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Relyvrio: ALS drug receives FDA approval despite uncertainty about efficacy

Relyvrio: ALS drug receives FDA approval despite uncertainty about efficacy
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A new treatment for amyotrophic lateral sclerosis, or ALS, has been approved by the US Food and Drug Administration.

The FDA on Thursday announced approval of Relyvrio, which was developed by Amylyx Pharmaceuticals. The oral drug can be taken as a standalone therapy or alongside other treatments, according to the company, and has been shown to slow the progression of the disease.

But there are still some uncertainties about the drug’s effectiveness: Amylyx’s regulatory filing is based on data from a small Phase 2 study, and the FDA’s own advisory committee initially voted this spring that the data did not show that the Drug was effective before it changed its mind this month.

“There are limitations to these results that result in a degree of residual uncertainty in the evidence of efficacy beyond what might ordinarily remain after the conclusion that substantial evidence of efficacy has been demonstrated,” says one FDA summary memorandum on the approval. But “given the serious and life-threatening nature of ALS and the significant unmet need, this level of uncertainty is acceptable in this case.”

The approval is the first in the US for Amylyx, CEOs Josh Cohen and Justin Klee said in a statement, and “is an exciting milestone” for the ALS community.

“The goal of Amylyx is that every person who is eligible for Relyvrio has access as quickly and efficiently as possible because we know that people with ALS and their families do not have time to wait,” they said. “While Amylyx is working on the rollout of Relyvrio, healthcare professionals can start writing prescriptions for Relyvrio immediately by registering their patients with us comprehensive funding program that we implement.”

Patients and some stakeholders had asked the FDA to approve the drug because of the limited treatment options for ALS, and the agency granted priority review in December.

ALS, also known as Lou Gehrig’s disease, affects up to 30,000 people in the United States. It is a neurodegenerative disease that causes muscles to weaken, eventually affecting the ability to speak, swallow, move and breathe.

“ALS is a terrible disease: quickly fatal and truly debilitating in the time from onset of symptoms to death. The FDA has approved a few treatments, but they’re minimally effective and certainly not a cure. As such, there is a major unmet need in this disease area that the FDA has recognized,” said Holly Fernandez Lynch, assistant professor of medical ethics and public health policy at the University of Pennsylvania.

Prior to the FDA decision, Lynch told CNN that she would be “shocked” if the drug didn’t get approved because the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee changed its mind and voted on the drug at a meeting this month got 7-2 in favor of approval.

In November, Amylyx submitted a drug application to the FDA for what was then called AMX0035 as an oral ALS treatment, seeking approval based on a Phase 2 study that enrolled 137 people with ALS who took either the drug for 24 weeks or received a placebo. The study was funded in part by a grant from the ALS Ice Bucket Challenge, the viral social media campaign that began in 2014 and saw people throw buckets of ice water over themselves to raise awareness and money for ALS.

The study also showed that the drug was generally well tolerated, but there was a greater incidence of gastrointestinal events in the group receiving the drug. Amylyx is now further evaluating its safety and efficacy in a Phase 3 study.

In March, the Advisory Committee on Drugs of the Peripheral and Central Nervous System voted 6-4 that a single Phase 2 study had failed to conclude that the drug was effective in treating ALS.

“In order to conclude that it is effective, we were asked to look for substantive evidence with compellingness and robustness, and I think this one study doesn’t quite meet that bar,” said Dr. Kenneth Fischbeck, a committee member and investigator at the National Institutes of Health, said at the March meeting. Fischbeck added that he has cared for ALS patients.

A key difference between the March and September FDA Advisory Committee meetings is that in the later meeting, Amylyx indicated that the company would consider withdrawing the drug from the market if the drug were approved, but the Phase 3 results study did not confirm the drug’s benefits, Lynch said. However, she added that the company didn’t say specifically what it would consider a failure.

“So when we voted, the Advisory Board members rotated and most said, ‘Yes, we now believe this product should be approved.’ And when they were asked why they changed their minds, some of them said, ‘Well, the company said they were pulling out,'” she said. “And they were also convinced by the statements of the patients that they absolutely wanted to try this drug.”

Overall, however, the FDA’s approval was based on Phase 2 study data, which Lynch says could send a message to other pharmaceutical companies that they don’t need robust Phase 3 study data to bring products to market.

Lynch said that while she understands why people with ALS want access to this promising drug, she has concerns that such a message could open the door to approval of drugs that have not been proven to work. The FDA could later withdraw these products if needed, she said, but doing so without a voluntary company agreement is “a huge pain” and often requires a very lengthy process.

As for Relyvrio, some ALS advocacy groups – including the ALS Association – have been campaigning for its approval for several months. After the FDA advisory committee meeting in March, when the panel initially voted against the drug, Calaneet Balas, president and CEO of the ALS Association, said in a statement that “the FDA has to make a decision — whether to approve a drug that it has been proven safe, which will help people living with ALS today, or will it delay approval and require more evidence while more people die with ALS.”

“We must not allow perfection to stand in the way of real progress in transforming ALS from a deadly disease into a livable one. The FDA’s ALS guidance recognizes that people with ALS are willing to accept greater risk for the possibility of benefit,” Balas said. “People with ALS and their families deserve better, and the FDA has the resources to make that happen urgently.”

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