Leqembi Granted Traditional Approval for Alzheimer Disease

The Food and Drug Administration (FDA) has granted traditional approval to Leqembi^® (lecanemab-irmb) for the treatment of Alzheimer disease (AD) based on the clinical benefit established in a confirmatory trial.

Leqembi is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. It reduces amyloid beta plaques in the brain, which is a defining pathophysiological feature of Alzheimer disease.

In January 2023, the FDA granted accelerated approval to lecanemab for the treatment of AD based on data from a phase 2b trial (ClinicalTrials.gov Identifier: NCT01767311). Full approval was granted based on efficacy and safety data from the confirmatory phase 3 Clarity AD trial (ClinicalTrials.gov Identifier: NCT03887455), which included 1795 patients with early AD. Patients were randomly assigned 1:1 to receive either lecanemab 10mg/kg via intravenous infusion once every 2 weeks or placebo. The primary endpoint was the change from baseline at 18 months in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

Results showed a statistically significant treatment difference in the CDR-SB score change (difference from placebo, -0.45; P =.0001), indicating a reduction in clinical decline of 27% with lecanemab over 18 months compared with placebo. Findings also showed statistically significant improvements in all key secondary endpoints compared with placebo (P <.001), including changes in amyloid levels in the brain (as measured by amyloid positron emission tomography), the AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog 14; difference from placebo, -1.442 [-26%]; P =.00065) and the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL; difference from placebo, 2.0; P <.0001).

“Today’s action is the first verification that a drug targeting the underlying disease process of Alzheimer disease has shown clinical benefit in this devastating disease,” said Teresa Buracchio, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “This confirmatory study verified that it is a safe and effective treatment for patients with Alzheimer disease.”

Findings also showed that both ApoE ε4 carriers and ApoE ε4 noncarriers showed statistically significant treatment differences for the primary and secondary endpoints. Fifteen percent of the study population were reported to be ApoE ε4 homozygotes. While a treatment effect was not observed on CDR-SB in this population, the analysis showed effects that favored lecanemab on ADAS-Cog 14 and ADCS MCI-ADL.

The most common adverse events reported with lecanemab were infusion reactions, amyloid related imaging abnormality (ARIA)-microhemorrhages, ARIA-edema/effusion, and headache. The incidence of ARIA was found to be higher in ApoE ε4 homozygotes than in heterozygotes and noncarriers; testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA, according to the prescribing information.

Analysis of the Clarity AD study also showed an increased number of intracerebral hemorrhages in patients taking lecanemab with an anticoagulant alone or combined with an antiplatelet medication or aspirin compared with placebo. Caution should be used when considering treatment in patients taking anticoagulants or with risk factors for intracerebral hemorrhage.

Leqembi is supplied as a preservative-free solution in single-dose vials of 500mg/5mL and 200mg/2mL. Treatment is administered by intravenous infusion once every 2 weeks. Leqembi should be initiated in patients with mild cognitive impairment or mild dementia stage of disease (the population in which treatment was initiated in clinical trials) and confirmed amyloid beta pathology.

The FDA’s traditional approval of Leqembi also clears the path for broader Medicare coverage. In a statement, the Centers for Medicare & Medicaid Services (CMS) Administrator Chiquita Brooks-LaSure said: “With FDA’s decision, CMS will cover this medication broadly while continuing to gather data that will help us understand how the drug works. This is welcome news for the millions of people in this country and their families who are affected by this debilitating disease.” The CMS-facilitated registry is now available for clinicians to submit required patient data to CMS.

A patient assistance program has also been established by Eisai to ensure appropriate patients get access to Leqembi.