NEW YORK – With a new generation of Alzheimer's disease drugs on the market, neurologists are grappling with how to safely prescribe them to the right patients.
Eisai and Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab) are two of the first drugs in what's expected to be a growing class of disease-modifying treatments for Alzheimer's. Both of the drugs target beta-amyloid proteins, buildup of which is a hallmark of and thought to be a contributor to the debilitating neurodegenerative disease, and both have been approved by the US Food and Drug Administration as treatments to slow progression of Alzheimer's, with Leqembi approved in 2023 and Kisunla approved in July of last year.
The two drugs are indicated for adult Alzheimer's patients with mild cognitive impairment or mild dementia and who have evidence of beta-amyloid pathology.
Many neurologists have described these anti-amyloid drugs as a paradigm shift for the field, as the medications are targeting what's thought to be an underlying cause of the disease. But use of one of these drugs requires neurologists to assess biomarkers that weren't previously part of standard care, coordinate treatment with other specialties, and engage in long-term monitoring, including for serious potential side effects.
The FDA required boxed warnings on Leqembi and Kisunla's labels related to amyloid-related imaging abnormalities (ARIA), a typically asymptomatic but sometimes fatal side effect of anti-amyloid medications. As part of the warning, the regulator recommended genetic testing to assess whether a patient carries two copies of the APOE4 allele before starting treatment, since homozygous carriers have a higher risk of experiencing ARIA.
To monitor patients for this side effect, physicians should obtain brain MRIs before and at multiple points after starting treatment, according to the drugs' labels.
Given the complexity of determining who's an appropriate fit for one of these drugs and of managing patients after they begin treatment, some hospitals have sought to create new processes to standardize how physicians prescribe them.
These institutions have set up specialized review boards to guide these decisions and help neurologists as they navigate the benefits, risks, and long-term monitoring needed to dispense anti-amyloid treatments. They're taking a page from oncology, where many hospitals already have set up molecular tumor boards composed of expert physicians to review molecular profiles of difficult-to-treat cancer patients and match them to appropriate targeted treatments.
"Many people like me anticipate that is the direction of the field," said Lawren VandeVrede, an assistant professor of neurology at the University of California, San Francisco, and a neurologist at the UCSF Memory and Aging Center. In the future, he expects that neurologists will have more tailored options available to treat Alzheimer's patients, which will make for more complex treatment decisions.
About a year ago, UCSF set up an expert panel of physicians and other healthcare practitioners with expertise in Alzheimer's to determine whether treatment with Leqembi, and more recently, Kisunla, would be suitable for individual patients.
Similar boards are cropping up around the country, as physicians acclimate to this new class of medications. However, not all neurologists agree that such review boards are productive.
In California, VandeVrede and colleagues were tasked with setting standards for how anti-amyloid drugs would be used across the University of California system and created a protocol that was approved by the UC Office of the President. One aspect of the protocol mandates forming a multidisciplinary board at each UC medical center campus to oversee an Alzheimer's Infusion Core group that manages administering these drugs. The Alzheimer's Infusion Core Board reviews patient cases to determine the appropriateness of treatment and possible barriers to care.
The intention was to ensure that "the use of this medicine was standardized," so that patients wouldn't get different answers from doctors within the same system, VandeVrede said. At UCSF, the board includes neuropsychologists, neuroradiologists, social workers, and other practitioners involved with treating Alzheimer's patients.
Neurologists, including both subspecialists and general neurologists, who believe they have a patient who might be a fit for an anti-amyloid drug submit an internal referral to the board. From there, each case is reviewed by nurses who assesses basic details of the case, such as whether the patient has undergone cognitive screening and beta-amyloid testing, and then by a behavioral neurology fellow, who reviews the case and presents it to the board, along with a recommendation. This process includes reviewing health history, MRIs, and biomarker data.
The board, once its members reach a consensus, makes a formal recommendation on whether an anti-amyloid drug is appropriate.
At UCSF, every patient who receives an anti-amyloid drug is reviewed by this board.
The board doesn't make treatment decisions, VandeVrede said. Its role is to review each case in detail to assess whether a patient is eligible based on the drug's label and criteria that's established in the UC system's protocol. For instance, the board might recommend against prescribing the drug depending on how far along the disease has progressed but also note that the patient has met biomarker and other criteria.
Patients who are deemed a fit for the medication will set up an appointment with a subspecialist, who ultimately makes the final treatment decision with the patient. There are just four behavioral neurologists, including VandeVrede, who prescribe anti-amyloid drugs at UCSF.
All in all, the goal is for the process, from referring to the review board to beginning the first infusion, to take less than a month. The board meets every two weeks.
There's not a set time frame for how long the board will continue at UCSF, VandeVrede said. In the future, the UC system may shift to an approach in which straightforward cases don't require review from the board, and the board focuses its discussions on only the more complicated cases. "The intention is to use it right now," VandeVrede said. "We're going to have to see where it goes."
That type of approach in which a board only reviews more complex patient cases is already in place at the University of Washington Medicine in Seattle.
Initially, the multidisciplinary Anti-Amyloid Monoclonal Antibody Approval Board at UW Medicine met monthly and reviewed nearly all of the cases of patients considering anti-amyloid treatment.
There was a "degree of shyness and trepidation" when neurologists first started prescribing Leqembi, as it is a completely new class of medications for the field with new risks to consider, said Michael Rosenbloom, an associate professor of neurology at UW Medicine and a neurologist at UW Medicine's Memory and Brain Wellness Center.
"This board was created to ensure that we had a good balance between risk and benefit," he said. "It was really helpful at the beginning."
However, as the number of patients being considered for these treatments ramped up, they decided it was no longer feasible to review each and every chart. After about three months, they switched to a system in which they only review more complex cases that present to the hospital system, such as patients who are APOE4 homozygotes or have other risk factors for ARIA.
While the board's focus is on the appropriateness of prescribing anti-amyloid drugs to particular patients, it also provides a space to discuss common concerns. For example, its members discuss cases of ARIA and assess patient histories to see if there are factors that may have contributed to a patient developing ARIA that could be considered for future patients.
Given controversy over the risk-benefit profile of these drugs, Rosenbloom said he expects there will continue to be a role for these types of review boards.
Neurologists are adjusting to a process in which they'll need input from a variety of stakeholders, including radiologists and neuropsychologists, and, as new medications are approved, may need to consider new treatments or combination therapy. "I don't see [review boards] going away any time soon," Rosenbloom said.
He acknowledged that not every organization will be able to set up such a robust system and review board, particularly among smaller institutions with fewer resources. He urged neurologists at larger academic medical centers to think about ways to support physicians at other institutions, who are also getting comfortable with these drugs and building processes to administer them.
As part of that effort, Rosenbloom and colleagues wrote a paper in CNS Drugs last year that outlined a framework for administering anti-amyloid drugs, including a discussion of the hospital system's decision to set up a formal review process for determining the appropriateness of treatment in the form of the approval board.
But these review boards aren't standard at all hospital systems, and not all neurologists believe that they're needed.
It's not necessary for a decision about a patient's treatment to be made by a board of experts, and specialists should be able to make these decisions for themselves, said Lawrence Honig, a professor of neurology at Columbia University's Irving Medical Center. He's one of fewer than a dozen Alzheimer's specialists at the medical center who prescribe anti-amyloid drugs.
Honig said he prescribes anti-amyloid drugs like any other medications, offering it among other treatment options and discussing potential benefits and side effects directly with his patients.
He raised the concern that providers are treating anti-amyloid drugs as if they are uniquely "special or dangerous" therapies, which he doesn't think is true.
"I, respectfully, would submit that there's no need for any special treatment of Alzheimer's patients with these new medicines," Honig said. "Just like we don't have review boards for treating migraine patients or multiple sclerosis patients or many other things."
That's not to say there aren't cases in which a patient's test results, for example, might be difficult to interpret and in which a provider may seek the opinion of another physician.
"It's perfectly reasonable for people to discuss with their colleagues," Honig said. "But there's no particular reason to be routinely discussing in some sort of group session."
He said he understands why some doctors would be uncomfortable prescribing these drugs and seek guidance from others. When Leqembi was initially approved, only a portion of neurologists — those who had participated in clinical trials — were familiar with it, and the product label details various considerations for who's a fit and how to monitor patients. Honig, for his part, was an investigator in the Phase III CLARITY AD trial that underpinned the FDA's approval of Leqembi. Even with the more recent approval of Kisunla, neurologists are still getting familiar with the class of medications.
Ultimately, a treatment plan should be decided between patients and their physicians, who can determine for themselves whether to seek out additional opinions. Even the cancer parallel doesn't hold water for him, since, in oncology, only the most difficult-to-treat cases are put before a molecular tumor board.
"I just don't see a need," Honig said.
At Sutter Health, meanwhile, the hospital system has established a board to review prescribing decisions for general neurologists but not for subspecialists focused on Alzheimer's.
The board, known as the Advanced Therapeutics for Alzheimer's Disease Review Board, is designed to provide support for general neurologists within Sutter Health's Northern California footprint whose patients may be a fit for an anti-amyloid drug. The goal is to enable general neurologists to prescribe these drugs and allow patients to stay in their local communities, rather than traveling to see a subspecialist.
"We're trying to figure out a way to bring these therapies across the healthcare system in a safe, efficient, local way," said Armen Moughamian, a cognitive neurologist and medical director of the Ray Dolby Brain Health Center at Sutter Health.
Moughamian is bullish on the potential of this class of medicines. He understands not every patient will want an anti-amyloid drug; however, he believes it's important that Alzheimer's patients and their caregivers be offered the drug and have an opportunity to discuss with their physicians whether they're a good fit for it.
That's challenging given the shortage of neurology subspecialists with the needed expertise in Alzheimer's to prescribe these drugs, he said. He didn't want to see a process put in place in which only cognitive neurologists could prescribe the drug.
That's the purpose of the Advanced Therapeutics for Alzheimer's Disease Review Board. The board comprises cognitive neurologists, a neuroradiologist, a pharmacist, and a nurse coordinator. It meets weekly to review patient cases referred by general neurologists, with referrals placed within the electronic health record system.
So far, the board has determined that anti-amyloid treatment was appropriate for about 70 percent of the referred cases.
The board doesn't review cases brought by cognitive neurologists, he said, adding that subspecialty neurologists should feel "empowered" to prescribe these drugs without this level of oversight. In his practice, for instance, he said he'll often seek input from his colleagues when reviewing images or other details of patient cases, but a formal review board isn't necessary.
Moughamian hopes to see other hospital systems take up this type of process, in which review boards support general neurologists seeing patients who might not have access to subspecialists. "We have to figure out how to facilitate general neurology in prescribing these medications, so that there's equitable access" for patients, he said.
In cases where a patient is deemed a good fit by the board, the patient's general neurologist will take on the responsibility of prescribing the drug and monitoring them. If a patient develops ARIA or other side effects, the physician is also able to reach back out to the board for support on managing that.
As more patients receive anti-amyloid drugs, these neurologists also will gain experience with the new drugs and how to manage patients taking them. One day, this review board may no longer be needed, or it may be repurposed to review other novel drugs as they hit the market, Moughamian said.
"We're here to help in this transition," he said, noting how different Leqembi and Kisunla are than previous types of Alzheimer's treatments. "But the ultimate success of this review board means that physicians don't have to refer to it. They feel enabled to roll these medicines out and feel they can do it in a safe way."