Exploring treatment guidelines for amyloid therapies in Alzheimer’s Disease Using Predictive Quantitative System Pharmacology Modeling

Abstract

AbstractThe recent approvals of amyloid antibodies for treatment of Alzheimer’s disease have heralded a new era in the physician’s treatment toolbox and the availability of individualized treatment guidelines for patients will greatly benefit an ever greater patient population. However, generating these guidelines using clinical experiments is not feasible.We used a mechanism‐based Quantitative Systems Pharmacology model, well validated with published natural history and group average clinical trial data of six amyloid antibodies and applied it to individual scenarios, including APOE genotype. For baseline SUVR between 70 and 180 centiloids, the time to reach amyloid negativity was predicted to range on average from 25 to 64 months for aducanumab, 18 to 47 months for lecanemab and 10 to 25 months for donanemab. Interestingly, we derived a relationship between the baseline SUVR load and the changes in plasma Ab42/Ab40 ratio or CSF Ab42 level associated with reaching amyloid negativity. This relationship is different for each antibody with lecanemab more sensitive than donanemab and aducanemab and provides an alternative to PET imaging to determine the time of reaching amyloid negativity. ARIA‐E liability for an APOE4 carrier ranges between 20 and 31% for aducanumab, 10‐18% for lecanamab and 17‐27% for donanemab during the time to reach Abeta negativity.After reaching amyloid negativity, stabilization over 10 years follow‐up can be achieved with a 32‐fold reduction in exposure for all three antibodies, either with a lower dose, lower frequency or a combination of both.For patients with a three‐month dose holiday after an ARIA‐E incident, the delay in reaching amyloid negativity is predicted to range from 3 to 6 months for aducanumab, 2 to 4 months for lecanemab and 1.7 to 3 months for donanemab, depending on the titration schedule after reinstatement of the treatment.Finally, after implementation of the trisomy 21 effect, we explored optimal trial designs for autosomal dominant Down syndrome patients for each of the three antibodies.This simulation can be applied to any newly approved drug given the pharmacology (affinities against different Abeta peptides) and PK profile and many individual case scenarios.