The approval of lecanemab for early Alzheimer’s disease by the MHRA: The pharmacovigilance perspective
The Medicines and Healthcare products Regulatory Agency (MHRA) has granted the approval of lecanemab for the treatment of Alzheimer’s disease (AD) in patients with mild cognitive impairment or mild dementia stage of the disease. In this blog, we discuss the background to this decision, the complex regulatory landscape, the initial benefit-risk profile of the drug, and the need for a pharmacovigilance perspective of lecanemab’s real-world safety and effectiveness.
Background
Administered every two weeks as an intravenous infusion, lecanemab binds to, neutralises and eliminates amyloid-beta (Aβ) aggregates in the brain. Lecanemab, a humanised IgG1 monoclonal antibody (mAb), promises a novel potential disease-modifying treatment pathway, representing a significant step forward in AD research (1). As the treatment of AD remains an unmet medical need, lecanemab first received accelerated approval following positive results from the Phase 3 global confirmatory Clarity AD clinical trial; with traditional approval granted by the United States Food & Drug Administration (FDA) in July 2023 (2).
The complex regulatory landscape
Following approval by the FDA, lecanemab has since been approved in other countries, including Japan, China, South Korea, the United Arab Emirates (UAE) and, most recently, the UK (3). The MHRA’s approval follows the rejection of the marketing authorisation application for lecanemab by the EMA in July 2024. The EMA’s Committee for Medicinal Products for Human Use (CHMP) determined that the observed benefits of treatment did not outweigh the risk of serious adverse events (SAEs) associated with the use of the drug in early disease (4). Similarly, the UK’s National Institute for Health and Care Excellence (NICE) has not recommended lecanemab for routine NHS use, citing high levels of uncertainty regarding the long-term effectiveness of lecanemab and a requirement for more evidence regarding its cost-effectiveness (5).
Benefits and risks
The benefits and risks arising from the use of lecanemab from clinical trial data provide an indicator of the initial benefit-risk profile. Lecanemab has a high selectivity for soluble aggregated species of amyloid-beta (Aβ) with moderate selectivity for the most toxic pathologic amyloid species, fibrillar amyloid (1). Lecanemab has shown a reduction in mean amyloid burden in early AD following treatment at 18 months when compared to placebo (1, 6, 7).
In terms of risks, the most common adverse events arising from clinical trial data for lecanemab included infusion-related reactions, amyloid-related imaging abnormalities (ARIA) with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis as ‘ARIA with hemosiderin deposition’ (ARIA-H) and ‘ARIA with oedema’ (ARIA-E), headache, and falls (1, 6, 7). ARIA-H and ARIA-E have since been noted as a boxed warning in US product information, with the risk of ARIA increased in patients with ApoE ε4 homozygotes compared to heterozygotes and non-carriers. Additionally,intracerebral haemorrhages greater than 1cm in diameter have also occurred with lecanemab (8).
The need for a pharmacovigilance perspective
As pre-marketing clinical trials are designed to assess the efficacy of an intervention in a strictly defined study population, these studies are often underpowered to detect adverse events in a broader real-world population. The clinical trial data for lecanemab excluded patients with exposure to antiplatelet agents or anticoagulants (other than aspirin), and excluded patients with various risk factors for intracerebral haemorrhage (8, 9). NICE notes that people with young-onset dementia, of diverse ethnicity and racial background, and a high lifetime risk of AD (such as people with Down's syndrome) were not fully represented in the clinical trials. Additionally, the limited duration of exposure in clinical trials of up to 18 months limits a comprehensive understanding of these long-term outcomes of the drug (10).
Due to these limitations, the monitoring of the safety and effectiveness of lecanemab in real-world clinical settings is fundamental to protecting patients. To monitor the complex benefit-risk profile of lecanemab, pharmacovigilance activities should comprise the ongoing review and assessment of multiple real-world data sources; including spontaneous reports (and associated signal detection and management activities), electronic healthcare records databases, post-authorisation safety and/or effectiveness studies (including Patient Reported Outcomes [PROs]), and published scientific literature including case reports, pharmacoepidemiological studies and systematic reviews and meta-analyses.
The risk minimisation measures for the safe use of lecanemab, including the use of baseline and periodic brain magnetic resonance imaging (MRI) scans, positron emission tomography (PET), and pharmacogenomic testing (ApoE ε4), should also be evaluated for effectiveness and suitability to real-world clinical settings. NICE notes that the safe use of lecanemab in the UK’s NHS would require a significant increase in system capacity, the disruption of current diagnostic and treatment pathways, and would substantially increase the demand for supportive services (5). Limitations also exist in the US, as product information indicates that an FDA-authorised test for the detection of ApoE ε4 alleles is not yet currently available for appropriate pharmacogenomic testing (8). These limitations in the real-world world clinical setting raise concerns over the effectiveness of proposed risk minimisation measures to ensure the safe use of the product.
Despite these identified risks and gaps in evidence, the development of anti-Aβ mAbs, such as lecanemab, represents a significant step forward in AD research. The DSRU welcomes this step forward and notes the need to proceed with caution as a robust pharmacovigilance perspective is needed for the safe and effective use of these products with intensive monitoring of their benefit-risk balance when used in a greater number of patients in the real-world setting.
References:
1. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388(1):9-21.
2. U.S. Food and Drug Administration. FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval FDA2023 [updated 06/07/2023]; cited 2024. Available from: https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval.
3. “LEQEMBI®” (Lecanemab) Approved for the Treatment of Alzheimer’s Disease in the United Arab Emirates [press release]. 2024.
4. European Medicines Agency (EMA). Refusal of the marketing authorisation for Leqembi (lecanemab). 2024.
5. National Institute for Health and Care Excellence (NICE). Draft guidance consultation – Lecanemab for treating mild cognitive impairment or mild dementia caused by Alzheimer’s disease. 2024.
6. Swanson CJ, Zhang Y, Dhadda S, Wang J, Kaplow J, Lai RY, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimer's research & therapy. 2021;13:1-14.
7. McDade E, Cummings JL, Dhadda S, Swanson CJ, Reyderman L, Kanekiyo M, et al. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimer's research & therapy. 2022;14(1):191.
8. US Product Information: Eisai Inc. LEQEMBI® (lecanemab-irmb) injection, for intravenous use. 2023.
9. Summary of Product Characteristics (SmPC): Eisai Europe Limited. LEQEMBI 100 mg/mL concentrate for solution for infusion. 2024. 10. Monti S, Grosso V, Todoerti M, Caporali R. Randomized controlled trials and real-world data: differences and similarities to untangle literature data. Rheumatology. 2018;57(Supplement_7):vii54-vii8.