Reporter |
Editor |Xie Xin
On November 30, Japanese pharmaceutical company Eisai presented detailed results of the Phase III trial for its investigational drug lecanemab targeting early Alzheimer's disease (AD) at the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference. The results were also simultaneously published in the authoritative international medical journal, The New England Journal of Medicine.
The trial, known as the Clarity AD study, is a placebo-controlled, double-blind, randomized global confirmatory Phase III trial. The trial enrolled 1,795 patients with early AD across 235 research sites in North America, Europe, and Asia. Participants were randomly assigned in a 1:1 ratio to receive either a placebo or lecanemab 10 mg/kg intravenous infusion every two weeks.
The primary endpoint of the study was the change in the Clinical Dementia Rating Sum of Boxes (CDR-SB) from baseline after 18 months of treatment, with higher scores indicating lower clinical function in patients. Key secondary endpoints included amyloid levels in the brain as measured by positron emission tomography (PET), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Composite Score (ADCOMS), and the Alzheimer’s Disease Cooperative Study – Mild Cognitive Impairment Activities of Daily Living (ADCS MCI-ADL) scale compared to baseline.
The results of Clarity AD showed that the study met its primary endpoint. After 18 months of treatment, the CDR-SB scores for the lecanemab group and the placebo group were 1.21 and 1.66, respectively. Compared to the placebo group, the lecanemab group had a 0.45 lower CDR-SB score (P=0.00005), representing a 27% reduction in the rate of score increase. Furthermore, significant differences in CDR-SB scores between the lecanemab group and the placebo group began to emerge as early as 6 months after treatment (P<0.01), with the absolute difference in scores between the two groups widening over time.
According to Eisai's official website, a slope analysis based on observed data and extrapolated to 30 months of CDR-SB indicates that receiving lecanemab treatment for 25.5 months is equivalent to the level of placebo treatment at 18 months, suggesting that lecanemab can delay disease progression by up to 7.5 months.
However, the result has also been controversial in the industry. According to a report by foreign biopharmaceutical media BioPharma Dive, Constantine Lyketsos, director of the Memory and Alzheimer's Treatment Center at Johns Hopkins School of Medicine, pointed out that many Alzheimer's experts believe that a drug needs to show an effect of at least 1 to 2 points on the CDR-SB scale to be considered clinically significant.
In addition, the study also met all secondary endpoints. After 18 months of treatment, the mean difference in Centiloids (measurement unit for PET diagnosis of AD) between the lecanemab group and the placebo group was -59.1 (P<0.00001). In terms of ADAS-Cog14, ADCOMS, and ADCS MCI-ADL scores, the mean differences between the Lecanemab group and the placebo group were -1.44, -0.050, and 2.016, respectively, with corresponding reductions in disease progression of 26% (P=0.00065), 24% (P=0.00002), and 37% (P<0.00001).
In terms of safety, 0.7% of participants in the lecanemab group and 0.8% in the placebo group died. The researchers concluded that no deaths were related to lecanemab or amyloid-related imaging abnormalities (ARIA). Additionally, serious adverse events occurred in 14.0% of participants in the lecanemab group and 11.3% in the placebo group, while adverse events occurred in 88.9% and 81.9% of participants, respectively. The most common adverse events in the lecanemab group included infusion reactions, ARIA-H (combined cerebral microhemorrhages, large cerebral hemorrhages, and superficial siderosis), ARIA-E (edema/effusion), headache, and falls.
Alzheimer's disease is the most common neurodegenerative disease among the elderly, but its drug development is very challenging, with limited drugs available on the market, and most of them focus on improving clinical symptoms. Since 2003, the only innovative drugs in this field that have been launched are Eisai/Biogen's Aduhelm and Green Valley Pharmaceutical's GV-971, which was conditionally approved in China. Both drugs have sparked significant controversy. Additionally, many multinational pharmaceutical companies such as Eli Lilly, Takeda, Merck, Pfizer, and Roche have previously faced setbacks in this area.
Lecanemab, jointly developed by Eisai and Biogen, is a drug targeting β-amyloid protein (Aβ) monoclonal antibody.Amyloid deposition is one of the hallmark features of the AD patient's brain.。lEcanemab has the potential to alter AD pathology and slow disease progression by binding to soluble Aβ aggregates and promoting their clearance.
In May this year, the two parties submitted a Biologics License Application (BLA) for lecanemab to the U.S. Food and Drug Administration (FDA). In July, the FDA granted it Priority Review, with a Prescription Drug User Fee Act (PDUFA) target action date of January 6, 2023. In March this year, Eisai also initiated the application process for lecanemab in Japan. The company also anticipates submitting a new drug marketing application in Europe during the fiscal year 2022 (ending March 31, 2023). However, in September this year, Eisai told Interface News that it has not yet decided when to apply this investigational drug in China.