Update 14 November 2024: After re-examination, the CHMP decided to recommend market authorisation for Leqembi limited to patients with less than two genomic copies of APOE4.

The treatment of Alzheimer’s disease with amyloid beta-targeting monoclonal antibodies, such as aducanumab, lecanemab and donanemab, has been under discussion since the approval of this therapy by the FDA. Past clinical trials showed that these antibodies exhibit a high affinity to amyloid protofibrils and fibrils and can indeed effectively reduce amyloid burden. However, all tested antibodies failed to significantly delay or revert cognitive decline and increased the risk of amyloid-related imaging abnormalities (ARIA), such as brain edema, in patients.

On 26 July 2024, the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA) advised against marketing authorization for Leqembi (lecanemab), three years after rejecting the market access for aducanumab (17 December 2021), and in the same month the FDA approved donanemab in the US. This decision may affect market access in the European Union, Iceland, Liechtenstein, and Norway. The CHMP stated:

“The CHMP recommended not granting a marketing authorisation for Leqembi (lecanemab), a medicine intended for the treatment of Alzheimer’s disease. The committee considered that the observed effect of Leqembi on delaying cognitive decline does not counterbalance the risk of serious side events associated with the medicine, in particular the frequent occurrence of amyloid-related imaging abnormalities (ARIA), involving swelling and potential bleedings in the brain of patients who received Leqembi” ^[1].

In the last two weeks since the announcement, numerous experts on the field shared their opinions on this matter online.

The CEO of the non-profit organization Alzheimer’s Disease International (ADI), Paola Barbarino, issued that this announcement “will undoubtedly be disappointing for our community and for those living with dementia across Europe.” She also showed concern that “it could create a situation where those who are eligible and who can afford it could travel to receive treatment, whereas the rest of the population could not” ^[2].

Experts from the “Deutsche Zentrum für Neurodegenerative Erkrankungen” (DZNE), including Professors Pierluigi Nicotera, Gabor Petzold, Johannes Levin, Frank Jessen, and Christian Haass, expressed regret over the EMA’s decision not to approve lecanemab, despite acknowledging the potential risks. Nicotera emphasized the need for new therapies to combat Alzheimer’s, which he called a global pandemic, while Petzold highlighted the disappointment among patients and families. Levin pointed out the potential for unequal access to the treatment, and Jessen noted that other countries have developed guidelines to ensure informed decisions by patients. Haass expressed dismay, underscoring lecanemab’s effectiveness in targeting the disease’s causes and improving daily activities for patients ^[3].

Professors from the UK Dementia Research Institute, including Bart De Strooper, Nick Fox, John Hardy, and Tara Spires-Jones, expressed concern and disappointment over the EMA’s decision not to approve lecanemab. They highlighted the drug’s potential to slow Alzheimer’s progression, contrasting the EMA’s caution with the FDA’s approval in the US. De Strooper criticized Europe’s conservative approach, while Fox and Hardy emphasized the need for real-world evidence to revisit the decision in the future. Tara Spire-Jones issued the importance of new research angles, allowing new and safer treatments. De Strooper and Hardy both consulted Eisai (company that developed Leqambi) in the past ^[4,5].

While many supporters of a causal role of amyloid in Alzheimer’s Disease expressed disappointment, there are also significant opposing viewpoints. Professors Robert Howard from UCL and Dr. Sebastian Walsh from the University of Cambridge supported the EMA’s decision not to approve lecanemab, citing modest efficacy and significant risks. Howard emphasized that the treatment’s potential harms outweigh its benefits, while Walsh pointed out that the trial’s controlled conditions may not reflect real-world complexities, and resources might be better spent on holistic care ^[5].

Some members of Alzheimer Europe also supported the decision. Monika Kaus, chair of the “Deutsche Alzheimer Gesellschaft” (DAlzG) expressed regret that no new medication will be available soon but acknowledged the EMA’s careful consideration of benefits and risks. She emphasized the importance of patient safety, noting that while Leqembi can slow cognitive decline, it also poses significant risks such as brain swelling and potential bleeding. Gerjoke Wilmink, director of Alzheimer Nederland, expressed disappointment but stressed the importance of the EMA’s careful evaluation. She remains hopeful that effective treatments for Alzheimer’s will be available soon ^[6,7].

In the German journal “Pharmazeutische Zeitung”, senior editor, former pharmacist, and professor for pharmaceutical biology Professor Theo Dingermann commented that the EMA’s rejection of lecanemab is well-reasoned. Dingermann noted that while lecanemab shows some effectiveness, it is not a “gamechanger” in the fight against Alzheimer’s and is subject to strict limitations. He stressed that the treatment is restricted to early-stage cognitive impairment and requires costly, advanced diagnostics such as spinal fluid analysis or PET scans, which are not currently covered by health insurance. Even if approved, lecanemab may not be reimbursable, limiting its availability and disappointing patients and their families ^[8].

Professor Peter Kolominsky-Rabas, neurologist and health economist at the University of Erlangen-Nürnberg and principal investigator of Germany’s largest dementia registry — digiDEM Bayern — considers “the EMA’s decision to be in the interests of patient safety and economic efficiency. Lecanemab’s effects on cognition were substantially smaller than the effect of cholinesterase inhibitors. The main argument in lecanemab’s favor is that it may lead to greater cognitive benefit over time. However, the duration of the clinical trial from which efficacy data for lecanemab were obtained was 18 months only, and time delay in disease progression was estimated to be approximately 6 months.  Beyond that, the population potentially eligible for treatment with lecanemab in the 27 European Union (EU) countries is — conservatively estimated — about 5.4 million individuals ^[9]. Treating all eligible patients in Europe with lecanemab would cost 133 billion EUR per year, assuming the drug would be priced similarly as in the US ($26,500). This amount represents over half of the total pharmaceutical expenditures in the EU member states. The high uncertainty around the long-term clinical and economic value of lecanemab strongly support EMA’s rejection of lecanemab.”

In addition, Christian Behl, Professor of Pathobiochemistry at the University Medical Center Mainz — and founder of NI²N — was expecting a “no” to lecanemab from the EMA based on the unfavorable risk-to-benefit ratio of the antibody. Moreover, Behl opposes the view that anti-amyloid antibodies signify a “causal” therapy within reach, since — as pointed out in detail in his recent book ^[10] — he sees Alzheimer’s as a multifactorial and multigenetic age-related disease, and amyloid beta not as its sole cause. Many researchers in the field agree that numerous additional pathogenetic factors and processes are involved in the onset and progression of the disease. Taken together, for Behl, EMA’s rejection of lecanemab was a rational consequence of what we objectively know about the pathogenesis of Alzheimer’s.

Leqembi (lecanemab) developer Biogen requested a re-examination of the decision. On 5 August 2024, the EMA approved this request and announced a re-examination and a final recommendation in the future ^[11].

References

[1] EMA (2024, July 26). Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22-25 July 2024. Negative opinion for one medicine. https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-22-25-july-2024. Retrieved 5 August 2024.

[2] ADI (2024, July 26). EMA’s advisory committee (CHMP) recommends not granting marketing authorization for lecanemab. https://www.alzint.org/news-events/news/emas-advisory-committee-chmp-recommends-not-granting-a-marketing-authorization-for-lecanemab/. Retrieved 5 August 2024.

[3] DZNE (2024, July). „Die Entscheidung ist nicht nachvollziehbar“. Experten-Stimmen des DZNE zur „Lecanemab“-Ablehnung durch EU-Arzneimittel-Agentur. https://www.dzne.de/im-fokus/meldungen/2024/die-entscheidung-ist-nicht-nachvollziehbar-experten-stimmen-des-dzne-zur-lecanemab-ablehnung-durch-eu-arzneimittel-agentur/. Retrieved 5 August 2024.

[4] UKDRI (2024, July 26). Comment: EMA refuses approval of lecanemab for Alzheimer’s. https://ukdri.ac.uk/news-and-events/comment-ema-decision-on-lecanemab-for-alzheimers-disease. Retrieved 5 August 2024.

[5] SMC (2024, July 26). Expert reaction to EMA decision on lecanemab for Alzheimer’s disease. Roundups & rapid reactions. https://www.sciencemediacentre.org/expert-reaction-to-ema-decision-on-lecanemab-for-alzheimers-disease/. Retrieved 5 August 2024.

[6] DAlzG (2024, July 30). Alzheimer Medikament Leqembi nicht zugelassen: Deutsche Alzheimer Gesellschaft zur Entscheidung der Europäischen Arzneimittel-Agentur (EMA). https://www.deutsche-alzheimer.de/artikel/alzheimer-medikament-leqembi-nicht-zugelassen-deutsche-alzheimer-gesellschaft-zur-entscheidung-der-europaeischen-arzneimittel-agentur-ema. Retrieved 5 August 2024.

[7] alzheimer nederland (2024, July 26). Alzheimermedicijn Lecanemab niet beschikbaar in Europa. https://www.alzheimer-nederland.nl/nieuws/alzheimermedicijn-lecanemab-niet-beschikbaar-in-europa. Retrieved 5 August 2024.

[8] Dingermann, T. (2024, July 29). Kommentar zum Aus von Lecanemab. Abgelehnt aus gutem Grund. Pharmazeutische Zeitung. https://www.pharmazeutische-zeitung.de/abgelehnt-aus-gutem-grund-149001/. Retrieved 5 August 2024.

[9] Jönsson, L. (2023, May 21) The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer’s disease: an European Alzheimer’s Disease Consortium Executive Committee viewpoint.
https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00076-5/fulltext
Retrieved 12 August 2024.

[10] Behl, C. (2023). Alzheimer’s Disease Research. Springer eBooks. DOI: 10.1007/978-3-031-31570-1

[11] EMA (2024, August). Leqembi. https://www.ema.europa.eu/en/medicines/human/EPAR/leqembi. Retrieved 5 August 2024.