But on Wednesday, after hours of discussion, several advisers said additional analysis submitted by the drug’s maker, Cambridge-based Amylyx, strengthened the case for approval, although uncertainties remain. Counselors were also affected by the severity of the disease and the lack of effective treatments. A promise by a top Amylyx official to pull the drug from the market if a larger study, involving 600 patients, fails to show its efficacy also factored into the vote.
The FDA, which generally follows the advice of its outside advisers but is not required to do so, is expected to decide whether to approve the drug before September 1. 29
The best fortunes in medicine occurred despite criticism from FDA staff last week on the effectiveness of the treatment, the conduct of its clinical trial, and the researchers’ interpretation of the data.
But the drug is considered safe, and the agency has come under intense pressure from ALS patients and doctors who say the treatment holds promise for a deadly disease that typically causes rapid deterioration and death.
Wednesday’s vote came after a dramatic moment with Billy Dunn, director of the FDA’s Office of Neuroscience, emphasizing that the agency can use broad flexibility to approve drugs for diseases like ALS that lack effective treatments.
Dunn also noted that the big test the manufacturer is running will be completed late next year or early 2024; that trial is expected to show definitively whether the drug works. In a highly unusual move, he asked company officials if they would voluntarily recall the product if it were approved now, but the larger trial failed to prove its effectiveness.
Justin Klee, co-CEO of the Cambridge-based biotech company, agreed If the larger trial is not successful, “we will do the right thing for patients, including taking the product off the market,” he said.
However, other experts cautioned that a voluntary commitment like Klee’s is not legally binding.
Still, Amylyx’s commitment and new analytics convinced some panel members to change their votes starting in March. Liana G. Apostolova, a neurologist at Indiana University School of Medicine, said the new tests left her “mildly to moderately” convinced that the drug extends life by at least several months. “Depriving ALS patients of a drug that might work is not something I’m very 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 that 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, depriving 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.” Each year another 6,000 are diagnosed. There are two FDA-approved therapies on the market, but they have limited efficacy.
The experimental treatment was dreamed of nearly a decade ago by Brown University undergraduates who later founded Amylyx: Klee and Josh Cohen, now co-CEOs.
The ALS drug 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 as a powder that dissolves in water at room temperature and is drunk or given through a feeding tube.
ALS advocates were delighted with Wednesday’s vote. “We applaud and thank the FDA Advisory Committee for their vote to support the approval of AMX0035 and urge the FDA to approve it quickly,” said Scott Kauffman, Chairman of the ALS Association Board of Directors. “Americans living with ALS can’t wait.”
During the public hearing portion of Wednesday’s session, top ALS doctors argued for approval of the drug, saying even small benefits could provide enormous help in treating a deadly neurodegenerative disease. Several patients who got 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 taking AMX0035 for three years, something he called “life changing.” He said that his condition has stabilized and that he has been able to walk in China and Tibet.
Gregory Canter said he participated in the ALS Association’s Ice Bucket Challenge several years ago, even though he “didn’t have ALS and didn’t know anyone who did.” A few years later, he was diagnosed with the disease and subsequently enrolled in the six-month Amylyx trial. He believes he received the placebo, but as a trial participant he was offered the drug after he finished the trial, as part of what is called an open-label study.
Canter said the drug has stabilized his breathing and has helped him in other ways. “I’m still alive, I’m living independently, and my disease progression has slowed down remarkably,” he said.
Brian Wallach, a former Obama White House staffer who was diagnosed five years ago, noted that some members of the panel said that he 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 “old-fashioned paternalism is misplaced,” he said through an aide because his speech is severely affected. “There is only one correct answer here. I just 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 trial that showed the drug was safe and reduced declines in essential functions like walking, talking, and cutting food by 25%. . .
In a follow-up study, in which the drug was offered to all participants, patients who received the treatment from the start of the trial lived an average of more than six months longer than those who did not receive it, the researchers found.
The most recent analyzes presented by the manufacturer showed that AMX0035 prolonged median survival several months longer than originally thought, delayed first hospitalizations, and reduced serious complications.
Still, the FDA has signaled for months that it had doubts about approving the drug in a single study, especially when the agency said it didn’t find the data “unusually persuasive.” The agency said the company failed to properly account for deaths during the trial and took issue with other aspects of the study. He said the additional analyzes did not include new information.
Canada recently approved AMX0035 conditionally. That means Amylyx can sell the drug, but must confirm its benefits based on the results of the larger trial. But the FDA’s approval processes are somewhat different than Canada’s.
Some ALS patients are already taking one or both components of AMX0035. Since sodium phenylbutyrate is approved for another purpose, doctors can prescribe it off-label for ALS. And the nutritional supplement, sometimes called TUDCO, is available from a variety of websites.
Some health policy experts said at the hearing that the drug should not be approved until additional data proves its effectiveness.
Others agreed that the FDA has a legal responsibility to determine that drugs are safe and effective, but noted that it has flexibility on how to do so. Cloudy data can complicate the picture.
“The science is complicated, and even well-designed trials won’t always give a clear answer,” said Holly Fernandez Lynch, a bioethicist at the University of Pennsylvania who is not on the panel.
