FDA advisers recommend approval of controversial ALS drug

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 that the evidence provided by 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, Massachusetts-based Amylyx, bolstered the case for approval, even though uncertainties remained. Advisers were also affected by the disease’s severity and the lack of effective treatments in deciding to support approval. A vow by a top Amylyx official to pull the drug from the market if a larger study, underway with 600 patients, fails to show effectiveness was also a factor.

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.

But Dunn also noted that the manufacturer, Amylyx, is conducting a large trial that will be completed late next year or early 2024; that trial is expected to show definitively whether the drug works or not. And in a highly unusual move, he asked company officials whether they would voluntarily withdraw the product from the market if it was approved now but the larger trial failed to show effectiveness.

Justin Klee, co-chief executive of the biotech company, immediately 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. Responding to questions from committee members, Dunn said the FDA can order a drug off the market if later studies show it is ineffective, but added the process is complicated and time-consuming.

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 FDA-approved 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, the co-chief executives at Amylyx.

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.

Amylyx applied to the FDA for approval of the drug in November . 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%.

In a follow-on study, in which all participants were offered the drug, patients who received the treatment 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.

But 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.

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 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.