Journal Article (Letter)

DZNE-2025-00652

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The regulatory rollercoaster continues-EMA refuses donanemab.

De Strooper, B. ; Haass, C.DZNE* ; Hardy, J. ; Zetterberg, H.

2025
Elsevier London [u.a.]

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Please use a persistent id in citations: doi:10.1016/S0140-6736(25)00833-5

Abstract: In 2024, the European Medicines Agency (EMA) approved lecanemab for the treatment of early Alzheimer's disease in patients without contraindications or risk factors for side-effects. This approval followed a nearly 2-year review process that involved multiple rounds of evaluation, initial rejections, formal appeals, and ultimately a reversal of the initially negative decision. In February, 2025, the Committee for Medicinal Products for Human Use formally endorsed the approval.1 Although Europe has been tied up in lengthy regulatory procedures, donanemab—another anti-amyloid therapy that has a similar amyloid-clearing effect as lecanemab—was approved in several other parts of the world. However, the EMA has once again set off a turbulent process by declining to approve donanemab. The rationale behind this decision remains unclear. Whether the outcome was driven purely by scientific evidence, or was influenced by political dynamics, entrenched scepticism towards the amyloid hypothesis, or a pervasive sense of fatalism surrounding Alzheimer's disease in Europe is uncertain.When comparing data from TRAILBLAZER-ALZ 22 and TRAILBLAZER-ALZ 6 (NCT05738486; both investigating donanemab) with CLARITY AD (investigating lecanemab),3 and accounting for differences in study population, designs, and endpoints, several key observations emerge: the cognitive benefit of donanemab appears to be at least comparable to lecanemab (with changes in the Clinical Dementia Rating-Sum of Boxes vs placebo of –0·7 for donanemab and –0·45 for lecanemab).2, 3 Furthermore, donanemab achieves fast and complete amyloid plaque clearance, which is an important factor given the correlation between plaque reduction and clinical benefit across amyloid-targeting therapies.4, 5 Although TRAILBLAZER-ALZ 2 (donanemab) reported a higher incidence of amyloid-related imaging abnormalities (ARIA) than CLARITY AD (lecanemab), the modified dosing regimen evaluated in TRAILBLAZER-ALZ 6 (available to the EMA) showed ARIA rates similar to lecanemab.6 The rates of ARIA-related or intracerebral haemorrhage-related deaths were also similar between the drugs (0·3% in TRAILBLAZER-ALZ 2 vs 0·2% in CLARITY AD).2, 3 For lecanemab, deaths have been tentatively linked to the APOE ε4 homozygous genotype, although this association might be overemphasised. In contrast, no similar genotype-related pattern was observed for donanemab. In the case of donanemab, fatalities occurred in APOE ε4 heterozygotes or in individuals with superficial siderosis, indicating that underlying cerebrovascular vulnerability might be a more relevant risk factor. Until this issue is further clarified, contraindicating use in patients with superficial siderosis, and monitoring patients during treatment for ARIA and adapting dosing accordingly could be reasonable interim precautions.During a public debate on April 1, 2025, at the AD/PD 2025 International Conference on Alzheimer's and Parkinson's Diseases in Vienna, Austria, the EMA asserted that its decisions are grounded in scientific evidence.7 However, the contrasting outcomes for lecanemab and donanemab challenge this self-assessment. In the absence of objective data clearly favouring lecanemab over donanemab, European taxpayers might rightly question why a regulatory body would favour one pharmaceutical company over another, especially when that choice limits competition and could drive up costs. By delaying the adoption of donanemab, the EMA has effectively signalled to Europe's patients with Alzheimer's disease that they are second-class citizens. Although the rest of the world cautiously but optimistically adopts disease-modifying treatments, Europe is lagging behind. This conservative stance not only delays patient access to innovation, but also sends a discouraging message to researchers and drug developers. Without greater clarity and coherence, Europe risks becoming an increasingly unattractive environment for pharmaceutical innovation in areas of urgent medical need.BDS has performed consultancies for Roche, Eisai, EQTpartners, Remynd, Tactile, Earlybird, Sironax, Montis, and Abyssinia; and is a shareholder of Muna Tx. CH collaborates with Denali Therapeutics and is a member of the advisory boards of AviadoBio, Cure Ventures, and Curie.Bio. JH reports grant support from Eli Lilly, and consultancy fees from Eisai. HZ is supported by grants from the Swedish Research Council (grant numbers 2023-00356, 2022-01018, and 2019-02397), EU's Horizon Europe Research and Innovation Programme (101053962), Swedish State Support for Clinical Research (ALFGBG-71320), Alzheimer's Drug Discovery Foundation (201809-2016862), Alzheimer's Disease Strategic Fund and Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C, and ADSF-24-1284328-C), Bluefield Project, Cure Alzheimer's Fund, Olav Thon Foundation, Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden (FO2022-0270), EU's Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie (86019), EU Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), National Institute for Health and Care Research at the University College London Hospitals Biomedical Research Centre, and UK Dementia Research Institute at University College London (UKDRI-1003); has served at scientific advisory boards or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Eli Lilly, Novo Nordisk, Roche, and WebMD; is Chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the IFCC WG-BND; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program.

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 90 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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