A Time-to-Event Exposure-Response Model for Amyloid-Related Imaging Abnormalities Following Administration of Aducanumab to Subjects With Early Alzheimer Disease.

Amyloid-related imaging abnormalities with edema (ARIA-E) have been reported in patients with early Alzheimer disease treated with aducanumab. ARIA-E incidence has been observed to be dependent on both dose and apolipoprotein E4 carrier status. A time-to-event (TTE) approach applying data from 2 phase 3 studies (studies 301 and 302) was used to describe the effect of aducanumab serum exposure on the instantaneous risk of 2 end points: the first incidence of ARIA-E and time to ARIA-E resolution. A total of 3251 subjects with 826 events supported the TTE model to characterize the first ARIA-E event. The TTE resolution model was supported by data from 768 of 826 subjects who had ARIA-E resolved. Relationships between drug concentrations and ARIA-E events were modeled with a hazard function dependent on time, aducanumab serum concentrations, attenuation of aducanumab exposure effects with time (ie, potential for tolerance to aducanumab exposure), study, and apolipoprotein E4 carrier status. The TTE model showed that ARIA-E incidence rates were higher during the first 200 days, followed by a reduction in rates. The change in event rate reflects the attenuation of drug effect, thereby providing support for the current proposed titration regimen. Time to ARIA-E resolution was characterized by a constant baseline hazard with a probability to resolution affected by baseline ARIA-E severity and aducanumab concentration. ARIA-E resolution was found to be driven primarily by baseline hazard and time and suggested that aducanumab concentration effect is a minor contributor to the time to resolution of ARIA-E.