UPDATE ON THE SAFETY AND TOLERABILITY OF GANTENERUMAB IN THE ONGOING OPEN-LABEL EXTENSION OF THE SCARLET ROAD STUDY IN PATIENTS WITH PRODROMAL ALZHEIMER'S DISEASE AFTER APPROXIMATELY 2 YEARS OF STUDY DURATION

Background: Gantenerumab, a fully human, anti-amyloid beta (Aβ) monoclonal antibody (mAb) that binds to and promotes removal of aggregated Aβ (plaques, fibrils, and oligomers), is under investigation as a disease-modifying treatment in early AD. Double-blind treatment with low-dose gantenerumab (105mg and 225mg) in the global, placebo-controlled SCarlet RoAD study (NCT01224106) was suspended for futility and the study converted to an open-label extension (OLE) to evaluate the safety, tolerability, and pharmacodynamics of gantenerumab gradually up-titrated to 1200 mg SC q4w. Initial OLE analyses confirmed that safety profile of gantenerumab remained unchanged with amyloid-related imaging abnormalities (ARIA) and injection-site reactions (ISR) as identified risks.1 Here we present data after up to 2 years' treatment with open-label gantenerumab. Methods: 154 study participants who did not have recurrent vasogenic edema (ARIA-E), >5 cerebral microhemorrhages/hemosiderosis (ARIA-H), or any condition potentially precluding safe participation, entered the OLE after a median of 78 weeks off-treatment. To reduce ARIA-E risk, gantenerumab doses were increased slowly using a 6- or 10-month titration scheme, based on apolipoprotein E4 genotype and last double-blind dose. Target dose and titration schemes were modelled based on all available data with mAb targeting aggregated amyloid, to achieve maximum amyloid reduction while maintaining safety and tolerability. Protocol measures included MRI monitoring and dosing algorithm. Results: As of January 16, 2018, OLE duration ranged 12–101 weeks (median: 63.9 weeks). 103/154 patients received 1200mg gantenerumab for 1–81 weeks. ARIAs were detected in 47/133 patients with a post-baseline MRI; 38 patients had ARIA-E, 61% of whom had ARIA-H. ARIA-E incidence increased with dose (Table), with overall rate 28.6%. Most ARIAs (84%) were asymptomatic and non-serious. Incidence (79%) and severity of adverse events (including ISRs) remained comparable to SCarlet RoAD low-dose double-blind treatment. Conclusions: This updated Scarlet RoAD OLE safety analysis showed no new or unexpected findings with longer exposure to high-dose gantenerumab. ARIA-E rate increased with dose, but the titration appeared to reduce ARIA-E risk with overall incidence <30%. ARIAs appeared manageable with implemented protocol measures. These data support the use of titration to high-dose gantenerumab in the phase 3 GRADUATE program. 1. Andjelkovic, CTAD 2017. [Figure presented]