Lecanemab approved by EMA in early Alzheimer’s after re-evaluation
- The European Medicines Agency (EMA) reversed its initial rejection and approved lecanemab (Leqembi) for early-stage Alzheimer’s, limiting its use to patients with one or no copies of the ApoE4 gene.
- The restriction of indication is intended to maximize the benefit-risk ratio of the new drug, as ApoE4 non-carriers displayed reduced risk of serious side effects such as amyloid-related imaging abnormalities (ARIA), and possibly higher efficacy than ApoE4 carriers. However, lecanemab’s approval includes strict preventive measures like routine MRI monitoring and controlled access program, with its long-term regulatory success hinging on real-world outcomes.
- While debates over its benefits persist, lecanemab’s approval marks a milestone for anti-amyloid therapies, even as research shifts toward alternative solutions to treat Alzheimer’s disease.
The European Medicines Agency (EMA) has reversed its earlier decision and recommended the approval of lecanemab (Leqembi) for treating early-stage Alzheimer’s disease. However, the use of the new drug has been restricted to patients with one or no copies of the ApoE4 gene, a genetic variant linked to a higher risk of amyloid-related imaging abnormalities (ARIA), a significant side effect associated with lecanemab and other anti-amyloid drugs. The availability of Leqembi marks a significant milestone for patients with mild cognitive impairment or dementia linked to Alzheimer’s, offering them a new hope to delay the disease progression.
Initially, the EMA issued a negative opinion in July 2024, citing among others a low magnitude of clinical improvement and serious side effects. However, upon re-evaluating data provided by the manufacturer, the committee concluded that the benefits of lecanemab in slowing cognitive decline outweighed the risks for a restricted patient group.
ARIA, the most feared complication of anti-amyloid drugs, includes two forms: ARIA-E, characterized by brain swelling due to rapid fluid accumulation and ARIA-H, which manifests as microhemorrhages or small bleeds in the brain. Clinical data reviewed by the EMA showed a lower incidence of both ARIA-E and ARIA-H among patients with limited ApoE4 expression compared to the broader population. In the main clinical studies, 8.9% of patients with one or no ApoE4 copies experienced ARIA-E, compared to 12.6% of the overall study population. For ARIA-H, the rates were 12.9% in the restricted population versus 16.9% in the broader group. In addition to better safety profile, there was also a trend towards higher effectiveness among in this subgroup. ApoE4 noncarriers receiving Leqembi demonstrated a 41% reduction in cognitive decline over 18 months, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale, compared to only 21% in ApoE4 carriers (27% in the overall lecanemab group). According to the EMA, approval in this restricted population, which comprised around one-third of all participants included in the pivotal trial, will help maximize the cognitive benefits, while substantially reducing ARIA risk.
To further improve the benefit-risk ratio, Leqembi will be prescribed under strict conditions, including routine MRI monitoring at frequent intervals and a controlled access program. Additional measures include healthcare professional training and post-authorization safety registries to ensure the responsible use of the drug. The regulatory fate of lecanemab will depend on real-life effectiveness of these measures.
Lecanemab, developed by Eisai and Biogen, is a monoclonal antibody designed to target amyloid-beta plaques in the brain—a hallmark and probably the most important driver of Alzheimer’s disease. By binding to amyloid-beta and promoting its clearance, the drug aims to slow the progression of cognitive decline. Similar mechanism is employed by other anti-amyloid monoclonals, including donanemab and aducanumab, which as of November 2024 are not authorized for use in the EU. In contrast, all three molecules are already approved in the U.S.
Despite the positive results of clinical trials, debates about the real-world benefits of the new anti-amyloid drugs persist, with some physicians highlighting only minute differences in cognition between the treated and untreated patients. However, the same critique could be applied to all previously approved medicines for Alzheimer’s disease (such as donepezil or memantine), where despite decades of research, no groundbreaking treatments have emerged. With the last drug, memantine, being approved over twenty years ago, patients and their caregivers have been anxiously waiting for even a modestly effective solution. Undoubtedly, this social pressure was one of the key factors that EMA considered when deciding in favor of lecanemab.
Admittedly, we seem to have reached the point where amyloid-beta plaques have already unveiled their maximum potential as a therapeutic target for Alzheimer’s although other drugs from this class (such as remternetug) are still in development. Luckily, many candidates with alternative mechanisms of action, including monoclonal antibodies, are currently evaluated in late-stage trials. Will any of them hold the promise and stall the disease progress in early phase? We will soon find out
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Sources and further reading
- European Medicines Agency (EMA) “Leqembi recommended for treatment of early Alzheimer’s disease” (November 14, 2024). Link: https://www.ema.europa.eu/en/news/leqembi-recommended-treatment-early-alzheimers-disease.2024).
- Van Dyck, Christopher H., et al. “Lecanemab in early Alzheimer’s disease.” New England Journal of Medicine 388.1 (2023): 9-21.
- Cummings, Jeffrey, et al. “Alzheimer’s disease drug development pipeline: 2024.” Alzheimer’s & Dementia: Translational Research & Clinical Interventions 10.2 (2024): e12465.