This article explores the use of quantitative systems pharmacology (QSP) modeling to provide further insights into the mechanism of action of neurodegenerative diseases and the likelihood of success of new drugs in development. This unique approach allows for the prediction of not only biomarkers but more importantly, clinical outcomes. Here we elaborate on the prospective prediction of lecanemab’s Phase 3 CLARITY AD clinical trial using Certara’s QSP Alzheimer’s disease platform. This prediction was based on the use of a so-called “virtual biomarker” and that concept can be applied to other neurodegenerative and rare diseases.
Alzheimer’s disease is an irreversible, progressive brain disorder affecting more than 6.5 million Americans.1 It is characterised by the formation of amyloid beta plaques and neurofibrillary, or tau, tangles in the brain, which result in the loss of neurons and their connections.1
On July 6, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval for Eisai’s Leqembi (lecanemab-irmb), an amyloid beta-directed antibody indicated to treat patients with Alzheimer’s disease.1 Leqembi was initially approved by the FDA in January 2023 under the Accelerated Approval pathway based on clinical data demonstrating the drug’s effect on a surrogate endpoint – reducing amyloid plaques in the brain – that was reasonably likely to predict a clinical benefit to patients. The decision to grant Leqembi traditional approval was made after the CLARITY AD confirmatory trial verified the drug’s efficacy.1 Leqembi became the first approved treatment shown to reduce the rate of disease progression and to slow cognitive and functional decline in adults with Alzheimer’s disease.2
It is widely agreed that the key to success in Alzheimer’s disease treatment is early intervention. It is important to identify at-risk patients and start meaningful treatment before they develop symptoms because at that point it is very difficult to reverse the disease.
Therefore, it is especially significant that Certara’s quantitative systems pharmacology (QSP) Alzheimer’s disease platform was able to predict the successful outcome of Eisai’s lecanemab CLARITY AD clinical trial one year before the data became available when all the previous monoclonal antibodies had failed. Certara’s results were presented by BioArctic at AD/PD 2022 the International Conference on Alzheimer’s and Parkinson’s disease in Barcelona, Spain in March 2022.3 Eisai licensed lecanemab from BioArctic.
QSP combines computational modelling and experimental data to examine the relationships between a drug, the biological system, and the disease process.
Certara’s QSP platform is particularly well suited to studying Alzheimer’s disease because it reflects the underlying biology of the amyloid aggregation pathway from the monomeric form to the plaque form. It is a mechanistic, realistic platform that integrates relevant biology and clinical data, and strikes a good balance between data and mechanism-driven approaches. As this tool helps to replace animal studies, it also enables drug developers to follow the guidance in the FDA Modernization Act 2.0.4