F.D.A. Panel Declines to Endorse Controversial Alzheimer’s Drug

A federal panel of medical experts on Friday sharply rejected arguments in support of a closely watched new Alzheimer’s drug, saying the evidence wasn’t persuasive enough for the drug to be approved as the first new Alzheimer’s therapy in nearly two decades.

The nonbinding vote by an advisory panel for the Food and Drug Administration does not mean the agency won’t approve the drug, aducanumab, made by Biogen. But it signals that many experts in the field are not convinced of its effectiveness, another major setback in the long journey to find a treatment for Alzheimer’s that works.

In a seven-hour virtual meeting on Friday, the panel showed pointed skepticism, which contrasted markedly with a presentation by Dr. Billy Dunn, director of the Food and Drug Administration’s office of neuroscience, who said that “the evidence supporting its approval appears strong.”

Overwhelmingly, the panel members disagreed.

“There are literally a dozen different red threads that suggest concerns about the consistency of evidence,” said one member, Dr. Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health. He said he could not understand “how the F.D.A. could conclude that there is substantial evidence of effectiveness.”

Ten of 11 panel members voted that it was not “reasonable” to consider the research presented as “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease.” The 11th member said he was uncertain.

It was a stunning turn of events, coming two days after the F.D.A. had posted documents that suggested most of the agency’s reviewers considered the evidence convincing, a development that sent Biogen’s stock price soaring by more than 40 percent. Most of Friday’s votes occurred after the financial markets had closed.

Nearly six million people in the United States and roughly 30 million globally have Alzheimer’s disease, a number that is expected to more than double by 2050. Aducanumab — which is given as a monthly intravenous infusion and would cost about $50,000 per year — would be the first medication to address cognitive decline by attacking the core biology of Alzheimer’s disease. It has been considered a potential medication for the roughly two million Americans estimated to have mild Alzheimer’s-related cognitive decline.

The drug’s path through clinical trials has been rocky, with only one of two Phase 3 trials showing positive results — and those results emerged only from an analysis of additional data after the trials were stopped in March 2019 by an independent data monitoring committee because the drug didn’t appear to be working.

The F.D.A. usually requires two convincing studies for a drug to be approved, although the agency has made exceptions, especially for severe or deadly diseases for which little or no treatment is available.

Samantha Budd Haeberlein, a Biogen senior vice president and head of neurodegeneration development, told the panel that “the benefit-risk profile for aducanumab is favorable and potentially prolonged patients’ independence by several months.”

Dr. Dunn of the F.D.A. said the single positive study was “highly persuasive” and provided “substantial evidence of the effectiveness of aducanumab.” The positive study found that patients on a high dose of the drug, 10 milligrams per kilogram, declined at a rate 23 percent slower than in people who had received a placebo. Dr. Dunn said the agency’s analysis concluded that the results of the negative study, which did not show that patients on the high dose benefited, did not contradict the successful study or show that the drug was ineffective.

Some members of the panel were uncomfortable with the idea that successful results of one trial should be considered over unsuccessful results of the other trial.

Dr. Scott Emerson, a professor emeritus of biostatistics at the University of Washington, said that having to ignore the negative study was like saying, “I’m going to, you know, choose two numbers and only tell you what the highest number I chose was.”

He later added that he was “very disturbed” that the F.D.A. seemed to be “starting out with the assumption that the treatment works” and then trying to figure out why the other study failed. He said the agency’s position seemed “weighted” toward the drug company, adding that “all of this was just terrifically one-sided.”

Of the 11 voting committee members, eight said that they did not even think the single study provided strong evidence that the drug was effective. Two members said they were uncertain.

The only member to vote that the single study’s evidence was convincing was the committee chairman, Dr. Nathan Fountain, a professor of neurology at the University of Virginia.

“I think there are lots of small issues with it, but the trends, I think, are all in the right direction,” he said.

There are currently five medications that have been approved to treat cognitive and memory symptoms, but they typically delay decline for only several months. The last new drug was approved in 2003, and none of them address the specific disease process of Alzheimer’s.

Aducanumab is a monoclonal antibody that targets the beta amyloid protein that clumps into plaques in Alzheimer’s disease. Many other drugs that reduce amyloid accumulation have not been shown to slow symptoms, so if aducanumab is determined to be effective, it would support a long-held theory that attacking amyloid can help if done early enough in the disease process, when memory and cognitive difficulties are still mild.

Some experts said that if aducanumab were approved, it would make it less likely that patients would participate in studies for other Alzheimer’s drugs that might ultimately work better.

“I think if we approve something where the data is not strong that we have a risk of delaying, good treatment and effective treatment for more than a couple of years — for many years,” said another panel member, Dr. Joel Perlmutter, a professor of neurology at the Washington University School of Medicine. “I think there’s a huge danger in approving something that turns out not to be effective.”

Several experts, including a Mayo Clinic neurologist who was a site investigator for an aducanumab trial, have said that another rigorous clinical trial should be conducted before a decision is made on whether the drug should be made available.

“Perfection may be the enemy of the good, but for aducanumab, the evidence doesn’t even rise to ‘good,’” the neurologist, Dr. David Knopman, wrote in a comment submitted to the panel before Friday’s hearing. Dr. Knopman, who sits on the advisory panel but was recused from the hearing because of his work with the aducanumab trials, added, “Contrary to the hope that aducanumab will help Alzheimer patients, the evidence shows it will offer improvement to none, it will harm some of those exposed, and it will consume enormous resources.”

Documents posted by the F.D.A. in advance of the hearing gave the impression that most of the agency’s reviewers were satisfied that data from the successful trial was strong and that safety issues, which mostly involved a type of brain swelling, were manageable.

But another F.D.A. reviewer expressed concerns in the documents. Tristan Massie, an F.D.A. mathematical statistician, wrote that he believed “there is no compelling, substantial evidence of treatment effect or disease slowing and that another study is needed.”

Other experts said that the degree of benefit the trial claims to show is slight, slowing cognitive decline over 18 months by half a point on a 3-point cognitive scale, the primary measurement in the study.

“My view is that it doesn’t do anything,” said Dr. Michael Greicius, medical director of the Stanford Center for Memory Disorders.

At Friday’s hearing, Dr. Budd Haeberlein said that based on another scale used as a secondary measure, the drug might prolong decline in a person’s daily functional ability by seven months in an 18-month period.

Patients’ groups argued forcefully for approval, citing the devastation caused by the disease.

“While the trial data has led to some uncertainty among the scientific community, this must be weighed against the certainty of what this disease will do to millions of Americans absent a treatment,” the Alzheimer’s Association wrote in a letter to the panel. “The potential to delay decline would be denied to millions, and that time lost for those spouses, partners, moms, dads, grandmothers, grandfathers, aunts, uncles, friends, and neighbors cannot be recovered. In the balance of these considerations, we urge approval.”

Friday’s meeting also featured poignant comments from several people with Alzheimer’s or their family members.

“After years of great disappointment in drug trials for those in the throes of urgency as our minds decline, please offer us some hope,” said Greg O’Brien, a former journalist who wrote a book about his experience with Alzheimer’s. “Please recommend approval of this drug therapy. Sorry I can’t properly pronounce the name of the Biogen drug, it’s just too complicated for me.”