Anti‐amyloid antibodies in Europe: Where are we now?

Recent marketing authorizations (MAs) of lecanemab and donanemab, together with EU market introduction and emerging real-world data, highlight the need to summarize the current landscape and imminent challenges for anti-amyloid therapy. On 15 April 2025, the European Commission (EC) granted a full MA for lecanemab for early Alzheimer's disease in a genotype-restricted indication (APOE ε4 non-carriers or heterozygotes) and with a comprehensive set of risk minimization measures (RMMs). The approval followed a positive opinion of the European Medicine's Agency Committee for Medicinal Products for Human Use (EMA's CHMP) in a re-examination procedure, reverting an earlier negative opinion. In the United Kingdom, an MA was granted on 22 August 2024 with the same APOE ε4 restriction, while in the United States, lecanemab was approved on 6 January 2023 without a genotype restriction in the label. Similarly, for donanemab, the CHMP first issued a negative opinion followed by a re-examination procedure resulting in a positive opinion for the same genotype-restricted population as for lecanemab. The EC granted a full MA on 24 September 2025. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) authorized donanemab on 23 October 2024 for adults with early Alzheimer's who are APOE ε4 non-carriers or heterozygotes. In contrast, the US FDA approved donanemab on 2 July 2024 without a genotype restriction in the label. The CHMP was concerned with the clinical relevance of the observed effect size for lecanemab. In the pivotal study in the overall population, the treatment showed a difference of −0.45 points between lecanemab and placebo in the adjusted mean change from baseline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) at 18 months (the primary endpoint). Safety concerns focused on amyloid-related imaging abnormalities (ARIA) as potentially fatal adverse events, with ARIA manifesting as oedema or effusion (ARIA-E) occurring in 12.6% of lecanemab-treated patients (vs. 1.7% on placebo) and ARIA manifesting as microhaemorrhages and hemosiderin deposits (ARIA-H) in 16.9% (vs. 8.9% on placebo) in the overall population. Excluding APOE ε4 homozygotes from the indication reduced ARIA-E incidence to 8.9% (vs. 1.3% on placebo) and ARIA-H to 12.9% (vs. 6.8% on placebo) while the mean difference in CDR-SB change from baseline was −0.54. However, concerns remained regarding reliance on a single pivotal trial in an area of multiple prior failures, uncertainties about the long-term ARIA sequelae, interactions with anticoagulants and practical challenges in implementing RMMs (including mandatory MRIs and management of risks in emergency situations).1 In the donanemab pivotal study, the treatment showed a difference of −0.53 points between donanemab and placebo in the adjusted mean CDR-SB change from baseline at 76 weeks (the key secondary endpoint), with an ARIA-E incidence of 24% (vs. 2.1% on placebo) and ARIA-H 31.4% (vs. 13.6% on placebo). Excluding APOE ε4 homozygotes from the indication reduced ARIA-E incidence to 20.6% (vs. 1.8% in placebo) and ARIA-H to 27.6% (vs. 12.2% on placebo) under the standard dosing regimen, while the mean difference in CDR-SB change from baseline was −0.69 points. Furthermore, additional data from the TRAILBLAZER-ALZ 6 trial demonstrated that a gradual titration scheme further reduced ARIA-E incidence at 24 weeks while maintaining efficacy.2 Views regarding the approval varied greatly. The clinical relevance observed in the phase 3 trial generated an intense debate, both in the expert community and in a larger audience. While some Alzheimer experts viewed the results as clinically relevant,3 others were critical of the approval and the RMMs imposed.4 As anti-amyloid antibodies transition from the rigours of regulatory assessment into clinical practice, the pivotal question evolves from efficacy to implementation. This entails three core challenges: defining clear pathways for access and reimbursement, ensuring robust safety vigilance in routine clinical care and establishing effective systems for tracking real-world outcomes. Real-world evidence should complement RCTs—nowhere more so than for anti-amyloid therapies, where routine and additional RMMs have been central to the benefit–risk balance during approval. Routine (summary of product characteristics [SmPC]-embedded) RMMs for lecanemab include a genotype-restricted patient population, specialist initiation of treatment (which, in clinical practice, increasingly involves multidisciplinary board evaluations), MRI monitoring schedule for ARIA (MRIs at baseline, before the 5th, 7th and 14th dose, additional if needed) and contraindications related to bleeding risk. Additional RMMs include a controlled access program to ensure prescribing aligns with the restricted population and monitoring requirements, educational materials for health care professionals and a patient alert card. Finally, an EU-wide registry to further characterize ARIA and assess the effectiveness of the RMM package is a condition to MA. However, the practical implementation of RMMs present significant logistical challenges that vary by clinical setting. Because RMMs are legally binding conditions for the marketing authorization holder (MAH), strict clinical compliance is mandatory. Failure to effectively implement these measures in the real world (or evidence of poor adherence to safety protocols) can trigger regulatory re-evaluation. Under the EU pharmacovigilance framework, if the benefit–risk balance is deemed no longer favourable due to ineffective risk management, regulators may suspend or ultimately revoke the drug's MA. While an EU MA is central, pricing, reimbursement and coverage are national or regional decisions. As of 23 September 2025, within the EU Leqembi (lecanemab) is launched only in Austria and Germany.5 In EU countries with publicly available information, coverage decisions are still underway. Recently, a French health technology assessment body (Haute Autorité de Santé [HAS]) issued an unfavourable opinion regarding early access to lecanemab. This opinion was criticized by a group of French clinicians.6 In the United Kingdom, the National Institute for Health and Care Excellence (NICE) final draft guidance from 19 June 2025 states that neither donanemab nor lecanemab should be provided on the National Health Service (NHS) in England and Wales for early Alzheimer's disease, because the benefits are judged as too small to justify the costs, alongside practical constraints. However, MAHs for both lecanemab and donanemab filed formal appeals, and the NICE guidance is therefore still not finalized. In Scotland, the Scottish Medicines Consortium (SMC) finalized their review and do not recommend lecanemab for use within NHS Scotland.7 In the meantime, real-world data accrue from countries with earlier approvals. Early real-world reports from an Israeli clinical-practice cohort and a US specialty memory clinic suggest lecanemab can be delivered in routine care using structured workflows (genotyping, MRI/ARIA surveillance and infusion pathways), with safety generally manageable and early outcomes broadly consistent with trials, although discontinuations and service logistics remain limiting.8, 9 As real-world use expands, risk minimization evolves. On 28 August 2025, the FDA advised adding an MRI before the 3rd infusion of Leqembi (lecanemab)—earlier than the previous schedule of MRIs before the 5th, 7th and 14th infusions—to detect ARIA-E sooner and allow timely treatment interruption when appropriate.10 While it is premature for any conclusions, early regulatory experience and emerging real-world signals argue for cautious, genotype-informed uptake coupled with rigorous post-authorization monitoring to ensure that benefits are achieved and risks contained. Practising clinicians should track EMA's safety communications, updates to the European public assessment report (including any changes to the product information and risk-management plan) and any direct healthcare professional communications (DHPC), alongside national health technology guidance. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22.11