Under patient pressure, FDA reviews ALS drug with modest data | Health, Medicine and Fitness
By MATTHEW PERRONE – AP Health Writer
WASHINGTON (AP) — When patients are battling a terminal illness and want access to an experimental drug, how much evidence that it works should regulators require before approval?
That’s the question behind many of the Food and Drug Administration’s toughest decisions, including last year’s. controversial endorsement of Aduhelm. Many experts – including the agency’s own outside advisers – 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 based on partial data debated by experts. The FDA is meeting next week to publicly review evidence from a small, mid-stage study of Amylyx Pharmaceuticals’ drug for ALS or amyotrophic lateral sclerosis.
Regulators told Amylyx last year that it would need to conduct a large confirmatory study before seeking approval, the company says. But after months of intense lobbying by ALS patients and their representatives in Congress, the agency said it could submit the drug based on the smallest study.
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The change was so abrupt that it even surprised some doctors who took part in the study of the treatment, which seems to slightly slow the decline of patients.
“The effect is there, but it’s not a home run,” said Dr. Jeffrey Rothstein of Johns Hopkins University. “Does this really work? I do not know. That’s why I would like to see a second study.
The FDA traditionally requires two large, late-stage studies for approval. For life-threatening diseases like cancer, a study showing promising early results is often accepted.
The Amylyx decision comes as government investigators reviewing Aduhelm’s approval, including whether the agency bowed to pressure from Alzheimer’s groups and pharmaceutical interests.
Experts who study FDA decision-making see a disturbing pattern in which the hard-pressed agency is continually pressured to accept weaker evidence, which undermines its scientific credibility and opens the door to ineffective treatments.
“That’s what worries a lot of people about the FDA approval precedent for Aduhelm,” said Dr. Joseph Ross of Yale University. “They basically capitulated to both industry and patient advocacy pressure, instead of conforming to the science.”
An FDA spokeswoman declined to discuss the review, citing agency rules, but noted that Amylyx’s submission “is not a decision on the merits of the application.” The FDA will release its initial review of the drug ahead of Wednesday’s meeting.
There are important differences between the two drugs. The FDA approved the Alzheimer’s drug based on lab measurements suggesting it helped slow cognitive decline, even though the company’s studies showed no significant patient benefit. In the case of Amylyx’s drug, ALS patients showed measurable improvement, but the therapy had no effect on lab results.
Given this patient benefit, advocates argue that the FDA should approve Amylyx’s treatment.
ALS, also known as Lou Gehrig’s disease, destroys the nerve cells needed to walk, talk, swallow and, eventually, breathe. There is no cure and most people die within three to five years.
Amylyx’s medicine is a combination of two older medicinal ingredients: a prescription drug for liver disorders and a dietary supplement associated with ancient Chinese medicine. Amylyx, based in Cambridge, Mass., patented the combination and claims 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 likely force insurers to cover the treatment.
In a study of 137 patients, people taking the drug progressed 25% slower than those taking a placebo, as measured on a 48-point questionnaire that tracks functions like walking, handwriting and swallowing. The difference in scores – 2.3 points – was statistically significant, but experts differ on its significance for patients.
Dr Catherine Lomen-Hoerth of the University of California, San Francisco said losing even one point can be significant.
“It’s the difference between being able to feed yourself or not being able to feed yourself,” said Lomen-Hoerth, who was not involved in the research.
A New England Journal of Medicine editorial called the results “incremental” and “modest” and recommended longer, larger studies.
An FDA decision emerged years later, but the findings sparked a campaign by patient groups, starting with a petition asking the agency to act. Proponents took credit when the FDA appeared to reverse its stance on the drug in September.
For people living with ALS, the logic is clear: any drug that can prolong or improve life is worth trying.
The FDA has only approved two therapies for ALS. The most effective prolongs life by several months, and many experts say Amylyx’s drug is likely to show a similar benefit.
“When you’re faced with a choice of nothing, you definitely want the opportunity to try anything that can help you,” said Larry Falivena, who was diagnosed with ALS in 2017. He is due to speak at the of the FDA meeting next week.
The 53-year-old father of two joined half a dozen other patients in asking the FDA to approve Amylyx’s drug during an online ‘listening session’ in last May.
The session was organized by the ALS Association, which has invested $2.2 million in Amylyx research. The group, major beneficiary of the 2014 “ice bucket challenge” viral fundraising campaign — could receive up to $3.3 million in revenue if the drug is approved.
The association says such arrangements are the norm among non-profit organizations that fund research and that profits go towards further studies. Reimbursement clauses are a way to help bring “effective treatments to market as quickly as possible,” the group said in a statement. He added that he would not argue for approval if the drug was not safe and effective.
During the listening 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 up approvals.
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 improved function even as measures such as muscle strength decline.
A few weeks later, Cavazzoni was summoned before a House of Representatives Subcommittee. During the five-hour hearing, requested by patient advocates, lawmakers pressed her on Amylyx’s drug status.
The co-founders of another patient group, I AM ALS, also testified. Brian Wallach and his wife, Sandra Abrevaya, worked in the Obama White House and formed their band after Wallach was diagnosed with ALS in 2017. The nonprofit quickly became a political force in Washington, making pass legislation in Congress that, among other things, requires the FDA to develop a five-year plan to accelerate drug development for ALS and similar conditions.
In their joint testimony, read by Abrevaya, they called on lawmakers to intervene on behalf of patients: “The answer is extremely simple: Get the FDA to act with the urgency and regulatory flexibility it has promised.”
A spokeswoman for I AM ALS dismissed the idea that the group would “tell the FDA what to do.”
“We’re not trying to pressure the FDA,” Theresa Garner said. “We’re following the standard process and just making sure the FDA and its advisory committee hear from people who are living with this disease.”
The FDA’s external expert advisory group meeting on Wednesday is the same one that voted against Aduhelm. The FDA ignored his advice and approved the drug, prompting three members to resign.
Since the same FDA scientists and executives oversee Amylyx, approval is widely expected.
Rothstein, the Johns Hopkins researcher, plans to prescribe the drug to his patients. But he would still like to see more data.
“I would rather the FDA wait for two trials,” he said. “Patients will say, ‘You’re depriving me of a drug.’ And the countercurrent is: “I may be depriving you of a drug that is not effective.”
Follow Matthew Perrone on Twitter: @AP_FDAwriter
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