An extra twist in the FDA’s Alzheimer’s decision: no limits on which patients can get the drug

As if the saga of aducanumab needed another twist, the Food and Drug Administration tossed in an extra curveball Monday as it approved the Alzheimer’s therapy by specifying who would be eligible for the treatment.

Or rather, not specifying.

Doctors had anticipated that if the FDA gave the green light to the therapy now called Aduhelm, it would endorse its use for patients like those who qualified for clinical trials: people in the earliest stages of Alzheimer’s disease, who also had the plaques of amyloid protein that the therapy aims to clear.

Instead, the FDA approved the therapy broadly for Alzheimer’s disease. On Aduhelm’s label, there was no mention of limiting its indication to any subset of patients.

Many experts were left stunned by that decision.

“That’s remarkable,” Marsel Mesulam, the director of Northwestern’s Center for Cognitive Neurology and Alzheimer’s Disease, said over the phone as he read the FDA’s prescribing information. “I must say, my first impulse is that I verify [that] this is actually what will be in the package.”

And indeed, it is. On a press call, FDA officials argued that because Aduhelm helped clear amyloid plaques, it could provide benefits for people in any stage of the disease — at the same time as they acknowledged that any benefit from Aduhelm, even for patients in the early stages of the disease, was still unclear. (Many experts also strongly push back against the claim that erasing amyloid plaques could help people in the late stages of the disease. Clinical trials of other amyloid-targeting therapies in moderate and severe Alzheimer’s have repeatedly failed to show a clinical benefit.)

“It’s important to recognize that Alzheimer’s really is a single disease but it exists across a continuum,” from asymptomatic to severe, said Peter Stein, the director of the FDA’s Office of New Drugs. But what unites them all is the fact that “amyloid pathology is a defining feature of Alzheimer’s disease.”

Stein added: “The expectation is that this drug would provide benefit across that spectrum.”

The broad approval from the FDA raises the stakes for some of the other players in the health care system, and could force some tough decisions. Insurers might now set tight limits on how they’ll cover the therapy, and clinicians could face even greater demand — and pressure — from families to prescribe the treatment.

Whereas some doctors presumed Aduhelm would only be authorized for people in the early stages of the disease — the only people that many doctors say the therapy might help — now families of people with more advanced Alzheimer’s could appeal for the therapy. Those pleas can be particularly powerful given the lack of other options for treating dementia, and the fact that this is the first new Alzheimer’s therapy in nearly two decades.

“A lot of people, in the absence of something they know is better, will want to try it,” said neurologist Victor Henderson of Stanford University, who has advised the Institute for Clinical and Economic Review, a nonprofit that estimates the value of new medicines.

Henderson said it could be hard for some physicians “to really hold back the flow of requests.”

“If you’re a neurologist in private practice, there’s probably more incentive to try to satisfy the family demands, the patient demands,” he said. Doctors also receive an extra markup when prescribing an infused drug.

Some experts, however, said they thought that “gatekeepers” would likely step in, effectively limiting the therapy only to patients like those participants in the clinical trials.

“Even if [the FDA] allows it, we will be dealing with insurers and other gatekeepers” who will try to restrict Aduhelm to the patients most likely to benefit, said neurologist Babak Tousi of the Cleveland Clinic, who was an investigator in the aducanumab trials and who has consulted for Biogen, the company that makes the therapy.

“This is a medication for the right patient, and the right patient in our mind is someone who is in early stages of the condition,” he said.

That means that, to receive Aduhelm and to get it covered, many patients will likely need to pass through a series of steps: first, getting a diagnosis from a neurologist or geriatrician of mild cognitive impairment or mild dementia tied to Alzheimer’s; then, confirming they have amyloid plaques, either through a type of imaging called a PET scan or through a test of the cerebrospinal fluid; and finally, getting a spot at an infusion center where they will be treated once a month. Experts have warned for years that the health system — with the shortage of specialists, equipment, and clinics at every step of that odyssey — is not prepared for a therapy like aducanumab. People could face long delays before they can get treated, all the more pressing given the degenerative nature of the disease.

“We’re hugely under-resourced as a country in terms of availability of PET scanners, we’re hugely under-resourced in terms of the specialists who would be required to make a diagnosis, and we’re hugely under-resourced in terms of the specialists” who can run the amyloid tests on cerebrospinal fluid, which is typically sampled via a lumbar puncture, neurologist Allan Levey of Emory University told STAT last week, ahead of the FDA decision.

On top of that, Levey said, there is limited capacity at the infusion centers that will deliver the therapy to patients.

Medicare and other payers have generally not covered PET scans for confirming the presence of amyloid, and coverage for the cerebrospinal fluid testing is mixed, experts say. With the FDA approval of Aduhelm, however, it’s thought that insurers could start paying for the procedures.

Identifying the patients who are most likely to benefit from Aduhelm could also require a fundamental shift in dementia care. Many people with dementia never receive a firm diagnosis, or wait years after experiencing the first hints of cognitive loss before seeking out a specialist. Advocacy groups have been pushing for earlier interventions for years, but because there have been so few therapeutic options, there hasn’t been an urgency. Now, though, patients have a tangible motivation to get a diagnosis when their conditions are still in the early stages.

One concern is that if insurers clamp down on who can receive the therapy, wealthy people will just pay for it on their own — even if they are unlikely to benefit from it. That could add a greater crunch at clinics like infusion centers, and potentially exacerbate access disparities in dementia care.

“There are going to be a lot of people who are driving up in their limousines who want treatment and will pay for it themselves,” Levey said.

It’s not just anxieties around health care costs that mean many clinicians will likely only recommend the therapy for particular patients, doctors stressed. (Some neurologists, meanwhile, preemptively announced they won’t prescribe the treatment at all because they don’t believe it works.)

Rather, if clearing away amyloid plaques really does slow the progression of the disease — as goes the argument supporting Aduhelm’s effectiveness — that will only make a difference before the progression has advanced to a certain point. For people with severe and even moderate disease, doctors say, it’s not worth the potential side effects of the therapy and the trouble of monthly infusions to get Aduhelm.

“This medication would not help anyone who has more than just mild changes,” said Douglas Scharre, a neurologist and director of cognitive neurology at Ohio State Wexner Medical Center, who was also an investigator in the aducanumab trials and has advised Biogen. “Everyone with Alzheimer’s disease should not be on this drug.”

Damian Garde contributed reporting.