EMA rejects leucovorinumab: A Major Setback for Alzheimer's Treatment in Europe

Rejection of Lecanemab by EMA: A Major Setback for Alzheimer's Treatment in Europe

Porto, Portugal - July 30, 2024
The European Medicines Agency (EMA) has decided not to grant approval for lecanemab, an Alzheimer's drug developed by Eisai and Biogen, citing concerns over its safety and efficacy. Lecanemab, marketed as Leqembi in the United States, aims to slow cognitive decline in early-stage Alzheimer's patients by targeting amyloid plaques in the brain. However, the EMA concluded that the drug's benefits did not sufficiently outweigh the risks, particularly the potential for serious side effects such as brain swelling and bleeding.
This decision is a significant setback for Alzheimer's treatment in Europe, where approximately seven million people live with the disease, a number expected to double by 2050. Despite the drug being approved in countries like the United States, Japan, and South Korea, the EMA's ruling underscores the stringent safety standards in Europe.

Policy Analysis
Efficacy and Safety Concerns
In clinical trials, lecanemab slowed cognitive decline by about 27% in early-stage Alzheimer's patients. However, the EMA highlighted the relatively small absolute difference in cognitive function improvement compared to the placebo. The primary safety concerns included amyloid-related imaging abnormalities (ARIA), which involve brain swelling and bleeding. These issues were deemed significant enough to outweigh the modest benefits observed​​.
Impact on Stakeholders
The decision has significant implications for various stakeholders:
1.Pharmaceutical Companies: The rejection is a setback for Eisai and Biogen, the companies behind lecanemab. Following the decision, Biogen's shares dropped by approximately 7%. The companies have indicated plans to seek re-examination of the recommendation​​.
2.Patients and Caregivers: The ruling is disappointing for many patients and their families, especially those who had hoped for access to this treatment. Alzheimer's Society and other advocacy groups have expressed their discontent but remain optimistic about future developments in Alzheimer's treatment research​.
3.Regulatory Bodies: The UK's Medicines and Healthcare products Regulatory Agency (MHRA) and the National Institute for Health and Care Excellence (NICE) are still evaluating lecanemab. Their forthcoming decisions will be crucial in determining the drug's future availability in the UK​.
Broader Implications
The EMA's decision underscores the complex balance between efficacy and safety in approving new treatments. The scrutiny over lecanemab could set a precedent for how similar Alzheimer's treatments are evaluated in the future. This includes Eli Lilly's donanemab, another amyloid-lowering drug currently under review by European regulators​​.

Market Overview
Regulatory Status and Approvals
Lecanemab, marketed as Leqembi, is a monoclonal antibody developed through a collaboration between Eisai and Biogen. It has received traditional approval from the U.S. FDA, marking a significant step as the first amyloid beta-directed antibody to transition from accelerated to traditional approval based on clinical benefit verification. Additionally, Leqembi is approved in Japan, China, and South Korea for the treatment of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia​.
Efficacy and Clinical Trials
In the Phase 3 CLARITY AD trial, lecanemab demonstrated a 27% reduction in clinical decline over 18 months compared to placebo, based on the Clinical Dementia Rating Sum of Boxes (CDR-SB). The drug also showed significant benefits on secondary endpoints, including the Alzheimer's Disease Assessment Scale Cognitive Subscale and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment​.
Market Potential and Challenges
Despite its potential, lecanemab faces several market challenges:
Safety Concerns: The most notable adverse effect is amyloid-related imaging abnormalities (ARIA), which include brain swelling and bleeding. While many cases of ARIA are asymptomatic, some can lead to serious complications, requiring careful monitoring and management​.
Cost and Accessibility: Lecanemab's annual cost is approximately £20,000 per patient in the U.S. The high price, coupled with the need for regular infusions and brain scans, poses accessibility issues. These factors contribute to bottlenecks in its adoption, even in approved markets like the U.S.
Regulatory Scrutiny: The European Medicines Agency (EMA) recently rejected lecanemab's application, citing concerns that the benefits did not outweigh the risks. This decision adds to the uncertainty surrounding the drug's market acceptance in Europe.
Market Impact and Future Outlook
The rejection by the EMA has had immediate financial implications, with Biogen's shares falling by about 7% following the announcement. However, the ongoing evaluation by the UK's MHRA and potential re-submissions for approval in the EU indicate that the market dynamics for lecanemab are still evolving​​.
The overall market for Alzheimer's treatments is substantial, with millions affected worldwide. The development and approval of lecanemab underscore a critical shift towards targeting the underlying mechanisms of Alzheimer's rather than just its symptoms, setting a precedent for future treatments. Despite the setbacks, continued research and development in amyloid-targeting therapies hold promise for significant advancements in the field​.

Regulation Differences
United States
The U.S. Food and Drug Administration (FDA) initially granted accelerated approval to lecanemab under the brand name Leqembi in January 2023. This accelerated approval was based on the drug's ability to reduce amyloid plaques in the brain, a surrogate endpoint likely to predict clinical benefit. In July 2023, following a confirmatory Phase 3 clinical trial (CLARITY AD), the FDA converted this to traditional approval, verifying its clinical benefits in slowing cognitive decline in early-stage Alzheimer's disease patients. The FDA's approval process involved a rigorous review of safety data, including the management of amyloid-related imaging abnormalities (ARIA), and included a boxed warning to inform patients and healthcare providers of potential serious side effects​.
European Union
In contrast, the European Medicines Agency (EMA) has rejected the approval of lecanemab. The EMA's Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of the drug did not outweigh the risks, particularly the serious side effects such as ARIA that include brain swelling and bleeding. The EMA's decision reflects a more cautious approach, emphasizing a higher threshold for balancing efficacy and safety in new treatments. The rejection means that Eisai and Biogen will need to provide additional data or possibly conduct further trials to address these safety concerns if they wish to pursue approval in the EU.
United Kingdom
In the UK, lecanemab is under review by the Medicines and Healthcare products Regulatory Agency (MHRA). The drug is being considered under the Innovative Licensing and Access Pathway (ILAP), which aims to accelerate the approval process for innovative treatments. Despite the EMA's rejection, the MHRA may still approve lecanemab if it deems the benefits to outweigh the risks based on its independent evaluation of the clinical data. The decision is eagerly awaited, as it will determine whether the drug can be made available to patients in the UK, potentially under different conditions or with additional monitoring requirements​​.

Key Drivers
Efficacy and Clinical Evidence
The efficacy of lecanemab, a monoclonal antibody targeting amyloid-beta plaques, is a primary driver in its market potential. The Phase 3 CLARITY AD trial demonstrated that lecanemab slowed cognitive decline by 27% over 18 months compared to placebo, significantly impacting memory, orientation, and daily activities. These results, which were pivotal in achieving traditional FDA approval, provide strong clinical evidence supporting the drug's effectiveness in the early stages of Alzheimer's disease​​.
Unmet Medical Need
Alzheimer's disease remains a major unmet medical need, affecting millions globally. Current treatments like donepezil and memantine are symptomatic and do not alter disease progression. Lecanemab is one of the first treatments to show a potential to slow the disease's underlying progression, making it a groundbreaking development in Alzheimer's therapy. This unmet need drives demand for more effective treatments that can provide long-term benefits.
Market Expansion and Approvals
Lecanemab has been approved in multiple countries, including the U.S., Japan, China, and South Korea, with ongoing evaluations in the UK and other regions. Each approval expands the potential market, enabling more patients to access the drug. The approval processes in these regions highlight the global regulatory landscape and the demand for innovative Alzheimer's treatments​​.
Amyloid Hypothesis Validation
The success of lecanemab provides significant validation for the amyloid hypothesis, which posits that amyloid plaques in the brain are a primary cause of Alzheimer's disease. This validation encourages continued investment and research into amyloid-targeting therapies, potentially benefiting other drugs in development by companies like Roche and Lilly​.
Safety Profile and Monitoring
The safety profile of lecanemab, particularly the occurrence of amyloid-related imaging abnormalities (ARIA), remains a concern and a critical factor in its market acceptance. While many cases of ARIA are asymptomatic, the potential for serious side effects necessitates careful patient monitoring and may influence regulatory and clinical decisions. Ongoing studies aim to better understand and mitigate these risks​.
Research and Development Pipeline
The ongoing research and development pipeline for Alzheimer's disease treatments further drives the market for lecanemab. With over 140 experimental drugs in clinical testing, the success of lecanemab could pave the way for additional breakthroughs and collaborations in the field, reinforcing its market position as a leader in disease-modifying treatments.

Investment Opportunities
Strong Clinical Evidence
Lecanemab has shown significant efficacy in clinical trials, reducing cognitive decline by 27% over 18 months in patients with early-stage Alzheimer's. This robust clinical data underpins the drug's market potential, making it a promising investment opportunity in the biopharmaceutical sector. The FDA's full approval based on these results further solidifies its credibility and market viability.
Expanding Market Approvals
Lecanemab has received approvals in multiple regions, including the U.S., Japan, China, and South Korea, with pending evaluations in other regions like the EU. Each new approval expands its market reach, presenting significant growth opportunities for investors. This global expansion is critical for driving revenue growth and enhancing market penetration.
Collaboration and Partnerships
The collaboration between Eisai and Biogen in the development and commercialization of lecanemab enhances its market potential. This strategic partnership combines Eisai's strong development capabilities with Biogen's commercialization expertise, creating a solid foundation for the drug's market success. Additionally, collaborations with other research institutions further bolster the R&D pipeline, ensuring continuous innovation and improvement​.
Addressing Unmet Medical Needs
Alzheimer's disease represents a significant unmet medical need, with millions of patients worldwide seeking effective treatments. Lecanemab's ability to target the underlying disease mechanism rather than just symptoms positions it uniquely in the market. This differentiation enhances its value proposition and attractiveness to both patients and healthcare providers, potentially driving high demand and market uptake​.
Financial Stability and Market Confidence
Investing in companies like Biogen and Eisai, which have diversified portfolios and strong financial health, offers a level of stability. Biogen's recent focus on Alzheimer's treatments, despite past challenges with drugs like Aduhelm, shows a commitment to this critical therapeutic area. Moreover, the broader coverage now offered by Medicare for lecanemab following FDA approval boosts market confidence and accessibility, likely enhancing sales and revenue streams​​.
Competitive Landscape and Future Prospects
While the Alzheimer's treatment market is competitive, lecanemab's early success provides a competitive edge. The validation of the amyloid hypothesis by its clinical success paves the way for similar treatments under development by other companies like Roche and Eli Lilly. Investors should keep an eye on these developments, as the success of lecanemab could positively influence the entire sector and open up further investment opportunities​.

Related Market Reports
QY Research Releases Comprehensive Market Reports on the Alzheimer's drug Market, as shown in the links below. These reports provide an in-depth analysis of the current market landscape, key trends, and future growth opportunities.
Donepezil for Alzheimer
https://www.qyresearch.com/reports/2218630/donepezil-for-alzheimer
Alzheimer's Drugs
https://www.qyresearch.com/reports/2832182/alzheimer-s-drugs
Alzheimer's Disease
https://www.qyresearch.com/reports/3057003/alzheimer-s-disease

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