With a 6-4 vote, the group of independent advisers to the agency narrowly concluded that results from another clinical trial are needed to assess whether the therapy, called AMX0035, can help patients.
By a narrow margin, a federal panel of independent medical experts concluded Wednesday that there is not yet enough evidence that an 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 available scientific data on the therapy, a two-drug combination conceived by two college students, was insufficient to show it could help patients by slowing the progression of A.L.S., a ruthless disease that impairs people’s ability to move, speak, eat and ultimately breathe.
The nonbinding vote on the therapy, AMX0035, supported the F.D.A.’s own analysis. The agency will decide whether to approve the drug in the coming months.
Groups representing patients have waged an impassioned campaign for approval, given the dearth of medications for A.L.S., also called Lou Gehrig’s disease, which often causes death within two to five years.
“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.”
The panel’s patient representative, Mark Weston, who has A.L.S., voted that the treatment was effective. So did Dr. Avindra Nath, a clinical director of the National Institute of Neurological Disorders and Stroke, 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 fervent testimony from people living with A.L.S.
Vance Burghard testified that after being diagnosed in 2017, “I needed assistance to pull up my pants,” sometimes needed a wheelchair and “had to have my food cut for me.” A clinical trial participant, he said, “AMX0035 for me is a lifesaving and life-changing drug,” crediting it with allowing him to travel with his wife, walking “many miles in Europe, at the Great Wall of China and descending the stairs at the Potala Palace in Tibet.”
Becky Mourey, 58, was one of several patients who had lost so much speaking ability that family members read some of their words. In testimony read by her daughter, she 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, who said she has been taking the two drugs that comprise the therapy on her own, testified: “I implore you with literal life and death urgency to recommend approval of AMX0035.”
The F.D.A. typically requires two persuasive clinical trials, but in cases of severe disease with few available treatments, it can consider evidence from one clinical trial plus additional supporting data. The data comparing AMX0035 to a placebo came only from a Phase 2 trial, smaller than the preferred Phase 3 studies, with additional information from an open-label extension study that followed some patients after the trial ended when they were knowingly taking the medication.
Last June, in a 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 Aduhelm had unclear benefit and significant safety risks. Three committee members resigned in protest when Aduhelm was approved.
“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 AMX0035, Amylyx Pharmaceuticals, not apply for approval until the drug had completed its Phase 3 trial, for which results are expected by 2024. But in July, officials began suggesting that Amylyx submit an application for approval using existing data. The timing followed vociferous pressure from A.L.S. advocacy groups in the wake of the approval of Aduhelm.
A.L.S. is 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.
Amylyx’s co-founders, Justin Klee and Joshua 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.
Their company financed the bulk of the study, but the A.L.S. Association, a patient advocacy group, contributed $2.2 million, using money raised through the 2014 Ice Bucket Challenge. Amylyx agreed to use sales of the drug to repay 150 percent of the association’s grant to fund more research.
Two-thirds of 137 participants in the Phase 2 trial received AMX0035, a bitter-tasting powder mixed with water to be drunk or ingested 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 AMX0035, translating to a 25 percent slower decline 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. 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, Amylyx reported.
“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,” she added.
F.D.A. reviewers, however, identified many issues with the research.
Dr. Emily Freilich, a leader of the F.D.A. team, said Wednesday that the Phase 2 trial results suggesting that AMX0035 slowed functional decline 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 the evidence, even from the extension study, doesn’t demonstrate that patients receiving the therapy can 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,” she said.
Other F.D.A. concerns included: how researchers accounted for deaths of patients; whether patients could guess they were on AMX0035 from its bitter taste and gastrointestinal side effects; 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; and the fact that the trial’s data analysis method was not what the agency urged Amylyx to use.
Dr. Billy Dunn, director of the F.D.A.’s Office of Neuroscience, discussed the therapy’s lack of effect on a biological marker of injury to neurons.
“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 AMX0035 posed no significant safety risks.
Dr. Alexander, an internist and epidemiologist 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,” he said, “we would have dozens of therapies on the market that might not actually be therapeutic.”
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