Salvaging COVID‐19 interrupted Alzheimer clinical trials using virtual patient simulations: Developments in clinical trials and cognitive assessment

Geerts, Hugo; Van der Graaf, Piet

BACKGROUND: The COVID‐19 pandemic has halted many Alzheimer’s Disease clinical trials, with some forced to re‐start at different points along the trial time‐line with substantial protocol amendments and patients dropping out with substantial partial assessments. To align the functional outcomes of these protocol amendments with the original trial design at the individual patient level, we propose to use Physiology‐Based Pharmacokinetic (PBPK) and Quantitative Systems Pharmacology (QSP) Modeling to ‘correct’ the cognitive trajectory of mirror virtual patient population back to the original trail design. METHOD: The Virtual Twin approach creates a PBPK computer‐simulated model of each patient with a virtual twin QSP model of trial subjects, with the same co‐medications, common genotype variants affecting metabolism and cognitive outcome; β‐amyloid and tau biomarkers. The QSP platform is a previously ADAS‐Cog calibrated model of key neuronal circuits involved in cognition, allowing to model the effects of CNS active co‐medications based on their pharmacology and genotypes based on imaging studies. In this Virtual Twin approach, the platform will be extensively validated against the actual clinical data from the completer set and the fragmented outcomes of the restarters with their individual protocol amendments, before simulating the cognitive trajectory with the original trial design for those whose trial was interrupted. RESULT: Different interruption scenarios in a 24‐month AD study of a bi‐weekly amyloid antibody infusion are simulated with increased anxiolytics and anti‐depressants use after restart. The impact of changes is dependent upon the genotype combination with the 5‐HTTLPR rs 23351 > APOE > COMTVal158Met and different for placebo and active treatment. Anti‐depressants and benzo also differentially substantially affect the cognitive trajectory. We illustrate how to reconstruct the cognitive trajectory of 600 subjects (out of 1200) affected by the interruption. CONCLUSION: Combining QSP modeling of the biology with PBPK modeling and extensive validation with the fragmented clinical data available, in principle allows to reconstruct the original cognitive trajectory in patients affected by the COVID‐19 interruption. In this way, the original trial design and statistical analysis plan can be applied to achieve a fair evaluation of the clinical effect of the investigative new drug.