In the nearly 117 years since Dr. Alois Alzheimer’s diagnosed as the first-ever person with Alzheimer’s disease (AD), physicians and scientists have been relentless in their efforts to characterize the disease and create meaningful treatments. In parallel, millions of persons-with-AD, their caregivers, and advocates have been yearning for an opportunity to halt or slow down the progression of neurodegeneration. On Jan 6th, 2022, the FDA approved lecanemab (brand name: LeqembiTM), and many have made the case that this drug has finally created the breakthrough that we have long awaited. While there are certainly reasons to be hopeful about this scientific advancement, FDA accelerated approval of lecanemab is immature. This approval, in the setting of significant health risks that are baked into the trial data, and associated cost structure, suggests that we are unprepared as a nation to deliver AD disease-modifying therapeutics. As the co-founder of The Youth Movement Against Alzheimer’s, a final-year medical student, and an aspiring neurologist, I share my thoughts below in an effort to spur further discussion around this multifactorial topic. I note that none of this writing should be used as medical advice; decisions about the use of lecanemab should be driven by thoughtful physician-patient-caregiver discussion.
Hope: investment in science is paying its dividends
Lecanemab works. Both phase 2 and phase 3 clinical trial data show that at the 18-month mark, patients that receive lecanemab have significantly lower clinical dementia rating scale scores. This is a well-validated scale to measure multiple neurological and functional domains of AD. Notably, lecanemab works by binding to amyloid beta proteins and removing them from the brain. This would make lecanemab the first drug to provide evidence in humans to support the amyloid hypothesis: a theory, which recently came under scrutiny, that suggests that amyloid is the central driver of AD development and progression. While these trials are far from ending the mystery of causation, they may serve to provide more consensus in the scientific community. Of significant progress, the clinical trial had diverse sub-populations of African Americans and Latinos, a major shortcoming of several previous AD trials. This diversity, along with the wide age range of patients, suggests that trial data is more generalizable to the overall American patient. Taken together, these findings support the possibility that this disease is curable in my lifetime. Our increased support for research in AD is starting to pay its dividends, and further support is warranted.
Safety: the need for pause
There is reason to pause to bring attention to some of the risks that lecanemab poses. As previously mentioned, the drug works by drawing out amyloid from the brain. This process imposes significant stress on the blood-brain barrier, and it’s no surprise that the more people in the phase 3 treatment group (vs. control) experienced macro-hemorrhages (0.6% vs. 0.1%), bleeds as visible by imaging (17.3% vs. 9%), and symptomatic brain swelling (2.8% vs. unreported, possibly 0). In addition, there remains the case of the three sudden deaths of patients in these trials due to severe bleeds and seizures. Eisai, the pharmaceutical company behind lecanemab, which had known about these deaths, failed to disclose the news of the final fatality during their release of the phase 3 trial data in November of 2022. This discrepancy, along with their persistence that none of the three deaths had any association with lecanemab (contrary to the opinion of several neurologists), conjures skepticism about the completeness of the reported trial data.
Further apprehension also stems from FDA’s botched approval of lecanemab’s precursor, aducanumab. A recently published Congressional investigation sheds light on the FDA and Biogen, the pharmaceutical company behind aducanumab. They had several inappropriate meetings ahead of the accelerated approval and labeled it to be approved across all stages of AD, even though clinical trials included only early-stage persons-with-AD. The report further finds that “after just a three-week period following negative internal FDA feedback about [aducanumab’s] lack of demonstrated clinical benefit necessary for traditional approval, the agency abruptly changed course [from traditional approval], granting approval under the accelerated approval pathway—which allows the use of surrogate clinical endpoints to demonstrate effectiveness.” It is shocking that such a quick decision is possible especially when no members of FDA’s Peripheral and Central Nervous Systems Drugs Advisory Committee even voted for the drug’s approval. While these missteps by the FDA do not directly translate to the approval process for lecanemab, they suggest further caution be applied in future accelerated approval efforts.
No drug is without its side effects, and for many families, the risk of cerebral bleeding and edema may be worth the opportunity to slow cognitive decline. However, FDA’s accelerated approval, which is based on only data from 856 patients in the phase 2 trial, shortcuts the opportunity to have a meaningful discussion on this trade-off. The conclusion of the phase 3 trial report puts it best, “Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
Costs: no easy solutions
The per year cost of lecanemab is $26,500 and its accelerated approval is limited to patients with mild cognitive impairment (MCI) or early-stage Alzheimer’s disease who show evidence of amyloid pathology in the brain. This stage-specific approval, in contrast to that of aducanemab’s, is appropriate to align with trial data. However, if we briefly do some math, we understand the outrageous societal annual cost of this drug. The number of people with AD in the U.S. above 65 years-old (older adults), suggestive of medicare coverage, is nearly 6.5 million. Given the difficulty in precisely defining “early-stage”, no specific data exists on how many of these individuals would fall into that category, but we can conservatively estimate that it is at least one in four. This gives us about 1.6 million people. Additionally, 12.3 million older adults are considered to have MCI. It is estimated that 10-15% of these individuals will develop Alzheimer’s disease each year, giving us, conservatively, an additional 1.2 million people. In total, we can estimate that annually about 2.8 million Americans would qualify for lecanemab. If just a quarter of these people receives this drug, that is an additional burden for Medicare of at least $18 billion. This sticker price does not include the costs associated with confirming amyloid pathology (i.e. neuro-imaging), monitoring for side effects, and hospitalizations due to adverse events. Furthermore, as people live longer with the disease, there will likely be an even larger cost implication for Medicaid as the need for long-term care increases. Such costs may be why the Center for Medicare and Medicaid Services has elected to not cover lecanemab unless individuals are enrolled in its trials. Yet, Medicare coverage is the simplest approach to rapidly expanding access, and this pursuit should be followed once the aforementioned risks are better characterized. The societal costs associated with this treatment and any future AD treatment are likely to be seismic. It’s time we elevate the discussion of the disease to the national stage as these costs affect all Americans.
Caregivers: an unclear path forward
For many families, lecanemab may provide a meaningful change to clinical trajectory. This may mean more memories with loved ones. It is no surprise that phase 3 findings suggest that the drug significantly reduced caregiver burden. However, these numbers are all taken at the 18 month mark and it is unclear how caregiver burden will be affected as the disease course is prolonged. With nearly forty percent of AD caregivers diagnosed with clinical depression, this burden is not something that can be assessed within an 18-month time frame. The realities for how this drug would affect caregivers in the longer term is unclear, but we should continue to identify community-based strategies to support caregivers and ensure that persons-with-AD have the ability to age at home for as long as desired.
There is a promise of an effective therapeutic with the ability to significantly slow down cognitive decline. Yet, at its current stage, it may be too early for FDA to have approved the drug without comprehensive safety data. Significantly, behind the curtain, we see that lecanemab and all ensuing AD therapeutics have a significant associated financial cost; not only to individual families but to all tax-payers. It’s critical that we move the discussion of these costs beyond academic circles and support national policy efforts to prioritize expanding treatment access and care solutions in a way that is respectful of these associated costs. Finally, we must elevate the status of caregivers and appreciate that all efforts to treat this disease may have complications for their well-being. The ramifications of lecanemab are well beyond that which one may expect for most treatments. By accepting the complexities of AD treatment and care we can begin to formulate meaningful solutions for a world where we are able to live longer with less cognitive impairment.
Edited by: Dr. Amanda Porter, MD
