The US Food and Drug Administration (FDA) has approved sodium phenylbutyrate/taurursodiol (Relyvrio, Amylyx Pharmaceuticals), a novel drug to treat amyotrophic lateral sclerosis (ALS).
The approval was expected but comes at the end of an unusual review process that began in March with an initial recommendation from the FDA's Peripheral and Central Nervous System Drugs Advisory Committee not to approve the drug because, it said, there was insufficient evidence of efficacy.
The March decision was criticized by patients and other advocates for failing to consider the unmet medical need in ALS and the seriousness and lethality of the disease.
"When you are evaluating drugs that may be effective for a certain patient population, we do believe the threshold should be different when you are talking about a disease that is terminal, where there are very few treatment options available, and that question should have been considered," Melanie Lendnal, JD, senior vice president of policy and advocacy for the ALS Association, told Medscape Medical News.
Following submission of updated data analyses and new biomarker data from the manufacturer and an aggressive campaign by patients with ALS and associated advocates, the FDA delayed its final ruling on the drug's approval and reconvened the panel for a rare second review in early September, as reported by Medscape Medical News.
This time, the panel was not asked if the data provided conclusive evidence of efficacy, but if the data was sufficient for approval. It also received broader latitude to consider the unmet medical need and lethality of ALS.
Following this meeting, the committee did an about-face and voted 7 to 2 in favor of the drug's approval.
Advocacy Trumping Science?
The news about the drug was welcomed by patients and advocates. Still, others voiced concerns that the decision signals a growing and outsized role of patient advocacy in the drug approval process.
"There has been concern that advocacy is trumping science in some of these settings and I think the FDA has to be sure there are appropriate safeguards so that science leads the way," advisory panel member Caleb Alexander, MD, professor of epidemiology and medicine and co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News.
Alexander voted against approval in March and again earlier this month.
"You do have unmet need and you do have an emphasis of this notion of regulatory flexibility, but you also have evidentiary standards of approval and I think that what scientists and regulators have to do is navigate these sometimes-murky waters," Alexander said. "I don't think the evidence is there for this product at this time."
Lendnal countered that if a drug is safe and effective and intended for a serious illness with few available treatment options, there is a role for patient advocacy in the drug approval process.
"When you're talking about a really serious disease with a huge unmet need I do think there is a role for patients and their families to play in communications to decision-makers as they consider whether to approve a drug, and part of that consideration is how high should the bar be," she added.
The FDA has approved two therapies for ALS, but both have limited efficacy. Relyvrio is the first new drug approved for ALS in 5 years.
Slower Functional Decline
Typically, FDA approval requires two large studies or one study with a "very persuasive" effect on survival.
Amylyx's application was based on a single study, the multicenter, two-phase CENTAUR trial. In that trial, 137 people with ALS received AMX0035 or placebo for 24 weeks.
As previously reported by Medscape Medical News, researchers found that patients receiving AMX0035 had a 25% slower decline in function compared with those taking placebo. A change of 20% or more is considered clinically meaningful.
Investigators also found a statistically significant median difference of 4.8 months in time to death, first hospitalization, or tracheostomy/permanent assisted ventilation in the group originally assigned to receive AMX0035 compared with the group originally assigned to receive placebo (hazard ratio, 0.62; P = .023).
Amylyx is currently conducting a 48-week international, phase 3, placebo-controlled PHOENIX clinical trial of AMX0035. The study has enrolled about half of its 600-patient target and results are not expected for another year or two.
At the second committee review hearing in September, Amylyx Pharmaceuticals officials said that if the PHOENIX trial fails to prove efficacy, the company would withdraw the drug.
However, the company is under no legal requirement to pull the drug and the process for the FDA to remove a product from the market is fraught with complications, especially if the manufacturer doesn't cooperate.
No Going Back?
"Once a product is approved, to a large degree the horse is out of the barn," Alexander said. "The notion that the FDA and sponsor can simply agree that we're going to pull back the reigns if the next study isn't promising is a little bit foolhardy."
Another factor is that FDA approval does not require the company to complete the trial. However, the conditional approval Amylyx received in June is reliant on the outcome of PHOENIX. Approval in Europe is also contingent on final results of the trial.
That means the odds the company will complete the trial are good, said Holly Fernandez Lynch, JD, an assistant professor of medical ethics at the University of Pennsylvania Perelman School of Medicine, Philadelphia.
Also unanswered is the question of cost, she said, adding that "the company has been very quiet about how it's going to price this drug."
"It’s one thing to say, 'Fine, this product should be allowed on the market, even though we’re not 100% sure it works,' but it is wild to suggest that you ought to be able to charge as much as you would if you have proven that the product works, she said.
Relyvrio can be taken orally by combining one packet in 8 ounces of room temperature water. It can also be administered through a feeding tube. The recommended dosage for the first 3 weeks is one packet (3 grams sodium phenylbutyrate and 1 gram taurursodiol) daily. After 3 weeks, the dosage increases to one packet twice a day. The medication can be taken before a snack or meal.
The most common adverse reactions experienced with Relyvrio were diarrhea, abdominal pain, nausea, and upper respiratory tract infection. Relyvrio contains taurursodiol, a bile acid, which may cause worsening diarrhea in patients with disorders that interfere with bile acid circulation. These patients should consider consulting with a specialist before taking Relyvrio.
Kelli Whitlock Burton is a reporter for Medscape Medical News covering neurology and psychiatry.
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Cite this: FDA OKs Novel ALS Drug, Despite Unusual Path to Approval - Medscape - Sep 29, 2022.