The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
Dr. Maria C. Carrillo
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Dr. Philip R. Delio
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Douglas Scharre
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”