Inside the Bungled FDA Drug Approval of Relyvrio for Treating ALS

When Prudence Runyan, 71, lost control of her pitch while singing, she attributed it to a lack of practice, or simply aging. But when reaching the higher notes at her church choir practice became impossible, the ex-professional singer from East Windsor, New Jersey, who had once commanded ballads in musicals, grew concerned.

Seven months later, Runyan was diagnosed with amyotrophic lateral sclerosis, or ALS—a fatal neurodegenerative condition that affects chewing, talking and walking, progresses to paralysis and culminates in respiratory failure, typically within three to five years. An estimated 30,000 Americans live with ALS, sometimes referred to as Lou Gehrig’s disease.

“I was just kind of numb; it was the news I expected,” Runyan typed into the chat box of a video call during an interview with The Daily Beast. Since her diagnosis in spring, words have become muffled noises. It had taken a year of symptoms before she got answers, meanwhile her condition was deteriorating. There is no known cure.

On Sept. 29, the Food and Drug Administration approved Relyvrio from Amylyx Pharmaceuticals. It’s the first ALS medication to be approved in five years, and only one of three currently prescribed to patients to slow progression of the disease. An FDA advisory committee voted 7-2 in favor of recommending the drug’s approval, after a single phase 2 trial of 137 ALS patients found Relyvrio could help patients survive an estimated 10.6 more months, according to Amylyx’s analyses.

That may not seem like very much for the average person, but “10 months can mean going to a wedding. It can mean seeing the birth of a child or graduation,” Calaneet Balas, CEO and president of the ALS Association, told The Daily Beast.

“It’s been welcome news for us, who’ve been really hammering the FDA to be a little more flexible in their approval process when it comes to unmet needs,” Steve Kowalski, a 58-year-old diagnosed with ALS five years ago, told The Daily Beast. “Because we have a pretty big risk tolerance, you know, having a fatal illness.”

Relyvrio’s approval was fairly unusual. The FDA typically doesn’t sign off on new drugs until after the completion of a phase 3 clinical trial—the tests that actually assess whether a drug provides a better benefit than what is currently available. Relyvrio falls under the category of “priority review” meaning the FDA’s goal is to take action on an application within six months rather than 10.

But Relyvrio’s approval was based on a single, fairly small, fairly short phase 2 trial—unusual even for priority review, said Richard Bedlack, a neurologist at Duke University who supports the approval.

10 months can mean going to a wedding. It can mean seeing the birth of a child or graduation.

Calaneet Balas, The ALS Association

The FDA declined to answer The Daily Beast’s questions about why Relyvrio was afforded “priority review” and how often drugs are approved after a single phase 2 trial. A larger phase 3 trial is currently underway, but the results won’t be available until 2024.

On the surface, it would be easy to laud this as a victory for the tens of thousands of ALS patients looking for just a bit more time. But the story behind Relyvrio’s testing and approval isn’t so cut-and-dry. There are questions over efficacy that neither the drug’s makers nor the FDA are yet able to answer, creating downstream concerns that a company could charge exorbitant costs for an ineffective drug. But if Relyvrio is proven to be successful, the price for erring on the side of caution is losing months of life.

For ALS patients, very few victories come with caveats.

How We Got Here

The FDA itself admitted in a summary memorandum on Relyvrio’s approval that when it comes to the drug’s clinical trial results, “there are limitations to these findings that result in a degree of residual uncertainty about the evidence of effectiveness.” Back in March, the same FDA advisory committee that approved the drug had voted 6-4 that the phase 2 trial was insufficient to prove efficacy. “In terms of establishing the conclusion that it’s effective, we were asked to look for substantial evidence with persuasiveness and robustness and I think this one trial doesn’t quite meet that bar,” committee member Dr. Kenneth Fischbeck, who studies hereditary neurological diseases at the National Institutes of Health, stated at the March meeting.

However, the committee was asked to reconsider its verdict this September, after Amylyx provided additional analyses accounting for placebo crossover (when placebo participants are later offered the active drug to reassess survival rate), and how survival rates compared to disease data from the 1990s. “It was estimated that the actual survival benefit may be longer than the originally reported five months, but closer to 10 or 11 months,” Dr. Sabrina Paganoni, a physician scientist at the Healey Center for ALS at Massachusetts General Hospital who led Amylyx’s phase 2 trial, told The Daily Beast. Public pressure also ramped up, with advocates sending nearly 10,000 emails to the FDA urging approval.

But that hasn’t quelled skepticism. “The manufacturer provided reanalysis of data that was already in hand, as well as a variety of post hoc analyses,” Caleb Alexander, an epidemiologist at Johns Hopkins University, told The Daily Beast. “There wasn’t a lot of new evidence.” Alexander was on the FDA advisory committee, and voted against recommending approval for Relyvrio.

There wasn’t a lot of new evidence.

Caleb Alexander, Johns Hopkins University

At the meeting itself, Fishbeck said running analyses like this was like “trying to change the result of an athletic game” after it’s complete. He also voted against approval. He later told The Daily Beast in an interview, “You can always come up with a post hoc argument that fits a conclusion that you want.”

The FDA had noted other concerns about the results as well, including “inappropriate handling of deaths and missing data.”

In response to these criticisms, Paganoni told The Daily Beast: “Despite each individual method’s limitations, the results were all converging towards the same positive survivor benefit.” She recognized that different statisticians had their “preferred models,” but insisted that “the methods used were appropriate for this particular study.”

Cash Grab

But uncertainty about the data is relevant when Relyvrio’s price is considered: The drug will cost $158,000 for a year’s supply. Amylyx has said it is committed to eliminating the co-pay for privately insured patients, and a spokesperson said “we are working to ensure that people with government-funded insurance, like Medicare or Medicaid, will have access to Relyvrio as quickly and efficiently as possible.” The Centers for Medicare & Medicaid Services has not yet revealed when it will publish its coverage policy. Neurologists have also cautioned that the privately insured will likely face obstacles.

The Boston-based Institute for Clinical and Economic Review, a nonprofit watchdog of drug costs, has said the list price for the drug “far exceeds” measures of cost-effectiveness. It recommended in September that Relyvrio should be priced between $9,100–$30,700 per year.

The high costs are especially confusing considering that Relyvrio is really a combination of two drugs that many patients already self-administer as a DIY cocktail: sodium phenylbutyrate, which is available on Medicare; and taurursodiol, which can be ordered online. But according to Paganoni, the cocktail is not of pharmaceutical grade: “When people make their own version, combining products that are purchased online, they really don’t know the quality.”

The decision made no sense, because the drug did not meet the criteria required for regular approval.

Diana Zuckerman, National Center for Health Research

Beyond concerns over a high fee for a potentially ineffective drug, there is an existential concern about the FDA’s reputation. What happens when regulatory flexibility doesn’t pay off?

“This is a deterioration of the FDA from requiring two studies, to requiring just one study—a smaller study, a shorter-term study, a study that doesn’t even meet the agreed upon outcome,” Diana Zuckerman, a health analyst at the National Center for Health Research, told The Daily Beast. “The decision made no sense, because the drug did not meet the criteria required for regular approval.” Zuckerman voiced hesitancy about Relyvrio’s approval at the September FDA advisory hearing.

Echoing those sentiments, Alexander added: “The question is not do we want this drug to succeed, the question is what sort of evidence do we want? What sort of confidence do we want to have that FDA-approved products work?”

Culture Breakdown at the FDA

Relyvrio isn’t a rare exception for such scrutiny. Another approval pathway that has come under intense fire in recent years is the FDA’s accelerated approval program, that fast tracks drugs with urgent need. A scandal engulfed the agency in June last year when it greenlit Aduhelm, an Alzheimer’s drug made by Biogen. Aduhelm initially cost $56,000 for a year’s supply, and the approval went against an advisory panel’s recommendation that the evidence was inconclusive.

Then, a worst-case scenario unfolded: In April this year, Medicare made the unprecedented decision to restrict coverage exclusively to those in Adulhelm’s clinical trials, due to the drug’s negligible clinical benefit. The FDA’s reputation took a huge hit, and Alzheimer’s patients are still in limbo.

And just last month, the FDA again recommended pulling Makena off the market, an injection first approved over a decade ago to lower the risk of preterm birth for pregnant women. Makena, owned by Covis Pharma, was granted accelerated approval in 2011 following a smaller trial of 500 women, but then larger clinical trial results in 2019 showed no significant difference in frequency of preterm birth or infant mortality. Last month, an FDA meeting presented slides that read: “Retaining Makena’s approval likely hinders study of more promising treatments for preterm birth.”

The FDA’s efforts to take Makena off the market have spanned two years, thwarted by Covis Pharma’s demand for a hearing. Makena remains available.

At the latest advisory meeting for Relyvrio, an Amylyx leader agreed to voluntarily pull the drug if the next trial proves ineffective, which played a role in the committee’s decision. But Amylyx wouldn’t be compelled to do so if it changed its mind. An FDA spokesperson told The Daily Beast that most withdrawals occur voluntarily, but if the company refuses, “the FDA may begin proceedings to request withdrawal from the market.”

Pulling a drug from the market is an “unusual and complicated process, one that’s fraught with complexity,” said Alexander. It requires federal registry announcements and written public comments, which can take years, said Zuckerman. If the manufacturer is reluctant, it’s even longer.

At the September advisory hearing, Alexander stated that the offer to pull a drug from the market should not sway the decision-making process, nor should it be a substitute for evidentiary standards.

Can you imagine the mistake of saying no now, and then getting the confirmatory evidence in two years that this drug really did work?

Richard Bedlack, Duke University

Approving Relyvrio before its efficacy has been confirmed may end up disincentivizing participation in other ALS clinical trials, Zuckerman, Alexander, and Fishbeck warned. “Even if the U.S. enrollment in the [phase 3] study is completed, that doesn’t mean the follow-up has been completed,” Zuckerman said at the Sept. 7 hearing, referencing potentially low-uptake of trial volunteers if Relyvrio is publicly available. “And what about placebo-controlled studies of other ALS treatments? Nobody wants to be in a placebo group,” she said.

On the other hand, ALS advocates, doctors, and experts warn: what if Relyvrio isn’t another Aduhelm or Makena? Is needless haranguing over regulatory standards and trial analyses preventing access to a game-changing treatment that could add months or years to people’s lives?

“Can you imagine the mistake of saying no now, and then getting the confirmatory evidence in two years that this drug really did work?” Bedlack told The Daily Beast. Due to the short prognosis of ALS, many patients may not have time to await the outcome of phase 3 results—time which could potentially be bought with access to the drug. And with residual unknowns, the drug could be more effective than thought. “What mistake would you rather make?” he said.

The ALS clock is not the same clock that ticks for the average person. It’s very different.

Steve Kowalski

And approvals send a message to pharmaceutical investors: Drugs in this field can get approved and money can be made. “We need some wins—even if they’re small—to incentivize other pharmaceutical companies to want to get into this space,” said Kowalski. “The ALS clock is not the same clock that ticks for the average person. It’s very different.”

Runyan shares those sentiments. She plans to take her grandkids to Disneyland in January and is exploring technological aids. She’s recorded her voice into a text-to-speech app that predicts what users want to say. “It’s not as melodious as my voice, but it does sound like me,” Runyan said. She isn’t sure precisely how she has left, but she’s thinking in terms of experiences, not time. “I’m not letting ALS control me.”

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