Lecanemab

Lecanemab as a Treatment for Early-Onset AD

In January of this year, the FDA approved a drug called Lecanemab, a monoclonal antibody that targets beta-amyloid deposits through intravenous injection. The target population for this drug are patients that carry the APOE4 gene and are in the early-onset stages of AD. When assessing the cognition of patients, there are several diagnostic and statistical tests available to quantify their cognitive abilities. Some of which include the Alzheimer's Disease Composite Score (ADCOMS), the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14). In the following clinical trial, structured as a double-blind experiment, the researchers tested for the most efficient quantity of administered Lecanemab through dose-dependent conditions, using the patients' scores of the ADCOMS, the CDR-SB and the ADAS-Cog14 and means to quantify and diagram their results. 

Experimental Approach

Part of what they called Study 201, researchers employed seven different dose-dependent conditions to 854 qualified subjects in a double-blind experiment in order to find a target dose: placebo, 2.5 mg/kg biweekly, 2.5 mg/kg monthly, 5.0 mg/kg biweekly, 5.0 mg/kg monthly, 10 mg/kg biweekly, or 10 mg/kg monthly. They quantified their results through diagnostic clinical decline, changes in cerebral spinal fluid biomarker concentration, and total hippocampal volume. After establishing that the 10 mg/kg was their target dose, the researchers looked at both the 10 mg/kg biweekly and 10 mg/kg monthly test groups in order to attempt to combat future statistical caveats from lost subjects, purely focusing on volume of dose. The figures above focus on the diagnostic clinical decline comparing scores of the subjects who received the placebo, 10 mg/kg biweekly and 10 mg/kg monthly conditions over a period of eighteen months. 

Figure A: ADCOMS - Alzheimer's Disease Composite Score over time

Figure B: CDR-SB - Clinical Dementia Rating Scale (Sum of Boxes) over time

Figure C: ADAS-Cog14 - Alzheimer's Disease Assessment Scale-Cognitive Subscale over time

Summary

Using conventional statistical analysis, the researchers found that both test conditions of 10 mg/kg doses resulted in less clinical decline in comparison to the placebo. Of the two test conditions, the dose of 10 mg/kg biweekly produced the least clinical decline in comparison to the placebo: 30% less clinical decline on the ADCOMS; 26% less clinical decline on the CDR-SB; 47% less clinical decline on the ADAS-Cog14.

The results of this research are very important to the realm of drug development for Alzheimer's. Not only were they able to identify the most effective dosage of Lecanemab, but they were able to show in both biological (not discussed here) and clinical/cognitive measures that this dosage can have a positive impact in slowing the progression of AD. While Lecanemab may not perfectly cure Alzheimer's, this research supports that this treatment modality is a small breakthrough for AD drug development. 

References

Cao, Y., et al. Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China. Front. Neurol., 15 November 2022; Sec. Dementia and Neurodegenerative Diseases, Vol. 13. https://doi.org/10.3389/fneur.2022.1034243. 

Swanson et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody.  Alzheimer's Research & Therapy (2021) 13:80 https://doi.org/10.1186/s13195-021-00813-8.