The Washington Post

FDA advisers vote to recommend approval of ALS drug

The move increases the chance the drug will be cleared in coming weeks

- BY LAURIE MCGINLEY

Independen­t advisers to the Food and Drug Administra­tion on Wednesday voted 7 to 2 to recommend approval of an experiment­al ALS drug with strong support from patients and advocates, making it likely the hotly debated treatment will be cleared by the agency within weeks.

The vote was a stunning turnaround from late March when the panel voted 6 to 4 to recommend against FDA approval. At that meeting, the FDA’S Peripheral and Central Nervous System Drugs Advisory Committee concluded the evidence from a single clinical trial — with just 137 patients and some follow-up data — was not sufficient to show the drug, called AMX0035, slowed a degenerati­ve disease that usually kills people within three to five years.

But on Wednesday, after hours of discussion, several advisers said that additional analyses submitted by the drug’s manufactur­er, Cambridge-based Amylyx, bolstered the case for approval, even though uncertaint­ies remain. Advisers were also affected by the disease’s severity and the lack of effective treatments. A vow by a top Amylyx official to pull the drug from the market if a larger study, with 600 patients, fails to show effectiven­ess was also a factor in the vote.

The FDA, which usually follows the recommenda­tion of its outside advisers but is not required to, is expected to decide whether to approve the drug by Sept. 29.

The improved fortunes of the medicine came despite criticism from FDA staff as recently as last week about the treatment’s effectiven­ess, the conduct of its clinical trial and the researcher­s’ interpreta­tion of the data.

But the medicine is considered safe, and the agency has been under intense pressure from ALS patients and physicians who say the treatment holds promise for a fatal disease that typically causes rapid deteriorat­ion and death.

Wednesday’s vote came after a dramatic moment featuring Billy Dunn, director of the FDA’S Office of Neuroscien­ce, who stressed the agency may use broad flexibilit­y to clear drugs for diseases like ALS that lack effective treatments.

Dunn also noted the large trial being conducted by the manufactur­er will be completed late next year or in early 2024; that trial is expected to show definitive­ly whether the drug works. In a highly unusual move, he asked company officials whether they would voluntaril­y withdraw the product if it was approved now but the larger trial failed to show effectiven­ess.

Justin Klee, co-chief executive of the Cambridge-based biotech company, agreed. If the larger trial is not successful, “we will do what is right for patients, which includes withdrawin­g the product from the market,” he said.

Other experts cautioned, however, that a voluntary commitment like Klee’s is not legally binding.

Still, the commitment from Amylyx and its new analyses convinced some panel members to change their votes from March. Liana G. Apostolova, a neurologis­t at Indiana University School of Medicine, said the new analyses left her “mildly to moderately” persuaded the drug extends life by at least several months. “To deprive ALS patients of a drug that might work is not something I feel terribly comfortabl­e with,” she said.

Kenneth Fischbeck, a scientist at the National Institute of Neurologic­al Disorders and Stroke, voted no, as he had in March. He said he did not believe the drug had met the standard of substantia­l evidence of effectiven­ess.

ALS, or amyotrophi­c lateral sclerosis, destroys nerve cells in the brain and spinal cord. It typically paralyzes patients, robbing them of their ability to walk, talk and eventually breathe. About 30,000 people in the United States have ALS, sometimes called “Lou Gehrig’s disease.” Another 6,000 are diagnosed every year. There are two FDAapprove­d therapies on the market but they have limited effectiven­ess.

The experiment­al treatment was dreamed up almost a decade ago by Brown University undergradu­ates who went on to found Amylyx — Klee and Josh Cohen, now co-chief executives.

The ALS medicine is made up of two components — a prescripti­on drug called sodium phenylbuty­rate that is used to treat rare liver disorders and a nutritiona­l supplement called taurursodi­ol — designed to protect neurons from destructio­n. The treatment comes in a powder that is dissolved in room-temperatur­e water and drunk or administer­ed through a feeding tube.

ALS advocates were delighted by Wednesday’s vote. “We applaud and thank the FDA Advisory Committee for their vote to support approval of AMX0035 and we urge the FDA to swiftly approve,” said Scott Kauffman,” chairman of the ALS Associatio­n’s board of trustees. “Americans living with ALS cannot wait.”

During the public hearing portion of Wednesday’s session, leading ALS doctors pleaded for the drug’s approval, saying even small benefits could provide enormous help in dealing with a fatal neurodegen­erative disease. Several patients who have gotten the drug through clinical trials gave emotionall­y wrenching testimonia­ls asking for approval.

Vance Burghard said he was diagnosed with ALS in 2017 and soon needed help pulling up his pants. Through a clinical trial, he has been on AMX0035 for three years, something he called “lifechangi­ng.” He said his condition has stabilized and he has been able to hike in China and Tibet.

Gregory Canter said he participat­ed in the ALS Associatio­n’s Ice Bucket Challenge several years ago, although “I didn’t have ALS and I didn’t know anyone who did.” A few years later, he was diagnosed with the illness and subsequent­ly enrolled in the sixmonth Amylyx trial. He believes he got the placebo, but as a trial participan­t was offered the drug after the trial was over, as part of what is called an open-label study.

Canter said the drug has stabilized his breathing and helped him in other ways. “I am still alive, living independen­tly and my disease progressio­n has noticeably decreased,” he said.

Brian Wallach, a former Obama White House staffer who was diagnosed five years ago, noted that some panel members said they had voted against the drug in March to protect patients from false hope.

“I don’t need you to protect me from myself,” he said. Such “antiquated paternalis­m is misplaced,” he said through an aide because his speech is severely affected. “There is only one right answer here. I only hope you have the courage to recommend approval.”

Amylyx applied to the FDA for approval of the drug in November 2021. The company submitted data from a 24-week week trial that showed the drug was safe and slowed a decline in essential functions such as walking, talking and cutting food, by 25 percent.

In a follow-on study, in which all participan­ts were offered the drug, patients who received the treatment from the start of the trial lived a median of more than six months longer than those who did not, the investigat­ors found.

More recent analyses submitted by the manufactur­er showed AMX0035 extended median survival several months longer than originally thought, delayed first hospitaliz­ations and reduced severe complicati­ons.

Still, the FDA has signaled for months it had doubts about approving the drug on a single study, especially when the agency said it did not find the data “exceptiona­lly persuasive.” The agency said the company did not adequately account for deaths during the trial and took issue with other aspects of the study. It said the additional analyses included no new informatio­n.

Canada recently approved AMX0035 on a conditiona­l basis. That means Amylyx can sell the drug but is required to confirm its benefits based on the results of the larger trial. But the FDA’S approval processes are somewhat different from Canada’s.

Some ALS patients are already taking one or both components of AMX0035. Since sodium phenylbuty­rate is approved for another purpose, doctors are allowed to prescribe it off label for ALS. And the nutritiona­l supplement, sometimes called TUDCO, is available on a variety of websites.

Some health policy experts said in the hearing that the drug should not be approved until additional data proves its effectiven­ess.

Others agreed the FDA has a legal responsibi­lity to determine that drugs are safe and effective — but noted it has flexibilit­y about how to do that. Murky data can complicate the picture.

“Science is messy and even well-designed trials will not always give you a clear-cut answer,” said Holly Fernandez Lynch, a bioethicis­t at the University of Pennsylvan­ia who is not on the panel.

 ?? Jarvis Chen ?? Steve Kowalski, center in glasses, poses with people who participat­ed in the 2018 Ride to Defeat ALS in Massachuse­tts. At left are his daughter Anna and son Tyler, and at right is his son, Drew.
Jarvis Chen Steve Kowalski, center in glasses, poses with people who participat­ed in the 2018 Ride to Defeat ALS in Massachuse­tts. At left are his daughter Anna and son Tyler, and at right is his son, Drew.

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