Earlier this month, an FDA advisory panel unanimously agreed that lecanemab (Leqembi) showed clinical benefit in early Alzheimer's disease based on the phase III CLARITY AD trial results, paving the way for traditional approval of the drug.
From a scientific perspective, it would not come as a surprise to anyone who is in the Alzheimer's field for the FDA to grant the traditional full approval for lecanemab in July. CMS has already released a statement saying it will cover lecanemab (if approved) with the requirement of a registry that will continue to track real-world patients' experiences both in terms of side effects and amyloid-related imaging abnormalities (ARIAs). Interestingly, the Veterans' Health Administration, the largest single-payer system in the U.S., added lecanemab as part of its formulary in March this year.
While it's likely that the FDA will grant approval, and despite the preparatory actions already being taken by other relevant agencies, I'm concerned the healthcare system is not ready for the full approval of lecanemab. It is unclear at this time what CMS means in terms of a "registry" and how that may be different or the same as some other organization's registries, such as the Alzheimer's Association's ALZ-NET. More importantly, healthcare systems themselves aren't equipped to effectively screen and administer the therapy on a broader scale, and eligibility of certain groups is uncertain.
The Erosion of Public Trust
The aducanumab (Aduhelm) approval process eroded both the public's trust and clinician's trust. I have not met many geriatricians who are very enthusiastic about any of the monoclonal antibodies. However, we should not cast out the entire class of monoclonal anti-amyloid antibodies based on the aducanumab approval controversy, as lecanemab's results have been more robust and scientifically sound than aducanumab. Donanemab, another monoclonal antibody, showed an even greater number of participants who did not worsen over time compared to placebo, according to a recent press release. The full study results for donanemab are awaiting publication.
Although it might be beneficial to pharmaceutical companies to broaden the eligibility criteria for participants who were in the lecanemab trial into a wider category of potential patients with Alzheimer's disease, I believe this would be a mistake. This translation from the clinical trial population to the real-world population requires careful screening and monitoring over time.
Since the lecanemab results have come out, there have been multiple studies looking at the clinical trial eligibility criteria versus real-world data for aducanumab. Studies based on real-world memory clinics suggested that a range of less than 1% to 12% of patients who have dementia or mild cognitive impairment would be eligible for aducanumab due to its long list of contraindications. Inappropriately screened patients with underlying risks of intracranial bleeding may have a negative impact on use of subsequent anti-amyloid monoclonal antibodies.
It may take years to build back the trust that the aducanumab approval process eroded, and assuming the FDA moves forward with the full approval of lecanemab, taking every safety precaution will be essential for safe and effective use of all anti-amyloid monoclonal antibodies.
Our Healthcare Systems Aren't Ready
Another major barrier to effective use of lecanemab, if approved, is that our healthcare systems are simply not prepared to deliver anti-amyloid monoclonal antibodies.
One big issue is that Alzheimer's and related dementias are routinely underdiagnosed, especially among underrepresented racial/ethnic minority groups. Due to delays, many patients are already past the eligibility criteria for these monoclonal antibodies at the time of diagnosis. Typically, eligibility requires cognitive symptoms to be mild and barely affecting complex daily functions, such as managing finances and medications.
Another challenge is the limited number of memory specialists, coupled with the overburdened primary care system. There are also few neuroradiologists who could accurately identify ARIAs on MRIs -- a big safety concern for prescribing and eligibility. Health systems face limitations in space, both in terms of infusion clinics and clinical space to see patients. Memory clinics across the country already have months-long waiting lists, and very few clinics have well-developed triaging or referral systems in place that can funnel a potentially large number of patients who are interested in the monoclonal antibodies into carefully selected patients who fit eligibility and biomarker requirements. Again, the longer patients are waiting to be seen, the later they are potentially diagnosed.
There are some ways to improve early screening. Likely, the easiest screening tool that can be used in primary care is the Montreal Cognitive Assessment (MoCA), which is targeted to detect mild cognitive impairment, although mostly in a Caucasian population. However, adjustments can be based on the level of education as well as by race/ethnicity. A promising blood biomarker is phosphorylated tau181 (available within Labcorp), which is strongly associated with intracranial amyloid burden on amyloid PET scans. Perhaps if these initial tests are positive, then patients could get further testing (both cognitive testing and other PET testing within a memory clinic with robust monitoring and evaluation for ARIAs), and doctors could engaged them in discussions about other dementia-prevention strategies (intensive control of blood pressure, Mediterranean diet, aerobic exercise, evaluating and treating hearing and sleep problems, and social connections).
While many institutions are waiting for the FDA and CMS to decide about full lecanemab approval and the coverage decision before changing clinical workflows, I fear that we are ill-prepared in this moment. I am hopeful that general interest in monoclonal antibodies can be harnessed to make memory evaluations and dementia treatment better for all, not only the small minority of patients who will ultimately receive lecanemab. The next couple of months will be interesting for both clinicians and researchers -- like myself -- as we talk to our patients who have already started to ask about whether lecanemab is right for them.
Mia Yang, MD, MS, is a geriatrician/internist at Atrium Health Wake Forest Baptist in Winston-Salem, North Carolina. She hosts a podcast called "Ask Dr. Mia: Conversations on Aging Well." The opinions expressed are the author's and do not represent those of any institution or company with which she is affiliated.
Disclosures
Yang receives funding from NIH and the Patient-Centered Outcomes Research Institute, unrelated to Alzheimer's disease drug therapies.