Effect on amyloid plaque as measured by positron emission tomography imaging with Centiloid standardization of two therapeutic approaches targeting amyloid beta (Aβ) was investigated using exposure-re Show more
Effect on amyloid plaque as measured by positron emission tomography imaging with Centiloid standardization of two therapeutic approaches targeting amyloid beta (Aβ) was investigated using exposure-response modeling. Individual-level verubecestat data from the APECS trial were pooled with summary-level data from the literature for amyloid monoclonal antibodies (mAbs) and fitted in a joint non-linear mixed-effects model. An indirect-response (turnover) model with verubecestat inhibiting plaque formation and mAbs stimulating plaque removal well represented the data. The estimated plaque elimination half-life was 6.4 years. Daily verubecestat 40 mg was estimated to reduce formation by 91.8%. Aducanumab 10 mg/kg every 4 weeks (Q4W), donanemab 1400 mg Q4W, gantenerumab 1200 mg Q4W, and lecanemab 10 mg/kg Q2W were estimated to increase the removal rate by 9.3-, 18.6-, 5.3-, and 13.8-fold, respectively. The model provides a fundamental measure of drug effects on plaque, independent of disease stage and study-design factors, improving cross-study comparisons and enabling predictions. The plaque turnover model describes natural progression and BACE and mAb intervention.The model estimation of the underlying plaque elimination half-life is 6.4 years.Approach improves cross-study comparison independently of population and study design.Predictions of alternative regimens/therapeutic approaches will aid future study design. Show less