[P1–045]: THE EFFECT OF 6 MONTHS’ DOSING ON THE RATE OF AMYLOID‐RELATED IMAGING ABNORMALITIES (ARIA) IN THE MARGUERITE ROAD STUDY

Abstract

Gantenerumab, a fully human, anti-Aβ monoclonal antibody (mAb) binds and promotes removal of aggregated Aβ. As other mAb, gantenerumab has been associated with amyloid-related imaging abnormalities (ARIA) consisting of MRI signal changes representing either vasogenic edemas (ARIA-E) or cerebral microhemorrhage/superficial hemosiderosis (ARIA-H). Treatment with mAb may increase permeability of brain capillary endothelial cells resulting in increased extravasation (ARIA-E) and may also result in impaired vessel wall integrity leading to small amounts of red blood cells leakage (ARIA-H). Main risk factors for ARIA are APOE e4 genotype, age, and study drug dose. Gradual exposure to treatment is expected to “gently” remove Aβ from blood vessels allowing the recovery of the vasculature over time. Marguerite RoAD (NCT01224106), a phase III randomized, double-blind, placebo-controlled, efficacy and safety study of gantenerumab in patients with mild AD, randomized patients to monthly subcutaneous injections of either placebo or gantenerumab starting at 105 mg for 24 weeks. Following post week 24 MRI results confirming no significant ARIA findings (no ARIA-E and no > 1 new microbleed), patients received 225 mg. In case of ARIA-E findings, patients either remained on the 105 mg dose (if ARIA-E < 2 cm) or had their dose withheld (if symptomatic ARIA-E, multiple ARIA-E, or ARIA-E > 2 cm) with monthly MRI monitoring. In Marguerite RoAD, 192/387 patients received gantenerumab. The ARIA-E rate was 4.3% at week 24, 3.0%, 4.5%, and 0% at weeks 36, 48, and 104 respectively, with an overall ARIA-E rate of 10.8%. The ARIA-E rate on placebo ranged from 0 to 0.5% at the various visits, with an overall rate of 1.6%. ARIA-H occurred with or without ARIA-E at the following rates: 4.9% at week 24, and 4.2%, 8.4%, and 6.1% at weeks 36, 48, and 104 on gantenerumab, as compared with 4.9%, 2.4%, 4.0%, and 10.7% at weeks 24, 36, 48, and 104 respectively, on placebo. Six-month dosing at 105 mg gantenerumab prior to escalation to 225 mg resulted in an overall ARIA rate of 10.8%. ARIA-H occurred with or without ARIA-E at variable rates on placebo and gantenerumab.