Amyloid re‐accumulation after donanemab treatment: summary from 3 interventional trials

Abstract Background In TRAILBLAZER‐ALZ, amyloid clearance (defined as reaching <24.1 centiloids, CL) (Navitsky, 2018) was achieved for 40% of participants (mean baseline 107.6 CL) after 6 months of donanemab treatment (Mintun, 2021). The estimated time course of natural amyloid plaque accumulation at the amyloid‐negative stage is approximately 3.3 CL/year (Jagust, 2021). Our objective was to examine the longer‐term effect of donanemab on brain amyloid deposition by evaluating the amyloid re‐accumulation observed in trial participants who reached clearance and were no longer receiving donanemab infusions, and compare it with amyloid accumulation for untreated amyloid‐negative participants. Methods In I5T‐MC‐AACD (NCT02624778) and TRAILBLAZER‐ALZ (NCT03367403), we identified N = 46 participants with ≥2 post‐treatment florbetapir scans conducted approximately 6 months after reaching amyloid clearance (Table 1). Part C of ongoing TRAILBLAZER‐EXT trial (NCT04640077) is evaluating participants from TRAILBLAZER‐ALZ at least 52 weeks after the participant’s last dose of donanemab. To examine re‐accumulation rate, a linear regression was used to analyze change in amyloid level during post‐treatment using follow‐up time (in years) as a covariate. Furthermore, an advanced exposure‐response model (ERM) with all available dosing, pharmacokinetic and florbetapir data, over treatment and post‐treatment periods was employed (N = 304). Results Among 46 participants who achieved amyloid clearance after donanemab treatment, a single participant (∼2%) became amyloid‐positive. The average amyloid level (mean±SD) changed from 4.4±8.9 to 3.9±11.4 CL during the observation period (mean 9.7±3.1 months) after stopping dosing. The rate of annualized change in amyloid level is approximately 3.4 CL/year. The rate of change in amyloid level was not significantly associated with amount of amyloid reduced over the treatment period or amyloid level achieved post‐treatment. ERM predicted an average rate of 3.4 CL/year for amyloid re‐accumulation in patients who reached clearance. Conclusion The post‐treatment florbetapir scans at 9.7±3.1 months for amyloid‐negative I5T‐MC‐AACD and TRAILBLAZER‐ALZ participants suggest that a re‐accumulation rate is comparable with the inherent amyloid accumulation rate. Additional analyses of TRAILBLAZER‐EXT data with the longer post‐treatment period will be presented at the conference. Treatment with donanemab not only reduces amyloid levels in early, symptomatic AD patients below the amyloid‐positive threshold but also places them on a plaque accumulation trajectory similar to untreated, amyloid‐negative patients.