The FDA looks set to approve a new drug for ALS, but does it work?

The FDA looks set to approve a new drug for ALS, but does it work?

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

Manuel Balce Ceneta/AP

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

But it’s still unclear whether the drug, called AMX0035, really helps people with ALS, a rare and deadly neurological disorder that eventually makes 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 being pushed by 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 generally follows the recommendations of the advisory committee, said it would make a decision by September 29.

An endorsement is more likely now than it would have been decades ago, says Holly Fernandez Lynch, assistant professor of medical ethics and health policy at the University of Pennsylvania.

“The trajectory at the FDA has been an increased willingness to accept weaker evidence,” she 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 down ALS, which gradually destroys cells in the brain and spinal cord that control voluntary muscle movement.

AMX0035 was developed by Amylyx, a company based in Cambridge, Mass. which was founded in 2013 by two Brown University graduates.

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

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

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

“The plaintiff did not provide strong evidence,” said Dr. Bryan Traynor, a neurologist at the National Institute on Aging.

“The data is not as strong as we hoped,” said Dr. Liana Apostolova, an Alzheimer’s disease 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 hit the threshold,” said Stanford University pathologist Dr. Thomas J. Montine.

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

All six members of that committee voted no when asked if the evidence showed the drug was effective. Four other committee members voted yes.

Tips for Advisors

Typically, that kind of response would have been the end of it, 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 family members turned to the internet.

“There have been thousands of emails that have gone to [FDA] commissioner’s office,” explains Neil Thakur, head of mission at the ALS Association, which helped fund the Amylyx study. “There were over 1,100 comments that were passed on to the advisory board itself, and there was also a sustained effort from ALS clinical scientific leaders. “

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

“They were asking to keep this drug at the same level that they would keep any drug for any disease that wasn’t life-threatening and had a lot of effective treatments,” he says.

Currently, ALS patients are offered variations of only two drugs: edaravone and riluzole. And even with these drug treatments, they usually die within two to five years of being diagnosed.

From no to yes

The ALS patient email campaign appears to be having 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 considering the treatments available and the needs of the ALS community,” he says.

The committee also received additional patient data from the Amylyx study and data from a study of patients with Alzheimer’s disease who took AMX0035.

When the committee held its second public meeting on the drug, Dr. Billy Dunn, who heads the FDA’s Office of Neuroscience, offered advice. 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 to the committee. Instead of asking if the drug was effective, they simply asked if it should be approved.

After listening — instead of six no votes, seven of the nine committee members decided to vote yes.

Echoes of Aduhelm?

The process leading up to the yes vote was “shady,” says UPenn bioethicist Fernandez Lynch.

“The very cynical version of this is that there was some kind of objective to manipulate the advisory board into voting a different way,” she says.

“They were swayed by this concern that they might be making the wrong judgment if they recommended that the FDA not approve this product,” she says. “But no one, from what I’ve heard, has said that this drug meets the standard of substantial evidence.”

The substantial standard of proof was also in question when the FDA considered the controversial Alzheimer’s drug Aduhelm. The FDA approved the drug last year despite an overwhelming advisory committee vote that the standard had not been met.

If AMX0035 is approved, it could send a troubling message to pharmaceutical companies, Lynch says.

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

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