Lecanemab’s Path Forward: Navigating the Future of Alzheimer’s Treatment in Europe Amidst the EMA's Rejection

Abstract

Lecanemab (Leqembi^©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer’s disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab’s clinical outcomes have been modest, raising questions about its therapeutic role. The EMA’s refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence’s rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.

To date, the humanized anti-soluble-aggregated-amyloid-beta (Aβ) monoclonal antibody lecanemab (Leqembi^©, Biogen)—which recently replaced aducanumab as the primary drug for patients in the early stages of Alzheimer’s disease (AD)—has been approved for commercial use in the United States (US), Japan, China, South Korea, Hong Kong, and Israel. However, last July, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a negative opinion on the marketing authorization approval of lecanemab, much to the dismay of some physicians. While this decision has been met with disappointment by drug manufacturers, it is possible that some dementia specialists in Europe felt a degree of relief, given the anticipated challenges in implementing and managing these drugs in certain clinical settings [1].

Setting aside political and economic speculations beyond the scope of this commentary, the CHMP has determined that the benefits of the treatment are not significant enough to outweigh the risks associated with lecanemab. The data from the phase 3 trial showed a modest but statistically significant clinical effect in terms of slowing cognitive decline during the 18-month study period in a subset of patients [2]. However, the statistically significant difference between the drug and the placebo groups at the trial’s primary endpoint (a −0.45 change in the 18-point Clinical Dementia Rating—Sum of Boxes score) did not translate into a meaningful benefit for patients [3].

It is worth noting that lecanemab’s limited clinical impact aligns with longstanding research suggesting that amyloid might be a poor therapeutic target for AD [4, 5]. Of note, roughly 60% of cognitively unimpaired individuals aged over 85 years old exhibit a pathological amyloid burden [6], suggesting that brain resilience might be an overlooked player that adds complexity to the oversimplistic cause–effect framework posited by the amyloid hypothesis. Focusing solely on amyloid presence could lead to overdiagnosis and overtreatment, as amyloid pathology alone may not always translate into clinical symptoms or disease progression. On the other hand, the use of amyloid Positron Emission Tomography (PET) tracers to evaluate the therapeutic effects of anti-amyloid treatments has been questioned, partly due to the limited specificity of these tracers and partly due to doubts about their ability to accurately reflect amyloid removal that should correlate with a potential clinical benefit [7]. Alternative imaging methods, such as 18F-fluorodeoxyglucose PET, may provide better tools for assessing the clinical efficacy of these treatments [8]. Ultimately, any clinical benefit must be weighed against potential side effects, as anti-amyloid antibodies have been consistently associated with potentially life-threatening adverse events, such as amyloid-related imaging abnormalities (ARIAs), especially in the presence of the apolipoprotein E (APOE) ε4 allele, which is common in patients with AD [9].

In reaching its opinion, the CHMP considered the views of a scientific advisory group that included experts such as neurologists as well as people living with the disease. Thus, it is possible that the EMA’s decision may partly reflect the growing disconnect between the scientific research community and clinical specialists in healthcare. Since the introduction of the concept of AD as a biological continuum, which fundamentally changed our understanding of the disease, bridging the gap between basic research and clinical practice has become increasingly difficult. For example, there is ongoing criticism regarding the emphasis on biological markers for diagnosing AD, especially in its early stages, and the preference for evaluating treatment effectiveness based on biological outcomes rather than clinical improvements such as slowing cognitive decline [10, 11].

After years of failures in randomized clinical trials (RCTs) of anti-amyloid drugs, lecanemab’s approval was seen by many as a potential turning point. Its impressive biological effects suggested that it might offer clinical benefits for patients with AD, possibly addressing long-standing criticisms of these treatments. This success could have strengthened the notion that AD is a treatable disease and that the fear of dementia might be mitigated and faced with new therapeutic tools. However, clinicians were once again met with disappointment. Although lecanemab demonstrated promising biological effects, its clinical outcomes were less remarkable [12], and the FDA has clarified that lecanemab is not intended to cure AD but rather is the first traditionally approved treatment targeting the disease’s underlying biology [13].

Therefore, innovative anti-amyloid drugs seem to be confined to being a powerful treatment for a “biological concept” and not for a disease, and their use as such has been deemed unacceptable by many specialists involved in dementia care [14]. For this reason, the August 22 approval of lecanemab by the Medicines and Healthcare products Regulatory Agency in the United Kingdom came as quite a surprise [15], even though the National Institute for Health and Care Excellence opted not to recommend its use on the National Healthcare System due to concerns over cost-effectiveness [16]. This step once again fuels the ongoing debate surrounding the clinical value and economic feasibility of anti-amyloid therapies, reflecting the same persistent uncertainty within the medical community that led to the EMA’s refusal of approval.

For certain, if the EMA’s decision was taken on the grounds of doubts over the clinical value and overall manageability of anti-amyloid treatments, a clear unmet need must be addressed. Since its approval in the US in 2023, the use of lecanemab in clinical care has steadily increased, with an estimated 3000 patients currently on the drug, although exact numbers have not been officially disclosed. Aducanumab prescriptions in US also began in many states between July and September 2021, and nearly 3 years of observation were completed before the drug’s discontinuation in favor of lecanemab. Despite this, almost no information concerning clinical management has been made available so far, and many questions remain unanswered.

First and foremost, from a clinical perspective, it is crucial to assess whether anti-amyloid drugs have effectively slowed cognitive decline and improved everyday activities in patients, thereby corroborating the data from published RCTs and adding important information on the real-world effectiveness of these interventions. Also, the main side effect reported in RCTs is ARIA, which is observed primarily in APOE ε4 carriers, often in asymptomatic patients [2, 17, 18]. It would be important to determine whether physicians in the US and in countries that have started using these drugs confirmed this trend, including how many patients required hospitalization and, if any, how many patients experienced death related to the treatment. Indeed, the high prevalence of ARIA in ApoE ε4 carriers was considered a major hindrance to approval by the EMA, highlighting the need for further clarification on these issues, possibly aimed at revising treatment approaches. Moreover, any difficulties encountered in administering these drugs have not been disclosed. Understanding whether patient demand exceeded drug availability and assessing the quality of infrastructure, treatment accessibility, and patient compliance would provide valuable insights into the impact of any innovative treatments.

Overall, addressing these questions and providing data from this short-term but crucial period of real-world experience would enhance the robustness of existing evidence [2, 19–21]. Importantly, at last July’s Alzheimer’s Association International Conference (AAIC), many US clinical centers shared valuable updates on their experience with lecanemab so far, including the lower incidence of side effects compared to RCTs, with ARIAs occurring about half as frequently as previously reported [22]. At the same time, the FDA has attributed two new deaths due to ARIA edema to lecanemab. While reporting the drug’s good manageability in clinical settings, US neurologists also delved into the gray areas surrounding the optimal timing to initiate the treatment and the circumstances under which it should be discontinued, particularly in the case of ARIA. Clear guidelines on when to start or stop therapy are definitely crucial for maximizing patient outcomes while minimizing risks.

In summary, encouraging more-standardized and continuous reporting on the ongoing real-world use of lecanemab might have the potential to persuade specialists about the drug’s effectiveness and safety. However, the critical question remains: will this ultimately prompt the EMA to reconsider its decision? Furthermore, can European doctors reasonably expect to have access to these medications in the future? While there is some hope, the path to making these drugs a standard part of therapeutic options in Europe remains long and uncertain. While awaiting real-world data to confirm even partial but meaningful clinical efficacy for anti-amyloid treatments and the feasibility of safely managing associated adverse events, we suggest that neurologists continue to conduct precise and early diagnoses using biological and genetic markers. The lessons learned from lecanemab underscore that a rigorous diagnostic approach is essential for effectively identifying and stratifying patients, thereby facilitating their access to these or other innovative therapies.

Author Contributions

Alessandro Martorana, Chiara Giuseppina Bonomi, Martina Gaia Di Donna, and Caterina Motta contributed to the article’s conception. Material preparation was performed by Chiara Giuseppina Bonomi and Martina Gaia Di Donna. The first draft of the manuscript was written by Alessandro Martorana and Chiara Giuseppina Bonomi; the manuscript was then revised by Caterina Motta. All authors contributed to, read, and approved the final manuscript.

Funding

No funding or sponsorship was received for this study or the publication of this article. The Rapid Service Fee was funded by the authors.

Declarations

Conflict of Interest

Alessandro Martorana, Chiara Giuseppina Bonomi, Martina Gaia Di Donna, and Caterina Motta have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.