Lecanemab, a breakthrough Alzheimer’s drug, rejected by EMA

Lecanemab, an FDA-approved amyloid-targeting antibody for Alzheimer’s disease, has been recently rejected by the EMA on the ground of unfavorable benefit-risk ratio.
In the pivotal CLARITY-AD trial, lecanemab reduced cognitive decline by 27%, but the absolute benefit was very modest. The EMA doubted whether this small gain outweighs the risk of amyloid-related imaging abnormalities (ARIAs), dangerous neurological complications observed in a significant number of treated patients.
The FDA prioritized the need for new Alzheimer’s treatments and approved lecanemab, accepting risks like ARIA in light of the urgent demand, whereas the EMA demanded stronger evidence of meaningful clinical improvement and long-term safety data.
Lecanemab remains on the market in the U.S. and Japan, with increasing sales projections. Eisai and Biogen plan to resubmit their application to the EMA with additional data to address concerns.

Amyloid-targeting antibodies, such as lecanemab (Leqembi), have been at the center of a heated debate in the medical community, with one side praising them as first effective drugs against Alzheimer’s disease in more than two decades, and the other pointing to their modest benefits and serious safety issues. Developed by Eisai and Biogen, lecanemab was heralded as a breakthrough after receiving accelerated approval from the U.S. Food and Drug Administration (FDA) in early 2023, and then full approval in July 2023. However, in a surprising move, the European Medicines Agency (EMA) recently rejected its application for approval in the European Union.

The EMA’s decision to reject lecanemab was based on concerns over its efficacy and safety profile. Specifically, the agency concurred with the skeptical part of medical profession and raised doubts about the clinical benefit of the drug in relation to its risks. The EMA’s Committee for Medicinal Products for Human Use (CHMP) concluded that while lecanemab showed some promise in slowing cognitive decline in patients with early-stage Alzheimer’s disease, the magnitude of its benefit was not considered sufficient to outweigh the potential risks associated with its use. In the phase 3 study known as CLARITY-AD, which involved approximately 1,800 subjects treated for over 18 months, the new drug reduced clinical decline by 27% compared to placebo, as measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale – a validated assessment tool. However, the absolute benefit was modest. Patients treated with lecanemab experienced an average slowing of cognitive decline that amounted to only a few points on the CDR-SB scale, which some experts argue may not translate into meaningful clinical benefits for patients and caregivers.

Among the highlighted risks was the occurrence of amyloid-related imaging abnormalities (ARIA), a type of brain swelling or microhemorrhage that is often seen in patients treated with anti-amyloid therapies like lecanemab. In CLARITY-AD trial, approximately 21% of participants exposed to the new drug developed ARIA, although the majority of cases were asymptomatic or mild. The EMA expressed concerns that the incidence and severity of this dangerous side effect could limit the drug’s use in a broader patient population, especially given the challenges associated with its detection and management in general practice. Several deaths due to ARIA have been already reported in the U.S, however causal association with lecanemab is not certain.

Lecanemab is a monoclonal antibody that targets soluble aggregated forms of amyloid-beta (Aβ) peptides, a hallmark of Alzheimer’s disease pathology. The drug is designed to bind to these soluble aggregates, facilitating their clearance from the brain and potentially slowing the progression of cognitive impairment. The idea behind lecanemab and other anti-amyloid therapies is to intervene early in the disease process when amyloid-beta deposition is believed to contribute significantly to neurodegeneration.

How can we explain the divergent opinions of the two biggest drug agencies in the world? The issue is complex, but probably the explanation lies in different regulatory approaches and evidentiary standards. The FDA interpreted lecanemab’s data in light of the unmet medical need and paucity of effective treatments for Alzheimer’s disease. The philosophy was that even a modestly effective drug is better than no drug at all, especially considering the devastating nature of the treated condition. Without amyloid-targeting therapies, Alzheimer’s disease patients could be only managed with old drugs from a group of acetylcholine esterase inhibitors, which also display low effectiveness. The FDA reviewers were also convinced by the data showing profound and rapid reduction of brain amyloid levels, that could alter the disease course and improve long-term outcomes. The US agency did not underestimate the severity of neurological side effects such as ARIA, but considered the risk to be acceptable in light of the urgent need for new Alzheimer’s disease treatments. The reviewers noted the mild nature of most ARIA cases and that they occur mostly during the first weeks of therapy. Nevertheless, Eisai was obliged to conduct a post-marketing confirmatory study to provide further evidence on the drug’s benefit-risk ratio. If the study shows more evidence of harm, the FDA may warrant restriction of indications or even complete withdrawal from the market.

Unlike FDA, EMA took a more cautious approach. The EU regulator was not convinced that the observed reduction in symptoms severity is sufficiently large to justify the risk of serious side effects. It reasoned that the achieved 0.45-point difference on CDR-SB scale is too small to meaningfully improve the lives of Alzheimer’s disease patients and their families. Further data demonstrating positive influence on the quality of life and long-term outcomes would be necessary to reverse the negative opinion.

In terms of market position, lecanemab remains available in the U.S. and Japan, where it has been approved, and its developers are expected to resubmit their application to the EMA with additional data to address the raised concerns. The financial results from first half of 2024 show a substantial spike in its uptake, leading to optimistic sales prognoses for next years. Many investors consider the EMA’s rejection to be a temporary delay on a pathway to successful commercialization.

The rejection of lecanemab by the EMA underscores the complexities of introducing new Alzheimer’s treatments to the market. While the drug has shown some promise, concerns about its safety and the magnitude of its benefits have led to differing regulatory decisions across the globe. As research continues, the hope remains that new, more effective therapies will emerge, providing better future for millions of patients and their families affected by this devastating disease.

Prepared by:

Adam Tuszyner

Sources and further reading

Peter, Roohi Mariam. “European regulators reject Alzheimer’s drug Leqembi: is it downhill from here?” Labiotech (August 1, 2024).
European Medicines Agency (EMA). Questions and answers on the refusal of the marketing authorization for Leqembi (lecanemab). EMA/337466/2024 (July 26, 2024).
Food and Drug Administration (FDA). Drug Approval Package: LEQEMBI. Link: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/761269Orig1s000TOC.cfm.
Van Dyck, Christopher H., et al. “Lecanemab in early Alzheimer’s disease.” New England Journal of Medicine 388.1 (2023): 9-21.
Manalac, Tristan. “Biogen Beats Q1 Profit Estimates as Leqembi Sales Start to Take Off.” BioSpace (April 24, 2024).
Kansteiner, Fraiser. “Eisai, Biogen’s Alzheimer’s med Leqembi turned down in Europe—but analyst says it’s merely a ‘delay’” Fierce Pharma (July 26, 2024).