A new FDA-approved Alzheimer's medicine slowed cognitive decline in patients

The most effective dose led to a statistically meaningful decrease in brain plaques.
Mert Erdemir
Alzheimer's disease stock image.
Alzheimer's disease stock image.

Naeblys/iStock 

The ​U.S. Food and Drug Administration (FDA) approved Leqembi, a new drug that is intended to slow down cognitive decline in patients who have mild or early-stage Alzheimer's disease, according to a statement released by the federal agency on January 6.

Also known as lecanemab, Leqembi is the second drug of its kind – a medication that has been approved for treating Alzheimer's disease. This type of medication targets the fundamental pathophysiology of the disease and is considered a significant development in the effort to successfully treat Alzheimer's disease.

"Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones," said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research.

"This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease."

Approved through Accelerated Approval Program

Leqembi received approval from the FDA through the Accelerated Approval Program, which is used for earlier approval of drugs that address serious conditions for which there is a significant unmet medical need. In order for a drug to be approved through this pathway, it must demonstrate an effect on a surrogate endpoint, which is a measure that is likely to indicate a benefit to patients.

The Phase 3 clinical trial, which was conducted to confirm the drug's clinical benefit, has recently reported results, and the FDA is expecting to receive the data soon.

Researchers assessed Leqembi's effectiveness in a trial involving 856 patients with Alzheimer's disease. Treatment started with patients with mild cognitive impairment or mild dementia stage of the disease and confirmed the presence of amyloid beta pathology.

The patients in the treatment group experienced a noticeable decrease in amyloid beta plaques as the dosage and duration of the treatment increased. The most effective dose, ten milligrams per kilogram given every two weeks, led to a statistically meaningful decrease in brain plaques compared to the patients who received a placebo and saw no reduction in amyloid beta plaques.

These findings support Leqembi's accelerated approval, which is based on the observed reduction of amyloid beta plaque, a sign of Alzheimer's disease.

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In order to compare the levels of amyloid-beta plaque in a composite of brain regions expected to be severely affected by the pathology of Alzheimer's disease to a brain region expected to be spared from such pathology, amyloid-beta plaque was quantified using positron emission tomography (PET) imaging.

The prescription includes a warning

Leqembi comes with a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies from this class.

ARIA is typically asymptomatic, but in rare cases, it can cause serious and potentially fatal complications. The most common symptom of ARIA is temporary swelling in some areas of the brain that usually resolves on its own and may be accompanied by small bleeding spots on or in the brain. However, some individuals may experience symptoms such as headaches, confusion, dizziness, changes in vision, nausea, and seizures.

Additionally, there is a risk of infusion-related reactions with Leqembi, which can cause flu-like symptoms, nausea, vomiting, and changes in blood pressure. The most frequently reported side effects of Leqembi are infusion-related reactions, headaches, and ARIA.

According to the prescribing information for Leqembi, it is approved for the treatment of Alzheimer's disease. It is recommended that treatment with Leqembi is started in patients who have been diagnosed with mild cognitive impairment or the early stages of dementia, as these are the populations in which the drug has been tested and found to be effective in clinical trials.

The labeling for the drug also states that there is no evidence to support the safety or effectiveness of using Leqembi in patients who have more advanced or earlier stages of Alzheimer's disease than were studied.

Eisai, the pharmaceutical company that led the study, announced that Leqembi would have an estimated annual cost of $26,500 per patient, though the final cost could vary for each person. The president and CEO of the Alzheimer's Association, Joanne Pike, also stated her concern that this high cost could make the drug inaccessible for many Americans, particularly those who do not have coverage under the government-funded Medicare program for the elderly.

The results of the trial were published in the New England Journal of Medicine.

Abstract:

Background: The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.

Methods: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

Results: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P<0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.

Conclusions: Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455. opens in new tab.)

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