“Ultimately panel votes are non-binding — FDA can do what it wants, and we wouldn’t be surprised either way,” he wrote. “In turn, [Alnylam] shares may be volatile as the Onpattro probability of label expansion is arguably 50/50 now.”

Alnylam shares fell 9% Thursday morning after a trading halt during the advisory committee meeting.

Editor’s note: This story has been updated to note the change in Alnylam’s stock price. 

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