Breakthrough of Aβ antibody drug, Lecanemab Phase III Clinical Trial Meets Primary and Secondary Endpoints in AD

Jan 16,2023

Alzheimer's disease (AD) is the most common type of neurodegenerative disease. At the pathological level, it mainly manifests as amyloid Aβ deposition, glial cell activation, and brain atrophy. The behavioral symptoms include decreased memory function and cognitive function. At present, there are more than 44 million AD patients in the world, and the number is expected to reach 75 million in 2030. Although the Aβ plaque hypothesis has been questioned, multiple drugs targeting Aβ deposition have continued development after Biogen's Aducanumab was approved in 2021.


Biogen/Eisai Lecanemab Phase III Clinical Trial Meets Primary and Secondary Endpoints

On November 29, 2022, Biogen/Eisai published the complete data of the phase III clinical trial of lecanemab in the New England Journal of Medicine[1]. The experiment used the global cognition and function scale CDR-SB as the primary endpoint. The total score of the CDR-SB scale ranges from 0 to 18. The higher the score, the worse the cognitive function and daily living ability of the patient. Based on the results, Lecanemab successfully reached the clinical endpoint, and the patients were statistically different from the placebo group after 6 months of treatment.

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Fig1: Lecanemab phase III clinical trial reached the primary endpoint.

Image Credit: The New England Journal of Medicine


In addition, the changes in amyloid load in the clinical trial, as well as the three cognitive/behavioral assessments of ADAS-cog14, ADCOMS, and ADCS-MCL-ADL all met secondary endpoints.


Lilly's Donanemab phase III clinical results are better than Aducanumab

On November 30, 2022, Lilly released the latest data of TRAILBLAZER-ALZ4 in the Phase III clinical trial of Donanemab for the treatment of Alzheimer's disease[2]. After 6 months of treatment, 37.9% of the Donanemab treatment group showed that Amyloid was cleared in the brains of patients, while only 1.6% of patients in the aducanumab treatment group achieved this effect. At the same time, Donanemab reduced the level of amyloid plaques in the brains of patients by an average of 65.2%, compared with 17.0% in the aducanumab treatment group.

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Fig2: Lilly released the Phase III clinical data of Donanemab in the treatment of Alzheimer's disease. 

Image source: Lilly official website


GemPharmatech’s  FAD4T mouse model facilitates the development of new drugs

Based on the hypothesis of Aβ plaques, GemPharmatech has generated a novel AD mouse model, FAD4T. Mutated human APP (Swedish and Indiana) and PSEN1 (M146L, L286V) were introduced into C57BL/6J mice, causing obvious signs of Aβ plaque deposition as early as at the age of 2 months. 

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Fig3: FAD4T mice began to develop Aβ plaque deposition at 2 months of age, which increased with age


Aβ peptide exhibits complex structures in the deposits they form. Depending on the epitope that an antibody recognizes, different Aβ antibodies could bind to different parts or structural moieties of the same Aβ protein. Aβ protein in FAD4T mice can be recognized by multiple antibody drugs including Donanemab and Aducanumab.

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Fig4: Aβ plaque deposition in FAD4T mice can be recognized by therapeutic antibody drugs


FAD4T mice showed glial cell activation from 2.5 months of age, and obvious gliosis could be detected at 4 months of age.

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Fig5: FAD4T mice showed obvious gliosis at 4 months of age


In terms of behavioral phenotype, FAD4T mice showed obvious learning and memory impairment at 8 months of age, and can be used for drug efficacy evaluation experiments.

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Fig6: 8-month-old FAD4T mice showed obvious learning and memory impairment in Morris water maze (FAD4T vs Control). Drug (proprietary information by 3rd party collaboration) at low dose could reverse the deficit with statistical significance.


More data are being collected, so stay tuned!

Learn more about neurological disease mouse models: https://en.gempharmatech.com/product/models_list100139_170052.html


References

1. C.H. van Dyck, C.J. Swanson, et al. Lecanemab in Early Alzheimer’s Disease. The New England Journal of Medicine, 2022, DOI: 10.1056/NEJMoa2212948

2. Lilly Shares Positive Donanemab Data in First Active Comparator Study in Early Symptomatic Alzheimer's Disease. Retrieved December 1, 2022, from https://investor.lilly.com/news-releases/news-release-details/lilly-shares-positive-donanemab-data-first-active-comparator5.  Science (amylyx.com)