Their phones are ringing off the hook and their email inboxes are filling up with questions without answers.
Doctors who care for patients diagnosed with Alzheimer’s disease — or people worried that they might be — are feeling the brunt of last week’s decision by the Food and Drug Administration to grant conditional approval to the first new Alzheimer’s drug in 18 years. That approval is broad, making no distinction between the mild, moderate, and advanced stages of the memory-robbing disease and setting no requirements for its diagnosis.
“Families have been calling, [saying,] ‘You have to understand how this is a devastating disease,’” said Sharon Brangman, a geriatrician and director of the Upstate Center of Excellence for Alzheimer’s Disease at SUNY Upstate Medical Center in Syracuse, N.Y. The medical staff was getting so many inquiries that doctors crafted a statement for nurses to relay to families, saying the drug is not yet available for prescription, nor is the infrastructure needed to appropriately prescribe and monitor this medication.
“There is no cure, so everybody is looking for a drug that actually modifies the progression of the disease so that if you take it, you would be buying yourself more time,” Brangman said. “And we don’t have enough data to know if this is that drug.”
The FDA’s action came despite a 10-0 vote in November against approval by its panel of expert advisers, who were dubious that data from two clinical trials showed the drug was effective in early Alzheimer’s patients with mild cognitive impairment; three members resigned in protest from the panel last week. The surprising decision leaves doctors turning back to data from those trials, which had conflicting results: One barely met its primary endpoint and the other did not. As if that’s not confusing enough, the mental decline that is considered an early sign of Alzheimer’s disease is also present in other age-related disorders, which makes it hard to discern which patients have the disease.
The side effects of the drug, to be sold as Aduhelm by maker Biogen, are troubling and the cost is staggering, at $56,000 per year “forever,” doctors told STAT. More than one-third of trial participants developed brain swelling and 17% to 19% had small bleeds in their brains.
“The risks are known. The benefits are still in question,” said Zaldy Tan, a neurologist and medical director of the Center for Alzheimer’s and Memory Disorders at Cedars-Sinai in Los Angeles.
All of this will make conversations with patients and their families difficult.
“I’ve obviously done some thinking about what am I going to do today, how is my practice going to change. I’ve had one or two patients email me about it saying, ‘Can I come in next week and get my first dose?’” said Andrew Budson, a neurologist and chief of cognitive and behavioral neurology at the Veterans Affairs Boston Healthcare System. “I would make sure that the patients understood these very real potential side effects and the fact that we don’t know if [the drug] works or not. I would then go on to say that I don’t recommend this medication because it has known side effects that could possibly be detrimental to their thinking and memory and unproven benefits.”
George Avetian, a family medicine physician who sees older patients at the Geisinger 65 Forward Health Center in Wilkes-Barre, Pa., said patients have been bringing up Aduhelm already, and he expects to hear more. “From the patient population, it has been received very favorably and there’s a lot of excitement out there.”
He welcomes any new drug for Alzheimer’s, and favors prescribing it, but was struck by the three experts’ resignations from the FDA advisory panel. He’s also affected personally: His mother died in April after many years with Alzheimer’s.
“I’m happy to see that it was approved. For those impacted with Alzheimer’s, it’s devastating,” he said. “If it was available for my mother five years ago, I would have accepted it. I would have put her on a research protocol. Something that can address this issue is exciting, but then I understand from the scientific standpoint, it’s a departure from the typical protocols.”
Brangman sees another problem with the thin evidence for FDA’s decision. The two studies weren’t done in a racially diverse group of patients; there were very few African Americans, Asians, and Latinos included.
“So again, I have to figure out how to extrapolate that information to the diverse groups of patients that we take care of,” she said. “That’s a problem across the board in clinical research. In the case of Alzheimer’s disease, African Americans are twice as likely to get it. And Latinos, one-and-a-half times more likely to get it. So there are two groups that are extraordinarily impacted by the disease that we have no data on how this medication might work in them.”
The FDA did provide limited guidance on the label for Aduhelm. It requires patients to have an MRI within a year of first being prescribed the once-monthly infusion and then follow-up MRIs before the seventh and 12th doses. That imaging would reveal brain swelling or bleeding.
“There are people that are so desperate, they’re going to try anything. I want to make sure that we’re doing it as safely as possible,” Brangman said. “We’re still in the process of figuring that all out. There were no guidelines yet released that help us understand the infrastructure we have to have in place.”
Nowhere do amyloid PET scans appear on the label, but neurologists see them as necessary before prescribing a drug that’s supposed to clear clumps of the protein amyloid from the brain. Patients who participated in clinical trials were initially screened with PET scans to confirm they had amyloid deposits.
“I don’t see how anyone could start the use of a medication that costs $56,000 a year without some type of a biomarker test or a lumbar puncture or a PET scan to determine if it’s really Alzheimer’s disease or not,” Budson said. “A PET scan usually costs around $5,000, which sounds like a lot of money, but it’s a small amount of money when you compare it to $56,000 for, like, forever.”
Medicare may deliver more actionable information than the FDA when it decides how to cover not just the drug but PET scans as well. “We will need to see if Medicare and other insurers will limit access to this medication or at least reimbursement for these medications in terms of dementia stage,” Tan said.
Brangman said heightened interest in the new drug will strain neurologists and geriatricians who are already in short supply, and six-month waits for appointments aren’t uncommon. Diagnosing Alzheimer’s disease isn’t a one-step decision. Instead, it’s typically diagnosed after a doctor evaluates a patient history, results of pen-and-paper tests to gauge memory, bloodwork to detect metabolic abnormalities, and CT scans to rule out other illnesses. For people younger than the usual age of onset — 70s and 80s — more testing may be done, including PET scans, to be sure a brain tumor or stroke isn’t behind their mental decline.
Establishing the presence of amyloid adds another step to the diagnostic process. The neurologists who spoke to STAT would not prescribe Aduhelm without PET scan evidence of amyloid plaques.
“If I were talking to a patient, I would be talking about the uncertainty of this benefiting them, particularly if we don’t have evidence that they have amyloid in their brain,” Tan said.
All this for slight benefit, something Tan will take pains to explain to patients.
“It’s modest in terms of efficacy. It’s [statistically] significant, but it may not be observable by the family or caregiver or even the physician,” he said. “I would tell them this is not a cure — something to set the expectation that this is likely not going to be a dramatic improvement, but this could be something more subtle.”
Geisinger’s Avetian wishes he had more information from Biogen on Aduhelm. “I know I don’t really have a significant appreciation of the effectiveness or lack of effectiveness of this drug,” he said. “At this point in time, I’m in a situation where I’m just winging it. I don’t have that much comfort as far as my level of knowledge of this product. That will grow in the next few weeks, months.”
Something good might follow the drug’s approval, said Budson of the Boston VA.
“One positive thing that will come out of this is that people who might have been worrying if they have Alzheimer’s — or their family is worrying but no one has made a move on it — more people will go and see their doctor now that they understand that there are more medications that are FDA-approved to potentially help,” he said. “We’re certainly expecting a lot of people.”