Lecanemab for Alzheimer’s Disease: Do Not Use

In July 2023, the Food and Drug Administration (FDA) granted full approval to the drug lecanemab (LEQEMBI) to treat Alzheimer’s disease. Previously, the FDA had granted lecanemab accelerated approval. The drug, which is administered as an intravenous infusion over approximately one hour, is a monoclonal antibody that is designed to reduce the accumulation of abnormal protein deposits called beta amyloid plaques in the brains of patients with Alzheimer’s disease.

The FDA approved lecanemab for patients with mild cognitive impairment and in the mild dementia stages of the disease, the population that was studied in clinical trials.[1] Importantly, with full approval of lecanemab, a boxed warning about “amyloid related imaging abnormalities” was added to the prescribing information. A boxed warning, which is also known as a black-box warning, is the strongest warning that the FDA can require.

Public Citizen’s Health Research Group urged the FDA not to approve lecanemab[2] and subsequently not to grant full approval.[3] Based on the serious safety concerns about the drug and the very small treatment benefit, discussed in more detail below, Public Citizen’s Health Research Group has designated lecanemab as a Do Not Use drug.

Lecanemab is not a cure for Alzheimer’s disease, and the drug cannot restore cognitive function or bring back lost memories. Although patients are likely to continue to get worse while receiving treatment, the goal is to slow the progression of the disease.

Like aducanumab (ADUHELM) and other drugs targeting amyloid plaques, lecanemab is associated with serious adverse events. Amyloid-related imaging abnormalities may be a precursor to severe, life-threatening swelling or bleeding in the brain.[4] Moreover, to monitor for such brain bleeds, periodic brain scans prior to and throughout treatment are recommended, adding substantially to the time and cost associated with administering the drug.

About Alzheimer’s disease

Alzheimer’s disease is an irreversible, progressive disease of the brain that significantly impairs thinking, memory and — in the late stages — the ability to perform daily activities. It is the most common cause of dementia among the elderly, accounting for 60–80% of all dementia cases, and is the seventh leading cause of death among Americans in 2020.[5] Approximately 6.5 million Americans aged 65 or older have the disease, and by 2050, that number is expected to grow to more than 12 million.

The cause of Alzheimer’s disease is not fully understood, and at present there is no cure. However, because the condition is associated with amyloid plaques, treatments such as lecanemab that target beta amyloid plaques have been developed. Whether such treatments have meaningful effects on patients’ cognitive function remains uncertain, however.[6] In fact, other drugs of this type, such as aducanumab, have shown no or only minimal clinical benefit.[7]

Evidence for lecanemab’s efficacy

The full approval of lecanemab was based on one study that included 1,795 patients between 50 and 90 years of age with early Alzheimer’s disease and a confirmed buildup of beta amyloid plaques.[8] The subjects were randomized to receive an intravenous infusion of either lecanemab or a placebo every two weeks.

As compared to treatment with placebo, 79 weeks of treatment with lecanemab led to greater reduction of brain plaques and slightly better outcomes on several measures used to assess cognitive function.[9]

The primary endpoint of the study was a measure known as the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB, range of scores 0 to 18 with higher scores indicating greater impairment). When patients’ cognition (such as memory and orientation) and function (such as personal care) were assessed, scores decreased by 1.21 points in patients receiving lecanemab and by 1.66 points in the placebo group.[10] The 0.45 point difference was statistically significant but of uncertain clinical relevance. There is no accepted definition of what change in score is clinically meaningful. Small improvements may not be noticeable for patients and their families.[11]

The study only included a limited population of patients with Alzheimer’s disease. For example, many patients, including those with a history of brain bleeds, which are common among patients with Alzheimer’s disease, were excluded from the trial. Only about 30% of screened subjects were eventually selected to participate.[12] Participants were also relatively young (with an average age of 72),[13] and only 2.5% were Black. This is of particular concern because of the high risk of Alzheimer’s disease in Black people.[14]

Safety concerns

In the trial, treatment with lecanemab was associated with three deaths (during the open label extension of the study), and patients receiving the drug were at higher risk of many adverse events than patients in the placebo group.[15] For example, subjects receiving lecanemab (26%) were more likely than those on placebo (7%) to have infusion-related reactions, which included increased blood pressure, increased heart rate, fever, headache and vomiting. Treatment with lecanemab also was associated with a decrease in brain volume, and the FDA cautioned that the “clinical implications” of this decrease are not fully understood. Patients in the lecanemab group were 2.3 times more likely to have amyloid-related imaging abnormalities than patients on placebo.[16]

Patients who are using aspirin, blood thinners such as warfarin (COUMADIN) or medications that inhibit the aggregation of platelets, such as clopidogrel (PLAVIX), while receiving lecanemab may be at a higher risk of brain bleeds.[17] Also, those with a genetic mutation called ApoE4 have a higher risk of amyloid-related imaging abnormalities,[18] especially if they have two copies of this mutation (which is the case for about 15% of patients with Alzheimer’s disease).

What You Can Do

Healthy lifestyle behaviors, including physical activity, a healthy diet and maintaining a healthy weight, avoiding excessive drinking of alcohol and stopping smoking are important for all people at risk of Alzheimer’s disease. Conditions such as high blood pressure, diabetes, cataracts or substantial hearing loss should be adequately treated. Although patients and their families need and deserve better treatments for Alzheimer’s disease, lecanemab has minimal benefit and significant health risks. Public Citizen’s Health Research Group has therefore classified lecanemab as a Do Not Use drug.
 

References

[1] Eisai. Label: lecanemab-irmb (LEQEMBI). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s001lbl.pdf. Accessed August 9, 2023.

[2] Public Citizen. Lecanemab letter to the FDA. January 5, 2023. https://www.citizen.org/lecanemab-letter/. Accessed August 9, 2023.

[3] Public Citizen. Testimony before the FDA’s peripheral and central nervous system drugs Advisory Committee regarding lecanemab for the treatment of Alzheimer’s disease. June 9, 2023. https://www.citizen.org/article/testimony-before-the-fdas-peripheral-and-central-nervous-system-drugs-advisory-committee-regarding-lecanemab-for-the-treatment-of-alzheimers-disease/. Accessed August 9, 2023.

[4] Eisai. Label: lecanemab-irmb (LEQEMBI). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s001lbl.pdf. Accessed July 26, 2023.

[5] Food and Drug Administration. FDA briefing document, sBLA# 761269/s-001, drug name: lecanemab-irmb; Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. June 9, 2023. https://www.fda.gov/media/169263/download. Accessed August 9, 2023.

[6] Begley S. The maddening saga of how an Alzheimer’s ‘cabal’ thwarted progress toward a cure for decades STAT. June 25, 2019. https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/. Accessed July 26, 2023.

[7] Walsh S, Merrick R, Richard E, et al. Lecanemab for Alzheimer’s disease. BMJ. 2022;379:o3010.

[8] Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.

[9] Ibid.

[10] Food and Drug Administration. FDA Briefing document, sBLA# 761269/s-001, drug name: lecanemab-irmb; Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. June 9, 2023. https://www.fda.gov/media/169263/download. Accessed July 26, 2023.

[11] Liu KY, Schneider LS, Howard R. The need to show minimum clinically important differences in Alzheimer's disease trials. The Lancet Psychiatry. 2021;8(11):1013-6.

[12] Food and Drug Administration. FDA Briefing document, sBLA# 761269/s-001, drug name: lecanemab-irmb; Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. June 9, 2023. https://www.fda.gov/media/169263/download. Accessed July 26, 2023.

[13] Eisai. Label: lecanemab-irmb (LEQEMBI). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s001lbl.pdf. Accessed July 26, 2023.

[14] Matthews KA, Xu W, Gaglioti AH, et al. Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015–2060) in adults aged≥ 65 years. Alzheimers Dement. 2019;15(1):17-24.

[15] Food and Drug Administration. FDA Briefing document, sBLA# 761269/s-001, drug name: lecanemab-irmb; Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. June 9, 2023. https://www.fda.gov/media/169263/download. Accessed August 9, 2023.

[16] Ibid.

[17] Eisai. Label: lecanemab-irmb (LEQEMBI). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s001lbl.pdf. Accessed July 26, 2023.

[18] Food and Drug Administration. FDA Briefing document, sBLA# 761269/s-001, drug name: lecanemab-irmb; Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting. June 9, 2023. https://www.fda.gov/media/169263/download. Accessed July 26, 2023.