THE NEW ALZHEIMER’S DRUG—WHO KNOWS IF IT EVEN WORKS?
I’m one of millions who would welcome an effective Alzheimer’s disease treatment. My mother died of it and I know others who either have it presently or who’ve also died of Alzheimer’s. Now, last Monday, along comes the pharmaceutical manufacturer Biogen with their drug aducanumab, with the brand name Aduhelm, as the first treatment approved by the F.D.A. that targets the underlying disease process of Alzheimer’s rather the just its symptoms.
Biogen’s drug had been vigorously lobbied for approval by patient advocacy groups and some physicians eager to have an effective option for patients with the deadly disease. The Alzheimer’s Association wrote “The historic approval of aducanumab ushers in an exciting era in Alzheimer’s and dementia treatment and research. Approvals of the first drug in a new category benefit people living with the disease by invigorating the field, increasing investments in treatments and generating innovation.”
Biogen said that the list price for the drug would be $56,000 per year. Because Alzheimer’s primarily affects older adults, most costs are expected to be covered by Medicare. Not coincidentally, Biogen’s stock price surged 38% on Monday, adding $16 billion to the company’s market value.
However, many experts say there is not enough evidence that the drug can help patients. Here are excerpts from a June 7, 2021 New York times article by Pam Belluck and Rebecca Robbins, F.D.A. approves Alzheimer’s Drug Despite Fierce Debate Over Whether It Works:
The Food and Drug Administration on Monday approved the first new medication for Alzheimer’s disease in nearly two decades, a contentious decision made despite opposition from the agency’s independent advisory committee and some Alzheimer’s experts who said there was not enough evidence that the drug can help patients.
Aduhelm, is a monthly intravenous infusion intended to slow cognitive decline in people with mild memory and thinking problems. It is the first approved treatment to attack the disease process of Alzheimer’s instead of just addressing dementia symptoms.
Recognizing that clinical trials of the drug had provided incomplete evidence to demonstrate effectiveness, the F.D.A. granted approval for the drug to be used but required Biogen to conduct a new clinical trial.
If the new trial, called a Phase 4 trial, fails to show the drug is effective, the F.D.A. can — but is not required to — rescind its approval.
About six million people in the United States and roughly 30 million globally have Alzheimer’s, a number expected to double by 2050. Currently, five medications approved in the United States can delay cognitive decline for several months in various Alzheimer’s stages.
Some other drugs in clinical trials are more promising, but they are most likely three or four years away from potential approval.
Significant Doubts
The FDA advisory committee along with an independent think tank and several prominent experts — including some Alzheimer’s doctors who worked on the aducanumab clinical trials — said the evidence raised significant doubts about whether the drug is effective. They also said that even if it could slow cognitive decline in some patients, the benefit suggested by the evidence would be so slight that it would not outweigh the risk of swelling or bleeding in the brain that the drug caused in the trials.
“The data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit,” the F.D.A.’s director of the Center for Drug Evaluation and Research, Dr. Patrizia Cavazzoni, wrote on the agency’s website.
But, she said, the agency had decided to approve the drug through a program called accelerated approval, which is designed “to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit.”
Michel Vounatsos, Biogen’s chief executive, hailed the approval and said in a statement, “We are committed to sharing our future insights about Aduhelm with the scientific community as we collect more data from the real-world use of this treatment.”
Although the clinical trials were conducted on specific populations of patients — those with mild cognitive impairment or early-stage Alzheimer’s whose brains contained higher-than-normal levels of amyloid — the FDA’s label for the drug does not contain any such restrictions. The label simply says the drug is “for the treatment of Alzheimer’s disease.”
Alzheimer’s trials are already challenging to conduct because it is often difficult to recruit enough participants. Because the condition can progress very gradually, trials need to be large and continue for many months in order to be able to see if a drug is slowing cognitive decline.
Several experts expressed skepticism that Biogen would be able to recruit many participants in the United States for a post-market trial because patients who can get a drug from their doctors are often reluctant to take the chance of receiving a placebo in a clinical trial.
Aduhelm is a monoclonal antibody that targets a protein, amyloid, that clumps into plaques in the brains of Alzheimer’s patients and is considered a biomarker of the disease. One thing both critics and supporters of approval agree on is that the drug substantially reduces levels of amyloid. The F.D.A. said that the drug’s effect on a biomarker qualified it for the accelerated approval program.
Still, reducing amyloid is not the same thing as slowing symptoms of dementia. Over more than two decades of clinical trials, many amyloid-reducing drugs failed to address symptoms, a history that, some experts say, made it especially important that aducanumab’s data be convincing.
Biogen officials said that the drug provided long-awaited support for a theory that attacking amyloid can help if done early enough. Supporters of approval also said that it’s possible that clearing amyloid early on could help rein in the disease down the road, providing additional benefit beyond slightly delayed early decline. But Alzheimer’s experts note that supposition is completely untested.
Trial Contradictions
The crux of the controversy over the drug involved two Phase 3 trials with results that contradicted each other: One suggested the drug slightly slowed cognitive decline while the other trial showed no benefit. The trials were stopped early by a data monitoring committee that found the drug didn’t appear to be showing any benefit. Consequently, over a third of the 3,285 participants in those trials were never able to complete them.
Biogen later said that it had analyzed additional data and concluded that in one of the trials a high dose could delay cognitive decline by 22 percent or about four months over 18 months. In the trial’s primary measurement, the high dose appeared to slow decline by 0.39 on an 18-point scale rating memory, problem-solving skills and function. A lower dose in that trial and high and low doses in the other showed no statistically significant benefit over a placebo.
The risks with aducanumab involve brain swelling or bleeding experienced by about 40 percent of Phase 3 trial participants receiving the high dose. Most were either asymptomatic or had headaches, dizziness or nausea. But such effects prompted 6 percent of high-dose recipients to discontinue.
Biogen is expecting to launch the drug quickly, with more than 600 sites across the country expected to administer it. Clinics for patients with cognitive problems have been scrambling to prepare.
Dr. Jeffrey Burns, director of the University of Kansas Health System’s memory clinic and a site investigator for one trial, said he expected “the phone to be ringing off the hook.” He estimates 25 to 40 percent of the clinic’s roughly 3,000 patients might be eligible, but it doesn’t have enough neurologists.
Several Alzheimer’s doctors who believe the case for approving aducanumab is too weak said they would now feel ethically compelled to make it available. They believe that many patients, even when told of the problematic evidence, would try the drug because they would assume there was a compelling reason it received F.D.A. approval.
“I had this conversation with a real patient who was very interested in it,” said Dr. David Knopman, a clinical neurologist at the Mayo Clinic and a site principal investigator for one trial who co-wrote an article saying the evidence was insufficient to show benefit. “I presented the data to the patient and her husband, and they didn’t hear a word I said about my concerns. All they heard was there might be benefit.”
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Three FDA Panel Members Resign Over Aduhelm Approval
This week three out of the 11 members of the FDA’s Peripheral & Central Nevous system Drugs Advisory committee resigned in protest over the agency’s approval of Aduhelm: David S. Knopman, a neurologist at the Mayo Clinic; Joel S. Perlmutter, a neurologist at Washington University in St. Louis; and Aaron Kesselheim, a professor of Medicine at Harvard Medical School. The committee as a whole had overwhelmingly rejected evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s. Kesselheim in his resignation letter, said the agency’s decision on Biogen “was probably the worst drug approval decision in recent U.S. History.”
Even after all this debating, I believe that many Alzheimer’s sufferers and their families are so longing for a treatment—any treatment—that shows signs of slowing down the cognitive decline will eagerly sign up for Aduhelm injections and willingly take the risk of the patient’s brain swelling or bleeding along with the chance the drug doesn’t even work.