Breakthrough for dementia or FDA’s biggest blunder?

On June 7, 2021, the FDA approved Aduhelm (aducanumab). Biotechnology company Biogen is marketing Aduhelm as “the first new Alzheimer’s drug in almost 20 years.” Biogen makes clear that Aduhelm is not a cure for Alzheimer’s disease (AD), but an attempt to slow memory loss. 

So, is it time to celebrate with the six million families in the U.S. who suffer from this disease that Nancy Reagan once called the “the long, long goodbye?” Or is this a time to bemoan Big Pharma’s greed and the FDA’s kowtowing to the Alzheimer’s Association and Biogen?

How it works

One hypothesis about Alzheimer’s is that amyloid, a naturally occurring protein in the brain, clumps together to form plaques that collect between neurons and disrupt cell function. Aduhelm, a monoclonal antibody (which are currently used in treating several cancers, multiple sclerosis, and COVID-19), targets and binds to amyloid in the brain, breaks it down, and eliminates it from the brain and spinal fluid. 

The drug is administered as an intravenous infusion (45-60 minutes) every four weeks in a doctor’s office or infusion center.

In the clinical trials that brought Aduhelm to market, 35 percent of patients had evidence of brain swelling on MRI, and 19 percent had evidence of brain hemorrhage. Commonly reported side effects were headache, confusion, dizziness and unsteadiness. Over 6 percent of patients in the trials stopped Aduhelm because of brain swelling and bleeding, and one patient died of bleeding in the brain. 

Aduhelm was evaluated in two identical, randomized clinical trials. Patients with early AD (i.e. mild cognitive impairment or mild dementia due to AD) were given either Aduhelm or a placebo. Outcomes were evaluated based on a patient’s change in score on a dementia rating scale. Problematically, experts can’t agree on what an important difference is on this scale. 

In March 2019, both trials were terminated following an evaluation that showed that Aduhelm was not effective. Predictably, Biogen re-analyzed the data and found a possible positive treatment effect in one trial, but not the other. 

The FDA’s blunder

FDA Advisory Committees are independent, expert scientists and clinicians who provide advice to FDA decision-makers. In the vast majority of new drug approvals, the FDA follows the advice of their Advisory Committees. The Neurology Advisory Committee met in November 2020 and voted 10-0 not to approve the drug. Three days after the FDA approved Aduhelm anyway, members of the committee resigned in protest over the FDA’s decision.

“The FDA’s decision was probably the worst drug approval decision in recent U.S. history,” said former committee member and Harvard Professor of Medicine Aaron Kesselheim. “This decision will undermine the care of these patients, public trust in the FDA, the pursuit of therapeutic interventions and the affordability of the health care system.”

Another committee member who resigned—Mayo Clinic neurologist David Knopman—added, “I don’t wish to be a part of a sham process...The approval of Aduhelm appears to have been foreordained.”

The Institute of Clinical and Economic Review (ICER)—an independent organization that produces cost-effective analyses on how much new drugs should cost—similarly protested the FDA’s decision. ICER reported that “the FDA, in approving Aduhelm for the treatment of Alzheimer’s disease, has failed in its responsibility to protect patients and families from unproven treatments with known harms.” 

ICER estimated that the annual price for Aduhelm, assuming that the one “positive” study is accurate, should be $2,560 to $8,290. However, Biogen’s actual price is $56,000 per year with a promise from Biogen’s CEO that he won’t raise prices for four years. The estimated associated annual cost of MRIs, PET scans and infusions is $30,000. 

Why it matters

As a doctor with a long career in family medicine, I see many problems with the studies themselves. First, there are two nearly identical studies, but one says it works and the other says it doesn’t. That calls for a third study, not a rushed approval.

Second, it’s unclear what the caregiver assessments meant in the trials. Do the results in the “positive” study really mean something important for the patient? Probably not. 

Finally, there’s no clear understanding of what the swelling and bleeding associated with Aduhelm seen on MRI mean. 

How the FDA failed:

• Totally ignored the unanimous decision of their advisory committee not to approve this drug.

• Assumed that a positive study trumps a negative study. Usually, the FDA requires two positive studies to approve a drug.

• Assumed that the disappearance of amyloid on imaging is synonymous with clinical improvement or slowing of deterioration. There are actually lots of data suggesting that isn’t true.

• Approved Aduhelm for all Alzheimer’s patients when the Aduhelm studies were carried out exclusively in those with mild disease. 

Lastly, in approving this drug, the FDA created false hope for Alzheimer’s patients and their families. I’m optimistic that thoughtful physicians will spend the time to educate Alzheimer’s patients and their desperate loved ones about the lack of documented effectiveness and the potential harms of Aduhelm.

Phil Mohler, MD, is a contract employee of Rocky Mountain Health Plans. He spent the latter years of his career caring for nursing home patients, many who had dementia. Now he focuses on caring for his wife, Nancy, who suffers from Alzheimer’s dementia. Learn more about Dr. Mohler in the BEACON’s April 2021 cover story, “Over tested, over diagnosed and over medicated."