Two patients were on my mind in geriatric consult clinic when I read a news release sharing the preliminary clinical trial results for lecanemab, a new monoclonal antibody against amyloid protein. Mrs. B is an 80-year-old retired librarian with hypertension, diet-controlled diabetes, and a history of stroke, whom I diagnosed with Alzheimer's dementia with possible vascular contributions. In contrast, Mr. S is a 64-year-old civil engineer who stopped working as he could not problem-solve like he did in the past. After unremarkable labs and brain MRI, I diagnosed him with most likely early-onset Alzheimer's disease.
If FDA approved, who should get lecanemab? Mr. S or Mrs. B? Both? Or neither?
Clinical Trial Results
Lecanemab targets the abnormal protein called amyloid, which according to the amyloid hypothesis, is at least one of the mechanisms causing Alzheimer's disease. The lecanemab phase III clinical trial, known as Clarity AD, enrolled 1,906 people living with mild cognitive impairment or mild Alzheimer's dementia. Of its participants, 25% are Black or Hispanic. It met its primary outcome in that compared to placebo, those randomized to the lecanemab arm had a 0.45-point difference on an 18-point scale called the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). For context, a CDR-SB of 0.5 might mean that someone is having a little bit of cognitive impairment, but they are still able to maintain their daily functions. A CDR-SB of 1 might mean that someone is starting to need assistance with some of the more difficult instrumental activities of daily living, such as managing their medications or finances, but they're still able to do most of their daily activities.
Main side effects of amyloid-related imaging abnormalities (ARIAs) were 21.3% in the lecanemab group versus 9.3% in the placebo group. The trial was blinded at multiple levels: the participants, the people conducting the study, and the people who measured outcomes, none of them knew which arm the participant was assigned to. Full results are still pending for release in the next few months.
The Broader Context
In order to understand lecanemab, which is being developed by Biogen and Eisai, we have to talk about the context of Alzheimer's drug development. A similar drug, aducanumab (Aduhelm) was developed by Biogen and FDA approved last year. Aducanumab is similarly a monoclonal antibody against amyloid, but with a slightly different mechanism compared to lecanemab. The FDA approval process was highly controversial. There is a congressional investigation into the relationship between Biogen and the FDA that is currently ongoing. Medicare decided to not pay for aducanumab outright, but will only pay for participants in additional CMS-approved studies. In addition, just last week, Biogen settled a lawsuit for $900 million after a whistleblower within Biogen said the company was paying kickbacks to induce physicians to prescribe the company's multiple sclerosis drugs.
Even after the full Clarity AD trial results are published, there will still be many questions to be answered before it can be approved and before clinicians can determine if and whom to prescribe it to. Let's break the questions down by category:
Eligibility
Who truly has amyloid in the brain?
Even dementia specialists are not always correct when they diagnose someone as having clinical Alzheimer's disease. Patients' history may suggest that it's a slow progressing disease that started out with short-term memory problems first, but their brains may not show amyloid pathology. The reverse is also true: atypical history and exam findings for Alzheimer's disease may have amyloid pathology. We think that amyloid builds up for decades before people start having symptoms, but amyloid is not the only possible pathway to the clinical presentation of Alzheimer's disease. In our typical older population, there is significant overlap with vascular disease, such as Mrs. B's case above. Right now, Medicare only pays for an amyloid PET scan under an approved clinical trial. If lecanemab is FDA approved and if it is covered by insurance, there also needs to be broader coverage of an amyloid biomarker test.
How broadly will lecanemab be applicable?
The Clarity AD clinical trial excluded people who have significant, vascular risk factors such as strokes or those with high risk of brain bleeds, those with significant psychiatric illness, and other possible alternatives for memory loss. Mrs. B would not be eligible based on the clinical trial enrollment criteria due to her history of strokes.
Treatment Monitoring and Side Effects
The main side effect of ARIA is basically two phenomena that are detected on brain MRI. ARIA-edema indicate small areas of swelling in the brain, while ARIA-hemorrhage indicate small areas of bleeding in the brain. Most of these ARIAs are asymptomatic, meaning that it's only seen on MRI, but it raises the question of how often doctors will actually need to scan people who are receiving lecanemab in the real world. While most ARIAs are asymptomatic, in some cases symptoms could range from minor (headaches or confusion) to severe (seizures or brain bleeds).
We know that amyloid protein can build up for decades in someone's brain before they have symptoms, but we don't know how long the drug can be given safely, and the trial lasted only 18 months. Lecanemab is an infusion that is given once every 2 weeks, but does that mean that someone like Mr. S, who is only 64, will need to be on lecanemab for the rest of his life?
Cost
We don't know how much Biogen/Eisai will charge for lecanemab. When aducanumab was approved by the FDA last year, the initial price was $56,000 per year. Interestingly, when few bought aducanumab, Biogen put it on a 50% off sale, pricing it at $28,000, which is still a significant amount.
What would broad Medicare coverage for lecanemab mean for our healthcare system? Medicare increased premiums in 2022 due to the possibility of paying for aducanumab (though then reduced premiums after CMS' coverage decision). What about families and people living with dementia who are beyond the mild stage of disease, when they most need support and guidance navigating through the healthcare system through comprehensive dementia care?
Lecanemab is an exciting new development, but the full results have yet to be released and the reality will be much more complicated when expanding lecanemab from a clinical trial to the larger population.
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.
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