Long-Term Safety of Gantenerumab in Participants with Alzheimer's Disease: A Phase III, Double-Blind, and Open-Label Extension Study (Marguerite RoAD)

Abstract

Background: Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer's disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE).

Objective: The DB study aimed to assess the efficacy of gantenerumab compared with placebo from baseline to Week 104 in participants with mild AD dementia. Following conversion to an OLE, this objective became exploratory, as the OLE assessed the long-term safety and tolerability of SC gantenerumab at doses of up to 1,200 mg every 4 weeks (Q4W) in OLE participants.

Methods: Eligible DB study participants were offered the opportunity to receive gantenerumab up-titrated to 1,200 mg Q4W. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring.

Results: Overall, 225 participants were rolled over from the DB part of MR and received ≥1 gantenerumab dose in the OLE. The median treatment duration was 123 weeks. Fifty-nine (26.2%) and 41 (18.2%) participants had amyloid-related imaging abnormality (ARIA)-edema and ARIA-hemorrhage MRI findings, respectively. ARIA findings were manageable with MRI monitoring and dose intervention; most were asymptomatic. There were no unexpected safety findings.

Conclusions: SC gantenerumab at doses of up to 1,200 mg Q4W were well tolerated in participants with mild AD dementia.

Keywords: Alzheimer’s disease; clinical efficacy; clinical trial; gantenerumab; safety.

Fig. 1

Overview of study design for the double-blind and OLE stages. ^aIn addition to the initial 2 years in OLE, participants were given the option to continue receiving open-label gantenerumab treatment until the end of 2020. Participants who discontinued study drug at any time during OLE or who completed the first 2 years of OLE only were asked to complete follow-up visits at 4 and 16 weeks from their last dose. Participants who received open-label gantenerumab for an additional 3 years beyond the initial 2 years of OLE were given the option of enrolling in an open-label rollover study (Open RoAD [NCT04339413]) aimed at evaluating the safety and tolerability of long-term administration of gantenerumab. Participants who rolled over to Open RoAD had one follow-up visit 4 weeks following the last dose, and those who did not had follow-up visits at 4 and 16 weeks from their last dose. DB, double-blind; OLE, open-label extension.

Fig. 2

Up-titration regimens for Marguerite RoAD OLE. MRI performed prior to each dose increase and then at regular intervals. Implementation of dosing algorithms in case of ARIA findings. ARIA, amyloid-related imaging abnormalities; APOE ɛ4, apolipoprotein E ɛ4 allele; MRI, magnetic resonance imaging; OLE, open-label extension. Adapted from Bateman RJ, et al. Alz Res Therapy 14, 178 (2022) under the terms of the Creative Commons CC BY license https://creativecommons.org/licenses/by/4.0/.

Fig. 3

Disposition of participants in the MR DB part and OLE. AE, adverse event; DB, double-blind; MR, Marguerite RoAD; OLE, open-label extension.