When patients are battling a terminal illness and want access to an experimental drug, how much evidence that it works should regulators require before approval?
That's the question behind many of the Food and Drug Administration's toughest decisions, including last year's controversial approval of Aduhelm. Many experts — including the agency's own outside advisers — say that Alzheimer's drug is unlikely to help patients.
Less than a year later, the agency may soon approve another drug for a deadly neurodegenerative disease based on partial data that's being debated by experts. The FDA meets next week to publicly review evidence from a small, mid-stage study of Amylyx Pharmaceuticals' drug for ALS, or amyotrophic lateral sclerosis.
Regulators told Amylyx last year it would need to conduct a large, confirmatory study before seeking approval, according to the company. But after months of intense lobbying by ALS patients and their representatives in Congress, the agency said it could submit the drug based on the smaller study.
The change was so abrupt it surprised even some doctors who helped study the treatment, which appears to modestly slow patients' decline.
"The effect is there, but it's not a homerun," said Dr. Jeffrey Rothstein of Johns Hopkins University. "Does it really work? I don't know. That's why I'd like to see a second study."
The FDA traditionally requires two large, late-stage studies for approval. For deadly diseases like cancer, one study showing promising early results is often accepted.
The Amylyx decision comes as government investigators look into Aduhelm's approval, including whether the agency buckled under pressure from Alzheimer's groups and pharmaceutical interests.
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Experts who study FDA decision-making see a troubling pattern in which the beleaguered agency is continually pressured to accept weaker evidence, damaging its scientific credibility and opening the door to ineffective treatments.
"This is what many people were concerned about in terms of the precedent for FDA approving Aduhelm," said Dr. Joseph Ross of Yale University. "They essentially capitulated to both industry and patient advocacy pressure, as opposed to abiding by the science."
An FDA spokeswoman declined to discuss the review, citing agency rules, but noted that Amylyx's submission "is not a determination on the merits of the application." FDA will post its initial review of the drug ahead of Wednesday's meeting.
There are important differences between the two drugs. The FDA approved the Alzheimer's drug based on laboratory measures suggesting it helped slow cognitive decline, even though company studies failed to show a significant patient benefit. In the case of Amylyx's drug, ALS patients showed a measurable improvement, but the therapy had no effect on laboratory results.
Given that patient benefit, advocates argue the FDA should approve Amylyx's treatment.
ALS, also known as Lou Gehrig's disease, destroys nerve cells needed to walk, talk, swallow and — eventually — breathe. There is no cure and most people die within three to five years.
Amylyx's drug is a combination of two older drug ingredients: a prescription medication for liver disorders and a dietary supplement associated with ancient Chinese medicine. Cambridge, Mass.-based Amylyx has patented the combination and says the chemicals work together to shield cells from premature death. (Its co-founders declined interview requests for this story.)
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Some ALS patients already take both pills. FDA approval would likely compel insurers to cover the treatment.
In a 137-patient study, people taking the drug progressed 25% slower than those taking a placebo, as measured on a 48-point questionnaire that tracks functions like walking, handwriting and swallowing. The difference in scores — 2.3 points — was statistically significant, but experts differ on its meaning for patients.
Dr. Catherine Lomen-Hoerth of the University of California San Francisco said dropping even one point can be significant.
"That's the difference between being able to feed yourself or not feed yourself," said Lomen-Hoerth, who wasn't involved in the research.
A New England Journal of Medicine editorial called the results "incremental" and "modest," and recommended longer, larger studies.
An FDA decision appeared years away, but the results sparked a campaign by patient groups, beginning with a petition calling on the agency to act. Advocates took credit when FDA appeared to reverse its stance on the medication in September.
For people living with ALS, the logic is clear: Any drug that can extend or improve life is worth trying.
The FDA has approved only two therapies for ALS. The more effective one extends life by several months, and many experts say Amylyx's drug is likely to show a similar benefit.
"When you're faced with a choice of nothing, you certainly want an opportunity to try anything that can help you," said Larry Falivena, who was diagnosed with ALS in 2017. He's scheduled to speak at next week's FDA meeting.
The 53-year-old father of two joined a half-dozen other patients in calling on FDA to approve Amylyx's drug during an online "listening session" last May.
The session was organized by the ALS Association, which invested $2.2 million in Amylyx's research. The group — a major beneficiary of the 2014 "ice bucket challenge" viral fundraising campaign — could receive up to $3.3 million in proceeds if the drug is approved.
The association says such arrangements are standard among nonprofits that fund research and that proceeds go toward further studies. Payback clauses are one way of helping to bring "effective treatments to market as quickly as possible," the group said in a statement. It added that it wouldn't advocate for approval if the drug weren't safe and effective.
During the listening session, FDA's Dr. Patrizia Cavazzoni reiterated the agency's longstanding position: If drugmakers developed better biological measures of how their medicines worked, the agency could use them to speed approvals.
The 48-point scale used by Amylyx is the standard for ALS research, but some experts question its reliability. For instance, it's not uncommon for patients to report improving function even as measures like muscle strength decline.
Several weeks later, Cavazzoni was summoned before a House of Representatives subcommittee. During the five-hour hearing, which was requested by patient advocates, lawmakers pressed her on the status of Amylyx's drug.
The co-founders of another patient group, I AM ALS, also testified. Brian Wallach and his wife, Sandra Abrevaya, worked in the Obama White House and formed their group after Wallach's 2017 diagnosis with ALS. The nonprofit has quickly become a political force in Washington, pushing legislation through Congress that, among other things, requires FDA to develop a five-year plan to accelerate drug development for ALS and similar conditions.
In their joint testimony, read by Abrevaya, they called on lawmakers to intervene on patients' behalf: "The answer is abundantly simple: Make the FDA act with the urgency and regulatory flexibility that it promised."
A spokeswoman for I AM ALS rejected the idea that the group is "telling the FDA what to do."
"We are not trying to pressure the FDA," said Theresa Garner. "We're following the standard process and are just making sure that the FDA and its advisory committee hear from people who live with this disease."
The FDA advisory panel of outside experts meeting Wednesday is the same one that voted against Aduhelm. FDA disregarded its advice and approved the drug, prompting three members to resign.
Given that the same FDA scientists and leadership are overseeing Amylyx, approval is widely expected.
Rothstein, the Johns Hopkins researcher, plans to prescribe the drug to his patients. But he'd still like to see more data.
"I would prefer the FDA wait for two trials," he said. "Patients will say, 'You're depriving me of a drug.' And the counter to that is: 'I may be depriving you of a drug that isn't effective.'"