OO012 - THE IMPACT OF COMEDICATIONS AND GENOTYPES ON COGNITIVE OUTCOME IN AMYLOID - TAU COMBINATION THERAPIES. A QUANTITATIVE SYSTEMS PHARMACOLOGY STUDY (ID 529)

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Abstract

Aims

With the approval of Aducanumab, combination trials with tau modulating agents are being considered. While the impact on amyloid biomarkers can be anticipated based on prior clinical experience, the effect on the functional cognitive trajectory is more challenging to predict. In addition, cognitive performance is also affected by comedications and common genotype variants.

Methods

We use a Quantitative Systems Pharmacology (QSP) approach, basically a biophysically realistic computer model of neuronal circuits calibrated with ADAS-Cog from historical trials. The model includes the effect of Ab on glutamate and nicotinic neurotransmission, and of tau oligomers on voltage-gated ion channels. COMTVal156Met, 5-HTTLPR rs23351 and APOE genotype are implemented using human imaging studies. Comedications include standard-of-care AChE-I and memantine, antidepressants and benzodiazepines.

Results

In untreated patients, Tau pathology dominates amyloid pathology, in line with preclinical data and dose-dependently accelerates cognitive worsening with COMT MM having the greatest impact at early stages and COMTVV becoming gradually more important in later stages with a similar profile for 5-HTTss and 5-HTTLL. In patients treated with amyloid agents, tau pathology reduces the limited beneficial effect on ADAS-Cog. Virtual patient trials with distributions of comedications and genotypes using the PK profile of aducanumab underscore the importance of the right timing, dosing and stratification criteria for the combination trial. In general, the differential impact of tau pathology on cognitive trajectory decreases with increasing neurodegeneration.

Conclusions

In the absence of actual clinical experience, QSP might be a powerful approach to optimize clinical trial designs for amyloid-tau combinations.

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