Despite concerns, FDA panel reverses course on ALS drug, recommends approval: shots


Drugmaker Amylyx is asking the FDA to approve a new drug for ALS, a fatal neurodegenerative disease. It is possible that the agency could give the green light to the drug by the end of the month.

Manuel Balce Ceneta/AP


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Manuel Balce Ceneta/AP


Drugmaker Amylyx is asking the FDA to approve a new drug for ALS, a fatal neurodegenerative disease. It is possible that the agency could give the green light to the drug by the end of the month.

Manuel Balce Ceneta/AP

The Food and Drug Administration is likely to approve a controversial new drug for ALS by the end of the month.

But it’s still unclear whether the drug, called AMX0035, actually helps people with ALS, a rare and fatal neurological disorder that eventually leaves a person unable to walk, talk, swallow and breathe.

In March, the FDA’s Central and Peripheral Nervous System Drugs Advisory Committee concluded that a study of 137 ALS patients did not provide “substantial evidence” that AMX0035 was effective.

Then in September, after a push from FDA officials and an email campaign from patients and their families, the same committee met again and this time recommended approving the drug.

The FDA, which usually follows the advisory committee’s recommendations, has indicated it will make a decision by September 29.

Approval is more likely now than it was decades ago, says Holly Fernandez Lynch, assistant professor of medical ethics and health policy at the University of Pennsylvania.

“The FDA’s track record has increased the willingness to accept weaker evidence,” he says.

Two old products, one new drug

AMX0035 is a combination of two existing products. One is a dietary supplement called taurursodiol, which can be purchased online. The other is a prescription drug called sodium phenylbutyrate, which is used to treat a rare type of metabolic disorder.

The combination is intended to slow ALS, which gradually destroys cells in the brain and spinal cord that control voluntary muscle movement.

AMX0035 was developed by Amylyx, a Cambridge, Massachusetts-based company that was founded in 2013 by two Brown University graduates.

Amylyx sought FDA approval of its drug based on a single study of 137 ALS patients. The results suggested that AMX0035 could extend patients’ lives by several months.

But at a public meeting in March, most experts on the FDA’s advisory committee said they were not convinced by the study, called Centaur.

“There are many characteristics of Centaur that limit its persuasiveness,” said Dr. G. Caleb Alexander, an epidemiologist at Johns Hopkins University.

“The applicant has not provided strong evidence,” said Dr. Bryan Traynor, a neurologist at the National Institute on Aging.

“The data is not as strong as we might expect,” said Dr. Liana Apostolova, an Alzheimer’s expert at Indiana University.

The study was “problematic,” said Dr. Kenneth H. Fischbeck, a neurogenetics researcher at the National Institutes of Health.

“It didn’t meet the threshold,” said Dr. Thomas J. Montine, a pathologist at Stanford University.

“This study, by itself, does not establish that this drug is effective in the treatment of ALS,” said Dr. Robert C. Alexander, scientific director of the Alzheimer’s Prevention Initiative, led by the Institute Banner Alzheimer.

All six members of the committee voted no when asked if the tests showed the drug was effective. Four other members of the commission voted in favor.

Advice to advisers

Normally, that kind of response would have been the end, at least until Amylyx was ready to present data from a much larger study, which is already underway.

But after the March meeting, ALS patients and their families accessed the Internet.

“There were thousands of emails that went to [FDA] “There were more than 1,100 comments that went to the advisory committee itself, and there was also a sustained effort from ALS clinical science leaders.”

The small clinical trial has flaws, Thakur said, but the advisory committee should have been willing to overlook them when it first reviewed the evidence in the spring.

“They were asking to hold this drug to the same standard that they would hold any drug for any disease that is not fatal and has many effective treatments,” he says.

Right now, ALS patients are offered variants of only two drugs: edaravone and riluzole. And even with these drug treatments, they usually die between two and five years after a diagnosis.

From no to yes

The ALS patient email campaign appeared to have an effect on some FDA officials.

Earlier this month, the agency took the unusual step of reconvening its advisory committee to reconsider the drug Amylyx. And this time, the FDA encouraged committee members to take a different perspective, Thakur says.

“This committee, it was clear that they were being asked to make a decision based on available treatments and the needs of the ALS community,” he says.

The committee also received some additional data on patients from the Amylyx study and data from a study of Alzheimer’s patients taking AMX0035.

When the committee held its second public meeting on the drug, they were offered guidance from Dr. Billy Dunn, who heads the FDA’s Office of Neuroscience. He urged them to consider the plight of ALS patients and suggested his agency was open to approving the drug.

“For these serious diseases, like ALS and so many other neurological diseases, the maximum degree of regulatory flexibility is operational,” he said.

The FDA even revised its question in committee. Instead of asking whether the drug was effective, they simply asked whether it should be approved.

After listening, instead of six votes against, seven of the nine members of the committee decided to vote yes.

Echoes of Aduhelm?

The process that led to the yes was “sloppy,” says Fernandez Lynch, the UPenn bioethicist.

“The very cynical version of this is that there was some kind of objective to manipulate the advisory committee into voting differently,” he says.

“They were influenced by this concern that they might be making the wrong judgment if they recommended that the FDA not approve this product,” he says. “But no one, as far as I’ve heard, said that this drug meets the substantial evidence standard.”

The substantial evidence standard was also called into question when the FDA was considering the controversial Alzheimer’s drug Aduhelm. The FDA approved this drug last year despite an overwhelming advisory committee vote that the standard had not been met.

If AMX0035 is approved, that could send a worrying message to drug companies, Lynch says.

“The message to companies is that you don’t have to prove that your drug works,” he says. “You have to do the bare minimum to show it can work.”

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