Laurie McGinley, Washington Post: September 29, 2022
The Food and Drug Administration on Thursday overcame doubts from agency scientists and approved a fiercely debated drug for ALS, a move that heartened patients and advocates who pushed for the medication but raised concerns among some experts about whether treatments for dire conditions receive sufficient scrutiny.
“It’s a huge deal,” said Sunny Brous, 35, who was diagnosed with ALS seven years ago after she had trouble closing her left glove while playing softball. She plans to begin taking the drug as soon as she can.
“Anything that shows any amount of efficacy is important,” the resident of Pico, Tex., added. Even a small change, Brous said, “might be the difference between signing my own name and someone else signing it for me.”
The newly approved therapy, which will be sold under the brand name Relyvrio, is designed to slow the disease by protecting nerve cells in the brain and spinal cord destroyed by ALS — amyotrophic lateral sclerosis. The ailment paralyzes patients, robbing them of their ability to walk, talk and eventually breathe. Patients typically die within three to five years, though some live much longer with the condition sometimes called “Lou Gehrig’s disease” for the renowned baseball player diagnosed in 1939.
“This approval provides another important treatment option for ALS, a life-threatening disease that currently has no cure,” Billy Dunn, director of the FDA’s Office of Neuroscience, said in a statement.
The agency said the efficacy of Relyvrio, the first new therapy approved for ALS in five years, was demonstrated in a 24-week study in which 137 patients were randomized to receive Relyvrio or placebo. The patients treated with the drug experienced a 25 percent slower rate of decline in performing essential activities such as walking, talking and cutting food compared with those receiving a placebo.
In addition, the FDA said, a long-term analysis showed that patients who originally received Relyvrio vs. those who took the placebo lived longer. Amylyx, the Cambridge, Mass., biotech company that makes the drug, said that survival benefit was a median of about 10 months.
During reviews of the drug, the FDA staff expressed concerns about the medication’s effectiveness and posed questions about the clinical trial. On Thursday, the agency acknowledged there were “limitations” to the data that resulted in uncertainty about the drug’s degree of effectiveness. But the agency said that regulatory flexibility was acceptable because of the “serious and life-threatening nature of ALS and the substantial unmet need” for treatments.
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About 30,000 people in the United States have ALS, with 6,000 new cases diagnosed every year. Two other drugs — including Radicava, which came to the U.S. market in 2017 — are approved for the ailment but have extremely limited effectiveness.
Some drug policy experts, however, said insufficient evidence exists that the drug works. A trial with 600 patients won’t be completed until late 2023 or early 2024.
“There is some evidence to support the efficacy of the product, but I don’t think it hits the bar that the FDA typically requires,” said G. Caleb Alexander, an internist and epidemiologist at the Johns Hopkins Bloomberg School of Public Health who serves on the FDA advisory committee that reviewed the drug. “How much should the FDA lower the bar — if at all — for products for a devastating disease” that lacks effective treatments?
Diana Zuckerman, president of the of National Center for Health Research, a think tank, agreed.
“How many ineffective ALS drugs do we need?” Zuckerman said. “It would be better to have one that has been proven to make a meaningful difference to live longer.”
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In 2019, Brian Wallach, a staffer in the Obama White House, and his wife founded a group named I AM ALS after Wallach was diagnosed. That organization made getting the Amylyx drug onto the market a priority.
The two groups pressed the FDA to be faster and more flexible in clearing ALS drugs, saying patients would accept treatments with increased safety risks in return for even a small benefit — a viewpoint incorporated into the agency’s 2019 guidance to the pharmaceutical industry on developing ALS therapies. In 2020, the two ALS organizations submitted more than 50,000 signatures to the FDA calling for approval of AMX0035.
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Typically, the FDA expects drugmakers to submit “substantial evidence of effectiveness” provided by two well-designed clinical investigations. But the agency says a single trial may be sufficient if the study demonstrates a “clinically meaningful and statistically very persuasive effect” on extending survival or some other aspect of the disease.
In March, however, the FDA staff issued a mostly negative assessment — suggesting the data was not persuasive — and the agency’s advisers agreed, voting 6-4 to recommend against FDA approval. Patients and advocates flooded the FDA with more than 10,000 emails pleading for approval, advocates said.
In a rare move, the FDA held a second advisory meeting this month to consider additional analyses submitted by the company. Once again, the FDA staff suggested in a memo that there was not enough evidence of effectiveness to approve the drug. But the tone of the meeting differed markedly from that of the first session. At the outset, Dunn acknowledged the data for the drug raised numerous questions but also stressed the “tremendous unmet medical need” for ALS and the seriousness of the disease. He said the agency had the legal authority to be flexible. And in a highly unusual move, Dunn asked the Amylyx officials whether they would voluntarily withdraw the drug from the market if the large trial failed; they said they would.
With a few of the outside experts on the advisory committee changing their position, the panel recommended approval 7-2.
The debate over the drug has echoes of the battle over Aduhelm, the controversial Alzheimer’s drug approved by the agency in June 2021. Critics said there was scant evidence of efficacy for that medication, and Medicare declined to cover it except in trials. The drug collapsed in the marketplace, never gaining traction with patients or physicians.
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