A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.

Abstract

BACKGROUND:

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).

METHODS:

In 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.

RESULTS:

Of 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.

CONCLUSIONS:

The 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 REGISTRATION:

ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.

• Authors: Susanne Ostrowitzki, Robert A Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten Hofmann, Paul Delmar, Gregory Klein, Mirjana Andjelkovic, Bruno Dubois, Mercè Boada, Kaj Blennow, Luca Santarelli, Paulo Fontoura, SCarlet RoAD Investigators
• Journal: Alzheimer's research & therapy (Alzheimers Res Ther) Vol. 9 Issue 1 Pg. 95 (Dec 08 2017) ISSN: 1758-9193 [Electronic] England
• PMID: 29221491 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Amyloid beta-Peptides
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Apolipoprotein E4
• Immunologic Factors
• gantenerumab

Topics

• Aged
• Alzheimer Disease (diagnostic imaging, drug therapy, genetics)
• Amyloid beta-Peptides (cerebrospinal fluid)
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Apolipoprotein E4 (genetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Humans
• Immunologic Factors (therapeutic use)
• Longitudinal Studies
• Magnetic Resonance Imaging
• Middle Aged
• Neuropsychological Tests
• Positron-Emission Tomography
• Prodromal Symptoms
• Psychiatric Status Rating Scales
• Treatment Outcome