FDA advisers recommend approval of controversial ALS drug

Independent advisers to the Food and Drug Administration voted 7-2 on Wednesday to recommend approval of an experimental ALS drug with strong support from patients and advocates, making it likely the highly controversial treatment will be approved by the agency in a few weeks.

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

But on Wednesday, after hours of discussion, several advisers said additional testing submitted by the drug’s Cambridge-based maker Amylyx strengthened the approval case, although uncertainties remain. Counselors were also affected by the severity of the disease and the lack of effective treatments. A senior Amylyx official’s vow to pull the drug from the market if a larger study, involving 600 patients, failed to show its 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 September 29.

The improvement in the drug’s fortunes came despite criticism from FDA staff just last week over the treatment’s effectiveness, the conduct of its clinical trial and 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 shows promise for a deadly 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 pointed out that the agency could use great flexibility to phase out drugs for diseases like ALS that lack effective treatments.

Dunn also noted that the large manufacturer-led trial will wrap up late next year or early 2024; this trial should definitely show if the drug is working. In a highly unusual move, he asked company officials if they would voluntarily withdraw the product if it was approved now, but the wider trial showed no efficacy.

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 removing the product from the market,” he said.

Other experts have warned, however, that a voluntary pledge like Klee’s is not legally binding.

Still, Amylyx’s engagement 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 scans left her “slightly to moderately” confident the drug prolongs life by at least several months. “Depriving ALS patients of a drug that might work is not something I feel very comfortable with,” she said.

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

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 possibly breathe. About 30,000 people in the United States have ALS, sometimes called “Lou Gehrig’s disease.” Another 6,000 are diagnosed each year. There are two FDA-approved therapies on the market, but their effectiveness is limited.

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

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

Desperate patients want a new drug for ALS. The FDA isn’t sure it works.

ALS advocates were thrilled with Wednesday’s vote. “We commend and thank the FDA Advisory Committee for their vote to approve AMX0035 and urge the FDA to approve quickly,” said Scott Kauffman, Chairman of the Board of the ALS Association. . “Americans living with ALS can’t wait.”

During the public hearing portion of Wednesday’s session, leading ALS doctors argued for the drug’s approval, saying even small benefits could go a long way in treating a deadly neurodegenerative disease. Several patients who obtained the drug through clinical trials gave emotionally heartbreaking testimonials asking for approval.

Vance Burghard said he was diagnosed with ALS in 2017 and quickly needed help pulling up his pants. Through a clinical trial, he took AMX0035 for three years, which he called “life changing.” He said his condition stabilized and he was 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 had it.” A few years later, he was diagnosed with the disease and subsequently enrolled in the six-month Amylyx trial. He thinks he was given the placebo, but as a trial participant, he was offered the drug after the trial ended, in what is called an open-label study.

Canter said the drug stabilized his breathing and helped him in other ways. “I am still alive, living independently and my disease progression has decreased significantly,” 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 “old-fashioned paternalism is out of place,” he said through an aide, because his speech is severely affected. “There’s only one right 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 which showed the drug was safe and slowed the decline of essential functions such as walking, talk and cut food. .

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

More recent analyzes submitted by the manufacturer showed that AMX0035 extended 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 on a single study, particularly when the agency said it didn’t find the data “exceptionally compelling.” The agency said the company did not sufficiently account for deaths during the trial and disputed other aspects of the study. He said the additional scans did not include any new information.

Canada recently approved AMX0035 on a conditional basis. This means that Amylyx can sell the drug but must confirm its benefits based on the results of the larger trial. But the FDA approval processes are somewhat different from those in Canada.

Some ALS patients are already taking one or both components of AMX0035. Since sodium phenylbutyrate is approved for other purposes, doctors are allowed to prescribe it off-label for ALS. And the nutritional supplement, sometimes referred to as TUDCO, is available on various websites.

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

Others agreed that the FDA has the legal responsibility to determine that drugs are safe and effective, but noted that it has some flexibility on how to do this. Obscure data can complicate the picture.

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

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