Reporter |
Editor |Xie Xin
On September 27 Eastern Time, Eisai and Biogen jointly announced that lecanemab, their investigational therapy for Alzheimer's disease (AD), had met the primary endpoint in a Phase 3 validation clinical trial for treating mild Alzheimer’s disease and mild cognitive impairment (MCI) due to Alzheimer’s disease. Additionally, the trial achieved all key secondary endpoints.
In other words, in this clinical trial, lecanemab significantly alleviated cognitive decline in patients with mild Alzheimer's disease and mild cognitive impairment caused by Alzheimer's disease.
This Phase 3 global confirmatory trial included 1,795 patients. The results showed that after 18 months of lecanemab treatment, the clinical decline in the CDR-SB scale, which assesses cognitive and functional abilities, was reduced by 27% compared to the placebo group. In the intent-to-treat population, this represents a score difference of -0.45 (p=0.00005). A statistically significant difference between the lecanemab group and the placebo group was observed as early as 6 months after treatment initiation.
On September 28, EisaiToThe Interface News stated that the clinical data this time showed that the clinical trial met the primary endpoint expected to be achieved in the Phase 3 validation clinical trial. The results of this clinical study are crucial.
However, Biogen and Eisai did not disclose more details of the trial, and the two parties are expected to announce further information on November 29.Presented the full study results at the Alzheimer's Disease Clinical Trials conference and published the results in a peer-reviewed journal.。In addition, the side effects of Lecanemab are still relatively severe, with symptoms including brain swelling and brain bleeding. Among the 1,795 patients who participated in this trial, 21.3% of those who received the drug treatment experienced brain swelling or brain bleeding.
Alzheimer's disease is the most common neurodegenerative disease among the elderly, but the drug development for Alzheimer's disease is considered to be almost the most difficult in all pharmaceutical research and development. Over the years, clinical trials of countless potential drugs have ended in failure, making Alzheimer's disease known as the "graveyard" of new drug development.
The deposition of amyloid plaques is one of the hallmark characteristics in the brains of patients, making targeting amyloid a key direction in the development of new drugs for Alzheimer's disease. Lecanemab is currently one of the most closely watched therapies in the pipeline.
Lecanemab is a humanized monoclonal antibody, fully referred to as anti-amyloid beta (Aβ) antibody lecanemab (BAN2401). Lecanemab binds to soluble Aβ aggregates and promotes their clearance, with the potential to alter Alzheimer's disease pathology and slow disease progression.
Previously released data from the Phase 2b clinical trial showed that lecanemab reduced levels of amyloid plaques in the brain. After 18 months of treatment, lecanemab (10 mg/kg every two weeks) decreased brain amyloid levels by an average of 0.306 SUVr units (baseline value of 1.37). More than 80% of participants reached the amyloid-negative criterion upon visual read of their scans. Additionally, the level of amyloid reduction correlated with a slower rate of decline in multiple cognitive scores.
On September 28, Klaith, a drug clinical development professional, told Interface News that lecanemab is the first Alzheimer's disease drug to demonstrate efficacy in both cognition and function in a fully confirmatory clinical trial, and based on its mechanism of action, it may be considered a disease-modifying therapy (DMT). In other words, it can genuinely slow the progression of Alzheimer’s disease rather than merely controlling surface-level symptoms.
In May this year, Eisai and Biogen submitted a Biologics License Application (BLA) for lecanemab therapy to the U.S. Food and Drug Administration (FDA). In July, the U.S. FDA granted Priority Review status to its investigational Alzheimer's disease therapy lecanemab, with a Prescription Drug User Fee Act (PDUFA) target action date of January 6, 2023. In Japan, Eisai also initiated the application process for lecanemab in March this year. The company also anticipates submitting a new drug marketing application in Europe during the fiscal year 2022 (ending March 31, 2023).
As for whether it will explore the Chinese market at an appropriate time, EisaiToThe Paper said that it has not yet decided when to apply this research drug in China.
Currently, the development of Alzheimer's disease drugs is mainly based on the most recognized "hypothesis" — the deposition of β-amyloid protein. The abnormal deposition of β-amyloid protein in the brain may trigger a series of reactions such as excessive phosphorylation of Tau protein, neurotransmitter disorders, and oxidative stress, leading to neuronal damage and subsequent dementia. Preventing the deposition of β-amyloid protein is considered the most reliable treatment strategy.
However, recently, an investigative report published in the American journal *Science* pointed out that a key foundational research paper from 16 years ago in the field of Alzheimer's disease is suspected of fabrication. This threatens the mainstream theory of "β-amyloid plaque deposition (Aβ)" and could impact the research direction and new drug development. Currently, it remains inconclusive whether the paper is confirmed to be fraudulent.
Klaith believes that what is being questioned is not the beta-amyloid hypothesis, but a very small part of it. If the results of a series of Phase 3 trials of beta-amyloid drugs show efficacy rates of 20-30%, this would suggest that beta-amyloid may indeed play a role in the pathogenesis of Alzheimer's disease, but not necessarily the most crucial one. Klaith mentioned that upcoming research on the prevention of Alzheimer’s before the onset of clinical symptoms is also worth paying attention to.
Lecanemab is not the first collaborative attempt by Biogen and Eisai in the Alzheimer's disease field. In June 2021, the FDA approved Aducanumab, a new Alzheimer's drug jointly developed by Biogen and Eisai, through the accelerated approval pathway. This was the first Alzheimer's drug to be approved by the FDA in nearly 20 years. The journey to market for Aducanumab was not easy – the development of Aducanumab by Biogen and Eisai for Alzheimer’s treatment to the submission of this marketing application took nearly 15 years.
However, in reality, the results of two pivotal Phase III clinical trials of aducanumab were contradictory: the trials, code-named ENGAGE and EMERGE, had identical designs but produced conflicting outcomes. Only in the highest-dose group of EMERGE did the mean score of the CDR-SB scale, which assesses cognitive and functional abilities, decrease by 22% in patients with mild Alzheimer's disease and mild cognitive impairment caused by Alzheimer's. Additionally, about 40% of patients in the high-dose group of the Phase III trial experienced brain swelling or bleeding. Most were asymptomatic, while others reported headaches, dizziness, or nausea. Approximately 6% of high-dose participants eventually discontinued the drug due to side effects.
Therefore, the controversy surrounding Aducanumab has never stopped before and after its market launch. According to a report by The New York Times in July 2021, several large medical centers in the United States refused to prescribe Aducanumab for patients.
On December 17, 2021, the European Medicines Agency (EMA) rejected the European marketing authorization for aducanumab. Historically, the EMA has maintained a high level of consistency with the U.S. Food and Drug Administration (FDA) in marketing decisions, making this decision highly controversial. At the time, the EMA stated that the available experimental data failed to demonstrate the safety and efficacy of aducanumab. Five days later, Japan’s Ministry of Health also rejected the marketing application for aducanumab for similar reasons. On June 9, 2022, Biogen voluntarily withdrew aducanumab from regulatory review by Health Canada.
According to foreign media STAT, Biogen began large-scale layoffs in March this year. This move is seen by outsiders as a declaration of failure in the commercialization efforts for the controversial drug Aducanumab.