FDA will decide fate of contentious Alzheimer's drug. The stakes 'could not be higher.'

A Food and Drug Administration advisory panel today will debate whether to recommend the first new drug treatment for Alzheimer's disease in nearly two decades.

But in order to approve Biogen's aducanumab, the agency must conclude data from two studies halted prematurely is promising enough to approve the controversial drug as a treatment for 5.8 million Americans with the mind-robbing disease.

In a document released this week, FDA reviewers largely gave a positive assessment of aducanumab, finding "substantial evidence of effectiveness" as a treatment for Alzheimer's disease. However, in the same document, another reviewer raised questions about statistical methods, was not convinced of the evidence and recommended another trial.

Scientific experts on the Peripheral and Central Nervous System Drugs Advisory Committee will vote whether to recommend the agency should approve the drug. The FDA can accept or reject the committee's recommendation.

Aducanumab has stirred considerable debate among Alzheimer's researchers for its unconventional path to approval. 

After a small, initial study showed the monoclonal antibody was safe, Biogen launched two large trials in 2015 to gauge the effectiveness of the drug, which removes beta  amyloid plaques from the brain of an Alzheimer's patient.

In March 2019, the company halted companion studies that produced different results after an independent "futility analysis" concluded the drug did not seem to work. At the time, it appeared to join a growing list of amyloid-targeting drugs over the past two decades that looked promising in early studies only to fizzle in late-stage, expensive trials.

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But after reviewing data from the two trials, Biogen decided there was enough evidence from one trial with positive results and signals from a subgroup of the second trial to support high doses of the drug as safe and effective. The company held talks with the FDA and submitted a new drug application, which the agency has fast-tracked with priority review.

Dr. Howard Fillit, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation, said the FDA faces a "very challenging decision."

No new treatments have been approved since the early 2000s, and no drug effectively slows the progressive, fatal neurodegenerative disease that erodes a person's memory and ability to perform daily tasks. The disease burdens loved ones and caregivers, and cost families and taxpayers $305 billion in 2020, according to the Alzheimer's Association.

"We have a very serious disease to individuals, families and society ... and here’s a drug that looks promising," Fillit said. "So how does the FDA balance what they’re seeing in the data, deciding what the quality of the data is, and making that decision in the face of advocacy groups and the great unmet medical need here for getting a drug on the market?"

Fillit said if the agency wants the highest level of evidence, it would require another large-scale clinical trial to gauge the drug's effectiveness. However, such a study would take four or five years, cost hundreds of millions of dollars and "people would not have access to that drug."

The FDA document noted the drug had side effects called ARIA, or amyloid-related imaging abnormalities, which can lead to headaches or other symptoms. ARIA, commonly associated with anti-amyloid drugs, was more likely in patients on higher dosages, surfaced early during treatment and was more common in those who carried an Alzheimer's susceptibility gene. 

Advocacy groups such as the Alzheimer's Association say the publicly available data supports a favorable review and post-approval safety monitoring. 

"We understand the trial has led to uncertainty – it's not a clear-cut trial you would love to see in a perfect world," said Maria Carrillo, the Alzheimer's Association's chief science officer. "But this uncertainty has to be weighed against the certainly of what this is going to do to millions of Americans" who wouldn't have access to a drug that might slow the disease.

Other Alzheimer's experts say they don't see the evidence to support approval.

In a perspective published in the journal Alzheimer's & Dementia, Dr. David Knopman, a Mayo Clinic neurologist, and two co-authors argued the studies did not produce enough evidence to show the drug works. Knopman sits on the FDA advisory committee that will evaluate aducanumab but will recuse himself from today's meeting. 

While PET scans showed the drug appeared to remove amyloid from patients' brains, "no evidence was presented to correlate biomarker changes to cognitive benefits," the authors argued. They said Biogen should conduct another late-stage study.

"The pending FDA decision will be monumental for our field," Knopman and the co-authors wrote. "The stakes for offering genuine benefit for our current patients, for future health economics, and for future clinical trials in (Alzheimer's disease) could not be higher."

Dr. Eric Reiman, executive director of Banner Alzheimer's Institute and a researcher, said it was an unfortunate decision to halt the study early. That leaves the FDA with the difficult decision of evaluating one study with a positive results and a second study that failed but showed some positive signals.

"It’s a difficult decision – a close call," Reiman said. "I ask myself, if I had an affected family member, would I want the treatment available with the uncertainties? I think I would."

Ken Alltucker is on Twitter as @kalltucker or can be emailed at alltuck@usatoday.com