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 analyzes 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, 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.
Desperate patients want a new ALS drug. The FDA is not sure it works.
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 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 “life-changing.” 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 later enrolled in the six-month 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, independent 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 aid 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 he 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.