In July 2023, the FDA gave full approval for lecanemab to treat Alzheimer’s dementia. Lecanemab is a monoclonal antibody that targets a step in the amyloid plaque formation pathway in the brain.1 The story of the approval of this and similar medications is rife with controversy that internists should understand to allow a balanced conversation with patients regarding these treatments.
A major part of the controversy surrounding these drugs is that the earlier FDA approval of a slightly different amyloid antibody, aducanumab, resulted in the resignation of several key members of the advisory committee to the FDA.2 The FDA approved the medication despite the committee unanimously voting not to approve the medication. The two trials of adacanumab were stopped early due to futility and only published after lecanemab demonstrated better results. A newer amyloid antibody, donanemab, had trial results published recently. The information shared here should help readers considering referral for lecanemab treatment and donanemab (should it receive future FDA approval).
Lecanemab requires an infusion every other week. To qualify for treatment, the patient must be diagnosed with either mild cognitive impairment or early stage Alzheimer’s dementia. Other types of dementia or more severe cognitive impairment exclude patients from eligibility.
To receive Medicare reimbursement, prescribers of lecanemab must participate in monitoring via a registry to track outcomes.3 The FDA put no similar safety measure in place. The CMS registry asks about cognitive testing results, either the Montreal Cognitive Assessment Test (MoCA) or another type of cognitive test, and asks for verification of amyloid testing via an amyloid PET scan, lumbar puncture or other test that detects amyloid levels. Additionally, the prescriber must report functional testing results.
Finally, information is required on whether the patient is taking an antiplatelet or is on anticoagulation, presumably because of the potential adverse effects of this medication. The number needed to harm for potential cerebral hemorrhage (ARIA-H) is 12.1 people, which is alarmingly low.1 In addition to biweekly infusion center visits, patients are monitored for potential adverse reactions via brain imaging and other close monitoring while under treatment.
The Clinical Dementia Rating Sum of Boxes (CDR-SB) is a standard tool used in dementia research to evaluate the effectiveness of a treatment. It is evaluated on an 18 point scale. For clinical trials purposes, a difference of 0.3 is considered significant. In the lecanumab trial, the difference between the treatment group and placebo on the CDR-SB at 18 months was 0.45. The trial also demonstrated a significant decrease in amyloid volume in the lecanemab group compared to the placebo group at 18 months.
Let’s consider this: The drug currently carries a hefty price tag exceeding $25,000 per year. Now, add context to the equation. The Alzheimer’s Association reports that Black individuals are twice as likely as their Caucasian counterparts to receive a dementia diagnosis while Latinx individuals face a risk 1.5 times higher. However, the clinical trial enrollment figures reveal an alarming disparity. Black participants accounted for a mere 2.5%, Latinx individuals comprised just 12.4%, and Caucasians dominated at 77%. This glaring incongruity not only raises concern but also begs a crucial question: Shouldn’t those most impacted by the disease enjoy more equitable access to potential treatments, including the opportunity to participate in clinical trials? It’s time we confront these disparities and ensure that cost and systemic exclusion no longer act as a barrier to those most in need.4
In summary, when considering whether to refer patients to receive lecanemab treatment there are four key items to review with the patient and their loved ones helping them cope with dementia as it progresses:
- It is only indicated for the very mildest cases of cognitive impairment. Patients must meet treatment criteria through cognitive testing and amyloid testing. Some patients will appear to qualify on the surface, but may not after testing.
- Lecanemab does not cure Alzheimer’s dementia and at best slightly delays disease progression. Dementia will still progress eventually and patients will be forced to stop the treatment in time.
- The treatment regimen can be burdensome with infusions scheduled every two weeks.
- With such a low number needed to harm, the potential for serious adverse effects should not be ignored.
The striking lack of diversity in clinical trials assessing the efficacy of lecanemab raises critical questions about our understanding of its benefits and risks. Health equity principles underscore the urgent need for more inclusive research, as the disproportionate impact of Alzheimer’s dementia on various racial and ethnic groups demands comprehensive representation in our studies. To comprehend the medication’s potential, SGIM members must advocate for trials that reflect the rich diversity of the patients we aim to serve. By doing so, SGIM members can foster a more equitable healthcare landscape and ensure that every individual receives the care they deserve.
- van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi:10.1056/NEJMoa2212948. Epub 2022 Nov 29.
- Aduacnumab (Aduhelm) for the treatment of alzheimers: A podcast with Aaron Kesselheim and Jason Karlawish. GeriPal. https://geripal.org/aducanumab-aduhelm-for-the-treatment-of-alzheimers-a-podcast-with-aaron-kesselheim-and-jason-karlawish/. Broadcast July 29, 2021. Accessed November 15, 2023.
- Fact sheet: CMS announces new details of plan to cover new alzheimer’s drugs. CMS. https://www.cms.gov/files/document/fact-sheet-june-2023.pdf. Published June 22, 2023. Accessed November 15, 2023.
- Balls-Berry JJE, Babulal GM. Health disparities in dementia. Continuum (Minneap Minn).Jun 1 2022;28(3):872-884. doi: 10.1212/con.000000000000 1088.
Geriatrics/Palliative Care, Health Equity, Health Policy & Advocacy, SGIM, Vulnerable Populations
Dr. Carnahan (firstname.lastname@example.org) is a geriatrician at Indiana University School of Medicine and researcher at Regenstrief Institute. Dr. Scott (email@example.com) is an assistant professor at Albert Einstein College of Medicine and the associate program director, diverse and inclusive clinical education, for the Moses-Weiler Internal Medicine Residency Program. Both authors are graduates of SGIM’s program, LEAHP.
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