Alzheimer disease neuropathology in a patient previously treated with aducanumab.

Amyloid beta (Aß) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aß, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aß plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aß plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aß and IBA1 immunohistochemistry assays demonstrated sparse residual Aß plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aß plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.

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.

Population pharmacokinetics and standard uptake value ratio of aducanumab, an amyloid plaque-removing agent, in patients with Alzheimer's disease.

Aducanumab is a human immunoglobulin G1 anti-amyloid beta (Aß) antibody currently being evaluated for potential treatment of patients with early Alzheimer's disease. This paper describes the relationship between the population pharmacokinetics (PopPKs) and pharmacokinetics-pharmacodynamics (PKs-PDs) of aducanumab using data from phase I to III clinical studies, with standard uptake value ratio (SUVR) used as a PD marker. Across clinical studies, aducanumab was administered intravenously either as a single dose ranging from 0.3 to 60 mg/kg or as multiple doses of 1, 3, 6, or 10 mg/kg every 4 weeks. A titration regimen with maintenance doses of 3, 6, or 10 mg/kg was also evaluated. Aducanumab PK was characterized with a two-compartment model with first-order elimination. No nonlinearities in PKs were observed. The PopPK-PD model was developed using a sequential estimation approach. The time course of amyloid plaques, as expressed by composite SUVR measured using positron emission tomography, was described using an indirect response model with drug effect stimulating the elimination of SUVR. None of the identified covariates on PK and the PopPK-PD model were clinically relevant. The PopPK-PD model showed that magnitude, duration, and consistency of dosing are important factors determining the degree of Aß removal. The intrinsic pharmacology of aducanumab remained consistent across studies.