The Food and Drug Administration on Thursday approved an experimental treatment for ALS, a serious neurological disorder that causes paralysis and death, despite questions about the therapy’s effectiveness.
The treatment, conceived about a decade ago by two college students, was approved despite the fact that reviews by FDA reviewers concluded there was not yet enough evidence that the drug could help patients live longer or decrease the rate at which they lose functions such as muscle control, speaking or breathing without help. However, the agency decided to greenlight the drug without waiting two years for the results of a large clinical trial, citing data showing the treatment is safe and the desperation of patients with a disease that often kills within two to five years.
The drug, which has the scientific name AMX0035, will be marketed as Relyvrio.
in a drug summary memorandum the FDA wrote that there was “residual uncertainty about the evidence of effectiveness” but that “given the serious and life-threatening nature of ALS and the substantial unmet need, this level of uncertainty is acceptable in this case.” The memorandum also said that the benefits outweigh the risks because the treatment “has no significant safety signals of concern.”
The approval follows a passionate campaign by patients and advocacy groups. In addition, doctors treating ALS patients had requested approval in a letter to the FDA and testimony and in testimony before an FDA advisory committee.
“In your difficult job, there will always be the possibility of making a mistake; it all comes down to which mistake would you rather make,” said Dr. Richard Bedlack, director of the ALS clinic at Duke University, who was tested this month. “Passing AMX0035 and finding out in two years that it doesn’t work, I doubt many will be very upset because people with ALS tried something that was safe and looked promising in 2022.”
But he added: “Can you imagine the mistake of saying no and then getting confirmatory evidence in two years that this really worked? And realizing that all those patients were much more disabled or even dead when they didn’t have to? I don’t know how you can live with yourself if you make that mistake.”
ALS, or amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, is diagnosed in about 6,000 people around the world every year. There are only two other ALS drugs approved in the United States: riluzole, approved in 1995, which can extend survival by several months, and edaravone, approved in 2017, which can slow progression by about 33 percent.
The fight against ALS
The disease, also called Lou Gehrig’s disease, deprives people of their ability to move, speak, eat and, ultimately, breathe.
Relyvrio was conceived by Justin Klee and Joshua Cohen when they were undergraduates at Brown University. They proposed that combining taurursodiol, a supplement sometimes used to regulate liver enzymes, and sodium phenylbutyrate, a drug for a pediatric urea disorder, might protect neurons in the brain from damage in diseases such as ALS by preventing dysfunction. of two structures in cells: mitochondria and the endoplasmic reticulum. They later founded a small company in Massachusetts, Amylyx Pharmaceuticals.
As patients learned about the compound, some began to source the ingredients on their own from Amazon and other sources. In June, Canada became the first country to approve the treatment, under a special condition that required Amylyx to provide better evidence later that it worked. Advocacy groups predicted that some American patients would seek it out in Canada, where it is marketed as Albrioza, if the FDA does not approve it.
Amylyx did not immediately say what price it is considering for the treatment in the United States and has said the price is still being negotiated in Canada.
“Amylyx’s goal is for everyone eligible for Relyvrio to have access as quickly and efficiently as possible, as we know people with ALS and their families don’t have time to wait,” the company said in a statement after the meeting. FDA announcement.
The drug, a bitter-tasting powder mixed with water and drunk or ingested through a feeding tube, traveled an unusual and controversial path to approval. The FDA generally requires two persuasive clinical trials, usually Phase 3 trials, which are larger and more extensive than Phase 2 studies. For serious diseases with few treatments, the agency may accept one trial plus additional confirmatory data.
For Relyvrio, the data comes only from a Phase 2 trial in which 137 patients took the drug or a placebo, as well as an extension study that followed some patients after the trial ended when they were knowingly taking the drug.
The phase 2 trial involved patients who were considered to have rapidly progressing disease. Two-thirds of the participants received Relyvrio. Over 24 weeks, they experienced a 25% slower decline than participants who received placebo: a decline of 2.32 points less in a 48 point ALS scale which rates 12 physical skills, including walking, talking, swallowing, dressing, handwriting and breathing.
The open-label extension study involved 90 of those patients, including 34 from the placebo group, who began taking the drug about seven months later than those who received it from the start. Patients who received the treatment the longest had a median of about 6.5 months longer before they were hospitalized, put on a ventilator or died, Amylyx reported. The researchers later published another analysis that suggested Additional benefits.
The FDA initially recommended that Amylyx not apply for approval until the Phase 3 trial was completed in 2024.
ALS advocacy groups campaigned vehemently to persuade the FDA to reconsider, especially after the agency’s controversial approval last year of the Alzheimer’s drug Aduhelm, despite doubts about whether it worked. Shortly thereafter, FDA officials began suggesting that Amylyx file an application for approval using existing data.
In March, a committee of independent FDA advisors narrowly voted that the treatment had not yet been shown to be effective, a conclusion also reached by the The FDA’s own reviewers. The agency then allowed Amylyx to submit more data and took the unusual step of scheduling a second independent advisory committee meeting for September 7. In a report presented there, agency reviewers they said they also found the new data insufficient.
But Dr. Billy Dunn, director of the FDA’s office of neuroscience, told the advisory committee that “although some might reasonably argue that there is currently no substantial evidence” to justify approval, the agency should exercise “the widest flexibility.” ” when also considering the severity of the disease and the scarcity of available treatments.
dr Dunn posed a question to the company: If the treatment received approval now and was shown to be ineffective in the phase 3 trial, would Amylyx voluntarily withdraw it from the market, saving the agency a lengthy withdrawal process? Klee said the company would.
That commitment from Amylyx, plus emotional testimony from patients and doctors, convinced more members of the advisory committee at the September meeting, where the vote for approval was seven to two.
One of those who voted against approval, Dr. Kenneth Fischbeck, a distinguished researcher at the National Institutes of Health, said the company could provide the therapy to patients for free while they wait for better evidence, but “I don’t think that has met the standard of proof to allow them to sell the drug. .”
Mark Weston, an advisory committee member who has ELA, said he was disappointed that the new information the company submitted was not more robust. “I was expecting something more,” he said. But Mr. Weston, who earlier in the meeting named ALS patients who had died since the March hearing, said he voted for approval because “I can’t separate my thoughts on that from my thoughts on the need dissatisfied.”
That need for treatments was the overwhelming message from patients who were tested. “Instead of thinking you’re protecting me, I want you to recommend your approval so you have a chance at life,” said Brian Wallach, 41, co-founder of “I AM ALS,” an advocacy group, in testimony read mainly by a friend because ALS has profoundly damaged his ability to speak.
Gregory Canter, one of the Clinical trial participants said “the rate of my functional decline has slowed considerably” since starting the drug more than three years ago.
“ALS is the basement; this makes us go up the stairs,” Canter said. “It won’t take us to the top alone, but every step forward is important to point us in the right direction.”
Calaneet Balas, president and CEO of the ALS Association, said in a statement that the FDA’s decision was “a victory for the entire ALS community, who came together to advocate for early approval of AMX0035.” The association and other advocacy groups met with FDA officials, submitted a petition with more than 50,000 signatures, and organized a campaign that generated more than 13,000 emails to the agency.
The ALS Association contributed $2.2 million to the development and study of AMX0035, using money raised through the 2014 Ice Bucket Challenge. Amylyx agreed to use sales of the drug to pay 150 percent of the association’s grant to fund more research.