Eisai Submits Marketing Authorization Application for Lecanemab in South Korea, a Potential Breakthrough Treatment for Early Alzheimer’s Disease


Eisai Co., Ltd. and Biogen Inc. have taken a significant step forward in the development of a potential treatment for early Alzheimer’s disease. Eisai has submitted a marketing authorization application for lecanemab, an investigational anti-amyloid beta (Aβ) protofibril antibody, to the Ministry of Food and Drug Safety (MFDS) in South Korea.

This marks the first application for lecanemab in Asia outside of Japan and China, and Eisai plans to submit additional applications in other Asian countries.

The application is based on the results of two key studies: the confirmatory Phase III Clarity AD study and the Phase IIb clinical study known as Study 201. These studies demonstrated that lecanemab treatment led to a reduction in clinical decline in individuals with early Alzheimer’s disease.

Lecanemab specifically targets and eliminates soluble, toxic Aβ aggregates called protofibrils, which are believed to contribute to the neurotoxicity associated with Alzheimer’s disease. By targeting these aggregates, lecanemab has the potential to impact disease pathology and slow down the progression of the disease. The Clarity AD study successfully met its primary endpoint, as well as all key secondary endpoints, with highly statistically significant results.

In the development and regulatory submission of lecanemab, Eisai takes the lead globally, while both Eisai and Biogen will co-commercialize and co-promote the product. Eisai will have final decision-making authority in this collaboration.

Protofibrils, the target of lecanemab, are large aggregated soluble species of Aβ, ranging from 75 to 5000 Kd in size. These protofibrils are considered important contributors to the neurotoxicity observed in Alzheimer’s disease.

The submission of the marketing authorization application for lecanemab in South Korea represents a significant milestone in the effort to develop effective treatments for early Alzheimer’s disease. The results from the Clarity AD study and Study 201 provide encouraging evidence of lecanemab’s potential to reduce clinical decline in individuals with early-stage Alzheimer’s disease. By targeting and eliminating toxic Aβ protofibrils, lecanemab offers a unique approach to addressing the underlying pathology of the disease.

Alzheimer’s disease is a devastating condition that affects millions of people worldwide, and there is a significant unmet need for effective treatments. The submission of this application brings us one step closer to potentially providing a new therapeutic option for individuals with early Alzheimer’s disease in South Korea. As further applications are submitted in other Asian countries, it is hoped that lecanemab will become available to a broader population of patients in the region.

The development of lecanemab represents a promising advancement in the field of Alzheimer’s research, and it is a testament to the collaborative efforts of Eisai and Biogen. Through their joint commitment and expertise, they aim to bring forth innovative treatments that can make a meaningful difference in the lives of individuals affected by this devastating disease.

As the application undergoes review by regulatory authorities, researchers, healthcare professionals, and patients eagerly await the outcome. If approved, lecanemab could potentially become a significant addition to the treatment options available for early Alzheimer’s disease, offering hope and improved quality of life for patients and their families.

the research

The amyloid hypothesis has long been a leading theory in the field of Alzheimer’s disease (AD) research. According to this hypothesis, amyloid-beta (Aβ), the main component of extracellular plaques found in the brains of AD patients, plays a crucial role in initiating the disease process. As a result, targeting Aβ for therapeutic intervention has become an attractive strategy for developing treatments for AD.

Aβ exists in various forms, including monomers, soluble aggregates such as oligomers and protofibrils, and insoluble fibrils found in plaques. Studies have shown that soluble Aβ aggregates, particularly protofibrils, are highly neurotoxic and contribute to the progression of AD. In contrast, monomers and insoluble fibrils are considered to be less neurotoxic. Based on these findings, it is reasonable to propose that removing soluble Aβ aggregates could be an effective approach for AD treatment.

Immunotherapy, which involves using antibodies to target specific molecules, has emerged as a promising avenue for AD treatment. Several monoclonal antibodies have been developed and tested in clinical trials with varying degrees of success. For example, bapineuzumab, a monoclonal antibody targeting all forms of Aβ, failed to achieve the desired clinical effect and its clinical program was terminated. Similarly, solanezumab and crenezumab, which targeted soluble forms of Aβ, also did not meet primary clinical endpoints and showed limited plaque clearance.

Currently, there are four monoclonal antibodies targeting Aβ in late-phase clinical development: lecanemab, aducanumab, gantenerumab, and donanemab. These antibodies, all belonging to the IgG class, specifically target aggregated forms of Aβ. Lecanemab, a humanized version of the murine antibody mAb158, has shown significant plaque clearance and efficacy signals in a phase 2b clinical study. Aducanumab, developed by Biogen, initially faced challenges in its development, with the discontinuation of its phase 3 trials.

However, further analysis of the data revealed profound plaque clearance and efficacy signals, leading to its approval by the FDA in 2021. Gantenerumab, developed by Roche, targets both the N-terminal and mid-regions of the Aβ peptide. While initial phase 3 trials reported no efficacy on primary or secondary endpoints, the antibody has since reentered clinical development with ongoing trials.

Although late-phase clinical trials have shown positive effects of Aβ immunotherapy, there have been observed risks, particularly amyloid-related imaging abnormalities (ARIA) with edema (ARIA-E). ARIA-E has been associated with factors such as antibody dose and the presence of the apolipoprotein E4 (ApoE4) allele.

The exact mechanism underlying ARIA-E is not fully understood, but it may involve direct binding of Aβ antibodies to cerebral amyloid angiopathy (CAA) or accelerated formation of CAA. CAA is characterized by the deposition of fibrillar Aβ in blood vessel walls and is a common occurrence in AD. The frequencies of ARIA-E observed in clinical trials vary among the antibodies, with lecanemab at 10%, aducanumab at 35%, gantenerumab at 30%, and donanemab at 27%.

In a recent study, a comparison was conducted to examine the binding characteristics of three antibodies in late-phase clinical development: lecanemab, aducanumab, and gantenerumab. The study investigated the binding of these antibodies to various forms of Aβ, including monomers, cross-linked oligomers, small and large protofibrils, and fibrils.

The researchers used inhibition ELISA, immunodepletion, and surface plasmon resonance (SPR) techniques to assess the binding profiles. The results demonstrated that all three antibodies exhibited high selectivity for aggregated forms of Aβ. However, there were distinct differences in their binding preferences. Aducanumab and gantenerumab showed selectivity towards fibrils over protofibrils, while lecanemab exhibited stronger binding to protofibrils than to fibrils.

These findings align with previous data on mAb158, the murine precursor of lecanemab. This study represents the first side-by-side comparison of the binding profiles of these three antibodies. The differences observed in their binding profiles may potentially explain the variation in efficacy and frequency of ARIA-E observed in clinical trials.

In conclusion, the amyloid hypothesis has provided valuable insights into the pathogenesis of Alzheimer’s disease, with Aβ playing a central role in disease initiation and progression. Immunotherapy targeting Aβ has shown promise in clinical trials, although challenges such as ARIA-E have been observed.

The development of monoclonal antibodies, including lecanemab, aducanumab, and gantenerumab, has demonstrated varying levels of efficacy and safety. The recent study comparing the binding characteristics of these antibodies sheds light on their different interactions with various forms of Aβ and their potential implications for clinical outcomes. Further research and clinical trials will be necessary to fully understand the complex mechanisms underlying Aβ immunotherapy and optimize its effectiveness in treating Alzheimer’s disease.

reference link : https://doi.org/10.1007/s13311-022-01308-6


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