Abstract
BackgroundGantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD).MethodsIn this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose.ResultsOf the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints.ConclusionsThe study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy.Trial registrationClinicalTrials.gov, NCT01224106. Registered on October 14, 2010.
Highlights
Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis
Because cerebrospinal fluid (CSF) levels of Aβ42 have been found to be low in prodromal Alzheimer’s disease (AD) [6], CSF testing for low Aβ42 levels was required for inclusion in the SCarlet RoAD study
In the SCarlet RoAD study, we investigated the effects of 105 mg or 225 mg of SC gantenerumab or placebo given every 4 weeks in patients with prodromal AD
Summary
Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD). Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain. Clinical progression has been reported to follow a predictable pattern, with patients transitioning through a preclinical stage, followed by a prodromal stage characterized by biomarker findings indicative of accumulating disease burden and cognitive symptoms not of sufficient severity to impact patient functioning, and eventually reaching the dementia stage. Prior to the initiation of the SCarlet RoAD study (NCT01224106; WN25203), researchers in most clinical trials identified patients with mild cognitive impairment (MCI) using clinical criteria, such as an episodic memory deficit or Clinical Dementia Rating (CDR) global score. Because cerebrospinal fluid (CSF) levels of Aβ42 have been found to be low in prodromal AD [6], CSF testing for low Aβ42 levels was required for inclusion in the SCarlet RoAD study
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.