Eline Van Maanen1, Seth Rodney2, Idriss Bennacef2, Stephen Duffull1, Julie Stone2
1Certara, 2Merck & Co
Introduction: Positron-emission tomography (PET) using amyloid radiotracers allows the quantification of pathological amyloid deposition in brain tissues. An exposure-response (E-R) analysis was performed on individual study data of the ß-secretase-1 inhibitor verubecestat and summary-level data of four amyloid mAbs in Alzheimer’s disease (AD) patients. Objectives: This analysis aimed to quantify drug effects and plaque turnover rates, while also aiding in the prediction of unstudied treatment regimens. Methods: Individual-level verubecestat amyloid-PET plaque data (n=188; 65 placebo vs 123 verubecestat) and exposures from the phase 3 APECS trial [1] were combined with summary-level amyloid-PET data and serum exposures from literature for aducanumab [2-5], donanemab [5-8], gantenerumab [9-13] and lecanemab [14-18]. Amyloid plaque levels in SUVR units were converted to Centiloid [19]. Individual-level data and aggregate data were simultaneously analyzed using a joint model in a hierarchical modeling approach through nonlinear mixed-effects modeling with NONMEM. In external validation, the model was applied to ADNI’s natural progression data set, which included individual amyloid PET measurements from amyloid-positive individuals (n=521) [20]. Simulations investigated the impact of mAb’s dose titration on the amyloid plaque dynamics. Results: An indirect response (turnover) model, where verubecestat inhibits plaque formation, and amyloid mAbs stimulate plaque removal, effectively represented the available data. All plaque time course data from natural progression (control arms), ß-secretase-1 inhibition and amyloid mAb treatment arms were well described by a joint model. The plaque turnover rate was estimated to be 0.00028 per day, corresponding to an elimination half-life of plaque of ~6.8 years. Verubecestat AUC50 was estimated as 0.313 uM*h, leading to a 91.8% reduction in plaque formation at the typical 40 mg exposure. 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 removal rate by 9.3-, 15.2-, 5.3-, and 13.7-fold, respectively. In the external-validation step, the model provided a good description of the amyloid progression over 6 years in the ADNI natural progression data set. Inhibition of ß-secretase-1 by verubecestat led to a modest reduction of amyloid plaque over 24 months. In contrast, mAb treatment resulted in a more significant reduction of amyloid plaque burden over the same period. Lecanemab was predicted to achieve similar plaque reduction to donanemab at 18 months, despite lower potency, due to starting with a 20-mg/kg monthly dose (10 mg/kg Q2W) versus donanemab’s 3-month 10-mg/kg titration. Aducanumab was predicted to have a lower plaque reduction than lecanemab at 18 months due to a 6-month titration to a 10 mg/kg Q4W dose, despite slightly greater potency. Gantenerumab was predicted to show much lower plaque reduction due to both lower potency and a slow 9-month titration to ~15 mg/kg. Conclusion: The joint turnover model, linking drug exposure with amyloid plaque load, effectively described both natural progression and treatment response, while also allowing for the estimation of the underlying turnover rate. This approach improves cross-study comparisons and enables the prediction of alternative regimens and therapeutic approaches by accounting for differences in baseline plaque load, dosing and titration regimens, and mechanism of action.
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Reference: PAGE 33 (2025) Abstr 11724 [www.page-meeting.org/?abstract=11724]
Poster: Drug/Disease Modelling - CNS