WASHINGTON (AP) — When patients are battling an incurable disease and want access to an experimental drug, how much evidence do regulators need before approval that it works?
That’s the question behind many of the Food and Drug Administration’s toughest decisions, including EduHelm’s controversial approval last year. Many experts – including the agency’s own outside consultants – say the Alzheimer’s drug is unlikely to help patients.
Less than a year later, the agency may soon approve another drug for a deadly neurodegenerative disease, which is being debated by experts, based on partial data. The FDA meets next week to publicly review evidence from a small, mid-stage study of Amylix Pharmaceuticals’ drug for ALS, or amyotrophic lateral sclerosis.
According to the company, regulators told Amylex last year that it would need to conduct a larger, confirmatory study before it could receive approval. But after months of intense lobbying by ALS patients and their representatives in Congress, the agency said it could submit the drug based on smaller studies.
The change was so sudden that it even surprised some doctors, who helped study the treatment, which appears to only modestly slow patients’ decline.
“The effect is there, but it’s not a domestic one,” said Dr. Jeffrey Rothstein of Johns Hopkins University. “Does it really work? I don’t know. So I’d like to see another study.”
The FDA has traditionally required two large, late-stage studies for approval. For fatal diseases such as cancer, a study showing promising early results is often accepted.
Amylyx’s decision comes as government investigators look into Aduhelm’s approval, including whether the agency has succumbed to pressure from Alzheimer’s groups and pharmaceutical interests.
Experts who study FDA decision-making see a troubling pattern in which the beleaguered agency is under constant pressure to accept weak evidence, damage its scientific credibility and open the door to ineffective treatments.
“A lot of people were concerned about the precedent of the FDA approving EduHelm,” said Dr. Joseph Ross of Yale University. “They were committed to both industry and patient advocacy pressure as opposed to essentially following the science.”
An FDA spokesperson declined to discuss the review, citing agency rules, but noted that Amylex’s submission “is not a determination on the merits of the application.” The FDA will post its preliminary review of the drug before Wednesday’s meeting.
There are significant differences between the two drugs. The FDA approved an Alzheimer’s drug based on laboratory measures suggesting it helps slow cognitive decline, even though the company’s studies failed to show a significant patient benefit. In the case of the drug Amylyx, ALS patients showed a measurable improvement, but the therapy had no effect on laboratory results.
Given that patient benefits, advocates argue that the FDA should approve Amylyx’s treatment.
ALS, also known as Lou Gehrig’s disease, destroys nerve cells necessary for walking, talking, swallowing, and eventually breathing. There is no cure and most people die within three to five years.
The drug Amylyx is a combination of two old pharmaceutical ingredients: a prescription medicine for liver disorders and a dietary supplement associated with ancient Chinese medicine. Cambridge, Mass.-based Amylyx has patented the combination and says the chemicals work together to protect cells from premature death. (Its co-founders declined interview requests for this story.)
Some ALS patients already take both pills. FDA approval would potentially force insurers to cover the treatment.
In the 137-patient study, people taking the drug progressed 25% slower than those taking a placebo, as measured on a 48-point questionnaire that tracks tasks such as walking, handwriting, and swallowing. The difference in scores – 2.3 points – was statistically significant, but experts differ on its meaning for patients.
Dr. Katherine Loemann-Horth of the University of California San Francisco said even a single digit drop could be important.
“It’s the difference between being able to feed or feed yourself,” said Lomen-Horth, who was not involved in the research.
An editorial in the New England Journal of Medicine called the results “incremental” and “modest” and recommended longer, larger studies.
An FDA decision appeared years away, but the results sparked a campaign by patient groups, beginning with a petition calling on the agency to take action. When the FDA appeared to reverse its stance on the drug in September, advocates took credit.
For people living with ALS, the logic is clear: Any drug that can prolong or improve life is worth trying.
The FDA has approved only two treatments for ALS. The more effective one is, the longer it extends life by several months, and many experts say that Amylex’s drug is likely to show a similar benefit.
Larry Falivena, who was diagnosed with ALS in 2017, said, “When you have no choice in front of you, you definitely want the opportunity to do anything that can help you.” He is due to speak at the FDA meeting next week.
The 53-year-old father of two joined half a dozen other patients in calling on the FDA to approve Amylix’s drug during an online “listening session” last May.
The session was organized by the ALS Association, which invested $2.2 million in research on Amylyx. The group — a major beneficiary of the 2014 “Ice Bucket Challenge” viral fundraising campaign — could receive up to $3.3 million in proceeds if the drug is approved.
The association says such arrangements are standard among nonprofits that fund research and that proceeds go toward further studies. The “payback clause” is a way to help bring effective treatments to market as quickly as possible, the group said in a statement. It said it would not advocate approval if the drug was not safe and effective.
During the hearing session, the FDA’s Dr. Patrizia Cavazzoni reiterated the agency’s longstanding position: If drugmakers develop better biological measures of how their drugs work, the agency could use them to speed approval.
The 48-point scale used by Amylyx is the standard for ALS research, but some experts question its reliability. For example, it is not uncommon for patients to report improvement in function despite measures such as decline in muscle strength.
Several weeks later, Cavazzoni was called before a House of Representatives subcommittee. During a five-hour hearing requested by patient advocates, lawmakers pressured her over the state of Amylex’s drug.
The co-founders of I AM ALS, another patient group, also testified. Brian Wallach and his wife, Sandra Abrevia, worked at the Obama White House and formed their group following Wallach’s 2017 diagnosis with ALS. The nonprofit quickly became a political force in Washington, pushing legislation through Congress to, among other things, give the FDA a five-year plan to accelerate drug development for ALS and similar conditions. needs to be developed.
In their joint testimony read by Abrevia, they called on lawmakers to intervene on behalf of patients: “The answer is very simple: make the FDA act immediately and with the regulatory flexibility it promised.”
A spokesperson for I Am ALS dismissed the idea, saying the group was “telling the FDA what to do.”
“We’re not trying to pressure the FDA,” Theresa Garner said. “We are following standard procedure and making sure that the FDA and its advisory committee hears from people living with this disease.”
The FDA advisory panel of outside experts meeting on Wednesday is the same one that voted against Aduhelm. The FDA disregarded its advice and approved the drug, forcing three members to resign.
Given that the same FDA scientists and leadership are overseeing Amylyx, approval is widely expected.
Johns Hopkins researcher Rothstein plans to prescribe the drug to his patients. But he still wants to see more data.
“I’d love to have the FDA wait for two tests,” he said. “Patients will say, ‘You’re depriving me of a drug.’ And the reverse is: ‘I can deny you a drug that is not effective.'”
Follow Matthew Perrone on Twitter: @AP_FDAwriter
The Associated Press Department of Health and Science receives support from the Howard Hughes Medical Institute’s Department of Science Education. AP is solely responsible for all content.