Data modeling sheds light on balancing donanemab efficacy and safety

medwireNews: Researchers have estimated that the majority of amyloid plaque reduction achieved with donanemab treatment occurs by 64 weeks of treatment, and once off treatment, the median reaccumulation rate in patients remains low. The findings, presented by Ivelina Gueorguieva (Eli Lilly, Indianapolis, USA) at AD/PD 2024, are based on pharmacodynamic and pharmacokinetic modeling of data from a phase 1 study (n=61) and the TRAILBLAZER-ALZ (n=257) and Extension (n=72) studies and TRAILBLAZER-ALZ 2 (n=1736) and Addendum 9 (n=1047) studies involving patients with early Alzheimer’s disease (AD). Her data predicted that maintaining a median threshold of donanemab of 15 µg/mL was sufficient for amyloid plaque reduction, but, on average, more than 80% of patients maintained concentrations above this threshold. According to simulations of 20,000 virtual patients beyond 76 weeks, based on the dosing regimen and stopping criteria in TRAILBLAZER-ALZ 2, most patients achieved amyloid plaque clearance (<24.1 centiloids) within 64 weeks of treatment, even those in the highest quartile for amyloid levels at baseline. The time to amyloid clearance was dependent on baseline amyloid levels, but not on age, apolipoprotein (APO)E ɛ4 genotype, or baseline tau level. These findings were supported by observed individual patient amyloid predictions, which ranged from 15 to 18 months (mean 22 months) for participants in the TRAILBLAZER Extension study and from 3 to 14 months (mean 8 months) in the TRAILBLAZER-ALZ 2 study. The simulations also showed that patients who achieved amyloid clearance and completed treatment within 6 months did not have a substantial increase in amyloid plaques over the subsequent 5 years, with the reaccumulation rate estimated to be a median of 2.8 centiloids/year. Gueorguieva said that treatment with donanemab therefore “placed patients on [a] plaque accumulation trajectory similar to untreated, amyloid-negative individuals.” The effect of donanemab-induced amyloid plaque reduction was associated with a significant slowing in disease progression compared with placebo, according to disease progression models on the Integrated Alzheimer’s Disease Rating Scale, particularly in participants with mild cognitive impairment (MCI) and individuals with low-to-medium tau, “suggesting that treating patients earlier provides more benefit,” Gueorguieva pointed out. This slowing in disease progression increased over time compared with placebo, but the presenter said, based on the simulations, that once amyloid is cleared treatment has little impact and could be stopped, given that the reappearance of amyloid once removed is very slow to reappear. In terms of exposure safety, specifically the risk for amyloid-related imaging abnormalities–edema/effusions (ARIA-E). A parametric time-to-event hazard model showed this was largely driven by having the APOE ɛ4 genotype, increasing number of baseline microhemorrhages, higher average concentration of donanemab at steady state, and increased mean arterial blood pressure, out of 21 possible covariates tested. The odds of ARIA-E at week 24 of treatment were estimated to be significantly increased by 1.8-fold for APOE ɛ4 heterozygotes and 3.9-fold for homozygotes compared with noncarriers, linearly with baseline microhemorrhages up to and including four, 1.2-fold for patients with the highest average steady-state donanemab concentrations of 233 µg/mL versus the median level of 52 µg/mL, and 1.04 times in patients with the highest baseline mean arterial blood pressure of 135 mmHg. Gueorguieva highlighted that there was “no impact of immunogenicity on ARIA-E risk.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group This article was originally published on Journey to a New Era for Alzheimer’s Disease, an independent education program developed by Springer Healthcare IME. This program is supported by an educational grant from Lilly. This content is intended for healthcare professionals outside of the UK. AD/PD 2024; Lisbon, Portugal: March 5–9

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Data modeling sheds light on balancing donanemab efficacy and safety

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