Alzheimer Disease Drug Lecanemab Successfully Reduces Cognitive, Functional Decline

A drug to treat early Alzheimer disease has shown success in reducing cognitive and functional decline. Eisai and Biogen announced topline results from a large global page 3 confirmatory trial of lecanemab that met both the primary endpoint and all secondary endpoints.

Biogen also developed aducanumab (Aduhelm), which was the first drug approved for Alzheimer disease (AD) in 18 years. The approval of aducanumab was controversial. Not only was there unclear evidence of benefit, but trials showed that the drug could cause brain swelling or brain bleeding. Despite the advisory panel for the FDA voting that the evidence for aducanumab wasn’t enough to approve the drug, the FDA ultimately did approve it.

However, the topline results of the phase 3 confirmatory CLARITY AD clinical trial of lecanemab have shown that the drug reduced cognitive and functional decline by 27% at 18 months compared with placebo. The trial used the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

As early as 6 months on treatment there were highly statistically significant changes in CDR-SB from baseline compared with placebo.

“These are the most encouraging results in clinical trials treating the underlying causes of Alzheimer’s to date,” the Alzheimer’s Association said in a statement.

Lecanemab is an investigational anti-amyloid beta protofibril antibody for the treatment of early AD—or mild cognitive impairment due to AD and mild AD—with confirmed presence of amyloid pathology in the brain. CLARITY AD was a placebo-controlled, double-blind, parallel-group, randomized study of 1795 people with early AD. Patients were randomized 1:1 to receive either placebo or 10 mg/kg bi-weekly of lecanemab.

Among patients taking lecanemab, the incidence of amyloid-related imaging abnormalities–edema/effusion (ARIA-E) was 12.5% vs 1.7% in the placebo group. The rate of ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H) was 17.0% in the lecanemab compared with 8.7% in the placebo group.

The FDA accepted a Biologics License Application for lecanemab under the accelerated approval pathway in July 2022, and it granted Priority Review. A decision on lecanemab is expected by January 6, 2023.

“Today’s announcement gives patients and their families hope that lecanemab, if approved, can potentially slow the progression of Alzheimer’s disease, and provide a clinically meaningful impact on cognition and function,” Michel Vounatsos, CEO at Biogen, said in a statement. “Importantly, the study shows that removal of aggregated amyloid beta in the brain is associated with a slowing of disease in patients at the early stage of the disease.

Eisai and Biogen highlighted the inclusion of ethnic and racial populations in the United States in the CLARITY AD trial, making the trial population comparable to the country’s Medicare population. Approximately 25% of participants were Hispanic and Black. This diversity is important because the trials for aducanumab had come under fire for their lack of diversity—only 0.6% of participants were Black and 3% were Hispanic.¹

However, if the drug is approved, it will be subject to a coverage decision put in place by CMS after the approval of aducanumab. With concerns over the effectiveness of aducanumab and a high price tag for the drug, CMS implemented a National Coverage Determination (NCD) for approved monoclonal antibodies directed against amyloid for the treatment of AD.

As a result, CMS will only cover aducanumab for patients in “qualifying” clinical trials that meet specific criteria set by CMS. For now, aducanumab is the only approved drug that falls into this category, but lecanemab would also be affected by the decision if it was approved. In addition, donanemab from Eli Lilly is in the pipeline and being investigated for the treatment of early AD.

The Alzheimer’s Association noted in its statement that CMS has indicated it will modify the NCD if warranted by evidence.

“If full CLARITY AD results are in line with today’s topline announcement and the FDA approves this treatment, Medicare beneficiaries living with Alzheimer’s, a terminal, progressive disease, deserve the same immediate, full coverage under Medicare afforded to those with other terminal diseases,” the association said.

Reference

1. Manly JJ, Glymour MM. What the aducanumab approval reveals about Alzheimer disease research. JAMA Neurol. 2021;78(11):1305-1306. doi:10.1001/jamaneurol.2021.3404