New A.L.S. Treatment Lacks Evidence of Benefit, F.D.A. Panel Finds

By a narrow margin, a federal panel of independent medical experts concluded Wednesday that there is not yet enough evidence that a new experimental therapy for amyotrophic lateral sclerosis, commonly known as A.L.S., is effective in treating the devastating and fatal neurological disorder.

The 10-member advisory panel to the Food and Drug Administration voted 6 to 4 that the available scientific data on the therapy, a two-drug combination conceived by two college students, was too weak to show that it could help patients by slowing the progression of A.L.S., a ruthless disease that robs people of their ability to move, speak, eat and ultimately breathe.

The nonbinding vote on the therapy, AMX0035, supported the analysis by the F.D.A. itself. The agency will decide whether to approve the drug in the coming months.

Groups representing A.L.S. patients have waged an impassioned campaign for the therapy to be approved, given the dearth of medications for the disorder, also called Lou Gehrig’s disease, which often causes death within two to five years. A petition drive received more than 50,000 signatures, and the groups met with F.D.A. officials and pressed members of Congress.

The committee members who voted that the evidence was lacking said it was difficult to disappoint patients hoping for an endorsement of the therapy.

“There’s no question of the burdensome nature of the disease and a huge unmet need for safe and effective treatment,” said one panel member, Dr. Kenneth Fischbeck, an investigator with the National Institute of Neurological Disorders and Stroke. “On the other hand,” he said, “we were asked to look for substantial evidence with persuasiveness and robustness. And I think this one trial doesn’t quite meet that bar.”

One of those who voted that the treatment was effective was Mark Weston, who has A.L.S. and served as the patient representative on the panel. Another was Dr. Avindra Nath, a clinical director of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, who said, “This was a very difficult decision for me and I could have gone either way. But after weighing all the factors and facts presented I hedged over to the yes side.”

All the panelists said they were moved by the fervent testimony from several people living with A.L.S., including a few who had lost so much of their ability to speak that some of their words were read by family members.

Vance Burghard said that after he was diagnosed in 2017, “I needed assistance to pull up my pants” and “had to have my food cut for me.” He sometimes needed a wheelchair and had to stop working at his store. He said that since he began participating in the AMX0035 clinical trial in 2018, he has been able to do construction work on a deck and has taken trips with his wife, walking “many miles in Europe, at the Great Wall of China and descending the stairs at the Potala Palace in Tibet.”

He added, “AMX0035 for me is a lifesaving and life-changing drug.”

In testimony read by her daughter, Becky Mourey, 58, a musician diagnosed with the disorder in 2020, likened A.L.S. to “those inflatable punching bags many of us had as kids — one stroke, it would bounce back up just to be hit again and again and again.”

Finishing in her own voice, Ms. Mourey said: “It is past time we take a step in the right direction toward meeting the critical unmet need of the disease. I implore you with literal life and death urgency to recommend approval of AMX0035.”

Testimony from two public interest groups, Public Citizen and the National Center for Health Research, said the F.D.A. should not approve the therapy without stronger evidence of effectiveness.

The F.D.A. typically requires two persuasive clinical trials to approve a medication, but in cases of severe disease with few available treatments, the agency can make exceptions and consider evidence from one clinical trial plus some additional supporting data. The data comparing AMX0035 to a placebo came only from a Phase 2 clinical trial, smaller than the preferred Phase 3 studies, withadditional information from following some of the patients after the trial ended when they were knowingly taking the medication, a format called an open-label extension study.

Last June, in a highly contentious decision, the F.D.A. approved the controversial Alzheimer’s drug Aduhelm, despite contradictory scientific results from two clinical trials that caused a council of senior F.D.A. officials and an independent advisory committee to determine that the drug did not provide a clear benefit and had significant safety risks. Three members of the committee resigned in protest when the drug was approved.

Wednesday’s hearing involved the same F.D.A. department that reviewed Aduhelm, the Office of Neuroscience, and the same advisory committee (with several different members).

“Some of the features are fairly similar in terms of you have this incredible demand for new treatments for a devastating disease in the midst of murky evidence that really doesn’t point in a clear direction,” Dr. G. Caleb Alexander, who served on the advisory committee in both cases, said in an interview. He voted no Wednesday.

Until last summer, the F.D.A. had recommended that the manufacturer of the new A.L.S. therapy, Amylyx Pharmaceuticals, not apply for approval until the drug had completed a Phase 3 trial, which the company started in 2021 and for which results were expected by 2024. But in July, according to Amylyx’s co-founders, Justin Klee and Joshua Cohen, F.D.A. officials sent an email asking the company to meet to discuss submitting an application for approval using the existing data.

Amylyx filed its application in September. The timing followed vociferous pressure from A.L.S. advocacy groups in the wake of the approval of Aduhelm, and in testimony from advocates and patients Wednesday, several said that if the agency could approve an Alzheimer’s drug with questionable efficacy, it should approve AMX0035.

A.L.S. is the most common motor neuron disorder, diagnosed in about 6,000 people worldwide each year. There are only two approved A.L.S. medications: riluzole, which can extend survival by several months, and edaravone, which can slow progression by about 33 percent.

Mr. Klee and Mr. Cohen were students at Brown University less than a decade ago when they proposed that a combination of two existing drugs, taurursodiol, a supplement sometimes used to regulate liver enzymes, and sodium phenylbutyrate, a medication for a pediatric urea disorder, could safeguard neurons by preventing dysfunction of two structures in cells: mitochondria and the endoplasmic reticulum.

sponsoring

Amylyx financed the bulk of the study, but the A.L.S. Association, a patient advocacy group, contributed $2.2 million in funding, using money raised through the 2014 Ice Bucket Challenge, which brought in about $220 million. Amylyx agreed to use a percentage of income from sales of the drug to repay 150 percent of the association’s grant to fund more research.

The Phase 2 clinical trial involved 137 patients who had developed symptoms of A.L.S. within 18 months before the study began and who were affected in at least three body regions, a sign that the disease is progressing quickly. Two-thirds received AMX0035, a bitter-tasting powder that patients mixed with water to drink or ingest through a feeding tube twice daily. The rest received a placebo.

The primary goal was to slow decline on a 48-point A.L.S. scale rating 12 physical abilities, including walking, speaking, swallowing, dressing, handwriting and breathing. Over 24 weeks, patients receiving a placebo declined 2.32 points more than those taking the drug combination, which translated to a 25 percent slower decline during that time for patients receiving the treatment.

The open-label extension study involved 90 of those patients, including 34 from the placebo group, who began taking AMX0035 about seven months after those who had received it from the beginning. The researchers reported to the F.D.A. that those who received the treatment the longest had a median of 4.8 months more time before being hospitalized, being put on a ventilator or dying.

“This is the first time that we have seen a benefit in both function and survival in an A.L.S. clinical trial,” said Dr. Sabrina Paganoni, the principal investigator of the clinical trial and a neuromuscular medicine specialist at Massachusetts General Hospital’s Healey Center for A.L.S.

“If access is delayed, the patients in my clinic today may never receive the time and function that they could have had. Delaying access is not a risk that we should take,” Dr. Paganoni said.

F.D.A. reviewers, however, identified many issues with both the Phase 2 clinical trial and the open-label extension. They said in briefing documents that the benefit identified was “borderline statistically significant and may not be sufficiently persuasive to allow an effectiveness determination based on a single study.”

Dr. Emily Freilich, a leader of the F.D.A. team, said at the hearing that the clinical trial results suggesting that the drug slowed decline on the A.L.S. functional scale were “not highly persuasive” and that the trial’s secondary measures — including muscle strength, respiratory ability and whether patients were hospitalized — were “not generally supportive” of benefit.

F.D.A. officials said that the evidence, even from the extension study, doesn’t demonstrate that the therapy can help patients live longer. Dr. Freilich said that patients who received the placebo and never switched to AMX0035 survived for a median of 1,295 days, while patients who received AMX0035 for longer than 96 weeks survived for a median of 1,237 days.

“Therefore, we need to ask ourselves if the noted survival benefit is by chance alone or due to underlying disease heterogeneity, rather than an effect of the drug,” Dr. Freilich said.

The F.D.A. also had concerns about the way missing data from some patients was analyzed; the way that the study accounted for the deaths of patients; and the fact that compared to people receiving the placebo, more patients receiving the treatment were also taking one of the other A.L.S. drugs, raising questions about whether the benefit they experienced was the result of AMX0035 or the other drug. The agency also questioned whether patients could guess they were on AMX0035 from its bitter taste and gastrointestinal side effects, and the F.D.A. objected to the trial’s method of analyzing data, which did not comport with the method it had urged the company to use.

In response to a question from a panel member, Dr. Billy Dunn, director of the F.D.A.’s Office of Neuroscience, discussed the therapy’s lack of impact on a biological marker of injury to neurons in the brain.

“Quite honestly,” Dr. Dunn said, “in the interest of having an effective medication available to A.L.S. patients, I think all of us in this space would have preferred to have seen a directional benefit there that was convincing. We didn’t, and we think that is of some concern in the overall picture.”

The F.D.A. did agree with Amylyx that the evidence showed no significant safety risks from the therapy. The advisory committee was not asked to vote on whether the drug was safe.

Dr. Alexander, who is an internist, epidemiologist and expert on drug safety and effectiveness at the Johns Hopkins Bloomberg School of Public Health, said that it would not be ethical or justified to approve a drug with unconvincing benefit just because it appears safe and desperate patients would be willing to try it.

“If you did, we would have dozens of therapies on the market that might not actually be therapeutic,” he said.