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Outrage of the Month: FDA Approval of Lecanemab for Alzheimer’s Disease

Health Letter, August 2023

By Robert Steinbrook, M.D.


If you’re not outraged,
you’re not paying attention!

Read what Public Citizen has to say about the biggest blunders and outrageous offenses in the world of public health, published monthly in Health Letter.

In early July 2023, the Food and Drug Administration (FDA) granted full approval to the drug lecanemab to treat Alzheimer’s disease. Lecanemab, which had received accelerated approval in January, is a monoclonal antibody that is designed to clear amyloid plaque from the brains of patients with the disease. In clinical trials, it has been studied in patients with mild cognitive impairment or in the mild dementia stage of Alzheimer’s disease.

Although expected, the FDA’s decision was misguided and very disappointing, as the clinical benefits of lecanemab are uncertain and the health risks are substantial. Previously, Public Citizen’s Health Research Group urged the FDA not to approve lecanemab, and in June we urged the agency not to grant full approval.

The serious safety concerns about lecanemab are demonstrated by the addition of a black-box warning for “amyloid related imaging abnormalities,” or ARIA, in the prescribing information for the drug. ARIA are atypical differences seen in magnetic resonance imaging of the brain in patients with Alzheimer’s disease. ARIA are associated with therapies that modify amyloid, such as lecanemab and aducanumab, another Alzheimer’s drug which was approved in 2021 but is rarely used. ARIA-E refers to brain swelling or cerebral edema and ARIA-H refers to micro and small brain bleeding or cerebral hemorrhages. Removal of amyloid plaques can be thought of as weakening blood vessels in the brain. Although ARIA in patients with Alzheimer’s disease are often asymptomatic or mild, intracerebral hemorrhage can be serious and life-threatening. In studies, treatment with lecanemab was associated with three deaths.

The minimal clinical benefits of lecanemab are demonstrated by the results of the clinical trial used to support the drug’s approval. The primary endpoint 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). Over a period of 18 months, dementia severity in patients receiving lecanemab worsened by 1.21 points with lecanemab and 1.66 points with placebo; the 0.45-point difference is statistically significant but of uncertain clinical relevance.

Later in July, a clinical trial of donanemab, a third monoclonal antibody for Alzheimer’s disease, was published. Among other endpoints in the donanemab study, dementia severity in patients receiving the drug worsened by 1.72 points on the CDR-SB and 2.42 points for patients in the placebo group, a difference of 0.70 points. On an 18-point scale, differences of 0.45 (with lecanemab) and 0.70 (with donanemab) are small — 2.5% and 3.9%, respectively. Three deaths in the donanemab group and one in the placebo group were considered treatment-related. Although the FDA rejected accelerated approval for donanemab in January 2023, it may receive full approval based on the new data.

FDA approval of drugs for Alzheimer’s disease with minimal benefit and significant health risks is not a path forward. Patients and their families desperately need and deserve better treatments.