Article In Brief
Experts advise that patients who meet criteria for lecanemab, the recently approved treatment for Alzheimer's disease, should undergo genotyping for APO4E to assess their potential risk for adverse events.
The importance of genotyping apolipoprotein E4 (APOE4) in clinical decision-making for physicians considering prescribing the newly approved Alzheimer's disease treatment lecanemab (Leqembi, Eisai) has been largely overlooked in the debate about the drug's benefits, experts argue in an editorial published March 13 in JAMA Neurology.
Moreover, decisions about genetic testing for the risk gene will pose significant clinical, legal, ethical, and financial concerns, wrote Madhav Thambisetty, MD, PhD, senior investigator and chief of the clinical and translational neuroscience section in the National Institute of Aging's Laboratory of Behavioral Neuroscience, and Robert Howard, MRCPsych, MD, professor of old age psychiatry at University College London. They noted that in the CLARITY AD trial that led to lecanemab's approval, patients who were homozygous for APOE4 were more than six times more likely than noncarriers to experience symptomatic amyloid-related imaging abnormalities (ARIA) with edema or effusions and more than three times more likely to experience ARIA with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis.
Clinicians who have determined that patients meet criteria for lecanemab should consider genotyping for APO4E to assess the potential risk for adverse events as well as include pre-test and post-test counseling, they wrote. In addition, physicians should consider “associated patient and/or caregiver distress,” especially if they determine that they'd likely not provide treatment for APOE4 carriers.
“If the physician decides that close monitoring is feasible and may be effective in avoidance of treatment-associated intracerebral hemorrhage with additional clinical evaluations and more frequent magnetic resonance imaging scans in APOE ε4 homozygous patients, the burden of these additional measures both on caregivers and patients must be determined and clearly presented prior to initiating treatment,” the authors said.
The US Food and Drug Administration (FDA) has not mandated APOE genotyping or provided specific guidance on additional safety monitoring in high-risk patients, they pointed out, but the warnings and precautions section of the prescribing label for lecanemab advises that physicians consider testing for APOE4 status “to inform the risk of developing ARIA when deciding to initiate treatment.”
A ‘New Paradigm’
It's a new paradigm, said Jason Karlawish, MD, professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania Perelman School of Medicine and co-director of the Penn Memory Center.
“Up until the approval of lecanemab, APOE testing was essentially a matter of personal preference,” he said. “Does someone want to learn their lifetime risk of ‘late-onset’ Alzheimer's as determined by that genotype? That was the argument. Testing was certainly not a part of routine clinical practice. But lecanemab changes all that. APOE testing in this context is to inform a patient's assessment of the risks and benefits of taking that drug. I think the data are compelling that testing ought to be strongly encouraged for patients considering taking lecanemab, particularly for those with onset of disease before the age of 70, where the possibility of being an APOE4 carrier is even more likely.”
Outside of tertiary care centers, APOE genotyping is likely to be less consistent, said Oscar Lopez, MD, FAAN, professor of neurology and psychiatry at the University of Pittsburgh. “If you go by the book, then yes, everybody should be genotyped,” he said. “Then you have the real world. I would expect that in places outside of the VA and major medical centers, patients will almost certainly get lecanemab without testing or counseling.”
The Exclusion Criteria
In February, the Department of Veterans Affairs' pharmacy benefit management service and medical advisory panel announced that it would cover lecanemab for its members 65 and older with mild cognitive impairment (MCI) or early Alzheimer's disease, but it included APOE4 homozygote status on its list of exclusion criteria.
Gregory A. Jicha, MD, PhD, the Robert T. and Nyles Y. McCowan Endowed Chair in Alzheimer's Research at the University of Kentucky, one of the clinical trial sites for lecanemab, believes that decision goes too far.
“It's a coverage decision made on the basis of a population group rather than an individual person's risk,” he said. “I'm not aware of any other situation where a risk gene is being used to determine levels of coverage for adverse events of taking a medication. This would be a new precedent in medicine and third-party payer coverage.”
Dr. Jicha suggested that the policy may run afoul of the Genetic Information Nondiscrimination Act of 2008 (GINA), which prohibits health insurers from discrimination based on the genetic information of enrollees.
“Specifically, health insurers may not use genetic information to determine if someone is eligible for insurance or to make coverage, underwriting, or premium-setting decisions,” according to a summary of the law from the National Human Genome Research Institute. “The health insurance protections of GINA extend to private health insurers, Medicare, Medicaid, Federal Employees Health Benefits, and the Veterans Health Administration.”
“This restriction is not in the package label, but the VA is doing it anyway, which strikes me as reduction in coverage on the basis of APOE genetic testing,” Dr. Jicha said. “I suspect this decision will be challenged in the future.”
Alzheimer's health policy expert Jalayne J. Arias, JD, MA, associate professor in health policy and behavioral sciences in the School of Public Health at Georgia State University, has a different view. She thinks GINA likely would not prevent the VA from implementing this restriction, nor would it prevent the Centers for Medicare and Medicaid Services (CMS) and private payers to adopt this policy should they choose to do so in the future.
“There is an exception under GINA stating that it only applies to individuals who are asymptomatic,” she noted. “The idea behind the law, which was passed prior to the Affordable Care Act, was that insurers shouldn't be able to discriminate in underwriting against an individual who is asymptomatic based on family history or genetic information. The person seeking lecanemab treatment is already symptomatic. And we do know that payers have the ability to make decisions about coverage based on factors such as contraindications. So while I think that this may be in a challenging gray zone under GINA, realistically, because there is evidence that indicates the APOE status might be a contraindication for lecanemab, it is unlikely that GINA would apply here.”
Arias, who called this “a novel situation,” expects more questions to arise.
“As a field, we've thought about the impact of GINA as it relates to APOE status but more in the context of exposure to employment or insurance discrimination for asymptomatic carriers,” she said. “This is the first time we'll be wrestling with what it means about access to a drug.”
Dr. Jicha acknowledged that the risk for ARIA, either with edema or hemorrhage, is increased with lecanemab in a gene dose-dependent manner. “If you have no gene variant, you have a lower rate of ARIA; if you have one ε4, the rate of ARIA is slightly higher; and if you have two copies, the rate is even higher,” he said. “That has been a consistent observation through every anti-amyloid antibody trial. The issue is balancing risks versus benefit. While understanding the patient's APOE status will help to guide our level of vigilance in monitoring for these potential adverse events, I don't believe that APOE homozygotes should be absolutely contraindicated from receiving lecanemab.”
It's a tough call, Dr. Karlawish said. “You could argue that the risk is the patient's to take. You could also argue that the balance of risk and benefits simply doesn't favor the prescription so it's simply not going to be offered. I'd like to hear more of the field weigh in on that; it strikes me as the perfect kind of question to ask an FDA advisory committee, and that opportunity should be available soon.”
Eisai has been granted priority review for conversion of lecanemab's accelerated approval to a conventional approval, with a Prescription Drug User Fee Act action date of July 6, 2023. The FDA plans to convene an advisory committee to discuss this application but has not yet publicly announced the meeting date.
Increased Demand for Genetic Counseling
Given the size of the population that could be evaluated for lecanemab—an analysis of data from the Chicago Health and Aging Project and the 2020 US census estimated that about two million people in the United States are in the early stages of AD and another 21 million have MCI—the demand for genetic counseling could dramatically increase with broader uptake of the drug.
“To a large extent, how widely the drug is prescribed will depend on whether the FDA decides to grant a full/traditional approval for lecanemab and, subsequently (if approved), whether the CMS decides to cover the cost,” Dr. Thambisetty said.
“That will determine the size of the overall population that may be seeking treatment with lecanemab, and this will in turn determine whether existing capabilities of health care systems can provide the required support to administer the medication, including genetic counseling for patients undergoing APOE genotyping,” he added.
Staffing constraints could be a concern. A 2018 analysis found that the US had just one genetic counselor per 81,700 people, and in 2019, the Government Accountability Office reported that there were approximately 4,700 certified genetic counselors in the United States. “We do not have enough genetic counselors in this nation to cover that need,” Dr. Jicha said.
“If you are going to do the testing, you have to do it right,” Dr. Lopez said. “The patient needs to be educated thoroughly in the implications should they be identified as APOE4 homozygous. It's preferred if you have a genetic counselor who is able to provide the genetic information in a way that patients can understand and won't cause significant anxiety.”
Family members, rather than patients, may be more affected by the genetic diagnosis, Dr. Jicha said. “Most of our patients with early AD, and those with MCI for whom we would entertain lecanemab, are already of the mindset that they have the disease, which is why they're seeking out the medication. So I do not think the genetic disclosure is going to be significantly negative for patients. But for family members, that is another matter. If you are carrying two copies of APOE4, there is a significant likelihood that your siblings are, and you definitely know that your children are at least heterozygous.”
Protocols to Guide Genetic Counseling
Dr. Thambisetty suggested that neurologists and other clinicians have limited ability to provide the kind of genetic counseling needed to evaluate lecanemab treatment. “My opinion is that while clinicians like me who care for patients with AD are mostly capable of providing risk estimates for AD associated with APOE4 carrier status to their patients, they are less likely to be aware of the legal, ethical, and financial implications of such disclosure both for patients as well as their biological children,” he said.
“I think it would serve our patients' interests well to develop standardized protocols that provide pre- and post-test counseling to patients who decide to pursue APOE genetic testing to determine their eligibility for novel AD treatments. Having such protocols in place is essential to ensure that patients are aware of the limitations of existing laws against genetic discrimination as well as the implications of disclosure of test results to their biological children.”
Dr. Jicha contends that neurologists can effectively take on this role. “In the studies we've been running over the years, degreed genetic counselors aren't always available, and what we see is that what is required for this kind of counseling is expertise in the field,” he said.
“I have been doing APOE genetic disclosure since 2006 and have done thousands. In the centers that have been working with the trials of these drugs, we have a highly trained health care professional population that is well versed in the genetics of APOE performing appropriate disclosures, answering questions, and providing follow-up. Just as with training radiologists in identifying ARIA on MRI, we need to train clinicians who are prescribing lecanemab, and potentially other agents, in the ability to appropriately disclose such results. Templated APOE disclosure education programs are available; I've taken at least a dozen of them.”
Dr. Karlawish agreed, adding, “I think a well-trained clinician who feels comfortable and confident in prescribing the drug should also feel comfortable and confident talking about APOE testing and results.”
“That's a learnable skill, which has been proven in the clinical trials that involved APOE testing to be eligible for the drug. Combining educational materials with telemedicine for centers across the United States and genetic counselors in Pennsylvania worked well with up to a few thousand people,” Dr. Karlawish said.
“Will there be scalability issues? Absolutely. That's the case with many other aspects of prescribing this drug as well, including amyloid testing, ascertaining correctly that someone has MCI, and assessments for microscopic hemorrhages. APOE testing is part of a larger conversation about developing an infrastructure to diagnose and care for people with Alzheimer's disease.”
Although there will be systemwide challenges of implementing the necessary processes for prescribing lecanemab responsibly, Dr. Jicha believes they are more than worth it.
“Slowing cognitive decline by 27 percent is quite significant for a patient with a disease course that is 10 to 12 years in duration,” he said. “The importance of buying an extra year or two of function, of time with family, cannot be overstated. After all, we still treat stage 4 metastatic cancer, even though it is incurable, to prolong life and enhance the quality of that life, and that's where we currently are with lecanemab. This is not the end of the work we're doing to provide better medicines for Alzheimer's disease, it's the beginning. It's the dawn of a new day.”
Arias and Drs. Thambisetty, and Lopez had no disclosures. Dr. Karlawish had been a site investigator for clinical trials sponsored by Biogen and Lilly Inc.