Efficacy, Safety and Biomarker Data from SCarlet RoAD - A Global Phase 3 Study of Gantenerumab in Patients with Prodromal AD (S1.002)

Objective: SCarlet RoAD (NCT01224106; WN25203) was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-year study testing the efficacy and safety of gantenerumab in prodromal AD. Background: Gantenerumab is a human, anti-Aβ monoclonal antibody that binds with high affinity to aggregated Aβ. Methods: Patients were 50-85 years old with MMSE scores ≥24, CDR-Global scores of 0.5 (memory box scores of 0.5 or 1.0) and evidence of amyloid pathology (CSF Aβ42 <600 pg/mL, Innotest®), with cognition and functional performance largely preserved—excluding a diagnosis of AD dementia. 799 patients were randomized to monthly subcutaneous injections of placebo, or 105 mg or 225 mg gantenerumab, depending on APOEε4 allele status (APOEε4 homozygotes received 105 mg or placebo). 114 patients were enrolled in a PET sub-study. Results: Gantenerumab and placebo treatment groups were not different in the primary endpoint (CDR-SB scores over 2 years). An exposure-dependent trend was shown for clinical benefit in patients predicted to have a faster progression rate. Serious adverse events were reported in 19.5[percnt], 17.3[percnt] and 16.9[percnt] of patients in the placebo, 105 mg and 225 mg gantenerumab arms, respectively. ARIA were dose- and APOEε4 allele-dependent. Amyloid-PET standardized uptake value (SUVr), using mean cerebellar gray as reference region, showed a dose-dependent reduction from baseline. CSF analyses found dose-dependent reductions in CSF p-Tau and t-Tau, but no changes in Aβ42 levels. Conclusions: Gantenerumab was well tolerated by patients with prodromal AD. Although no significant differences in primary efficacy endpoints between treatment arms were observed, gantenerumab was associated with an exposure-dependent clinical benefit in patients predicted to progress faster, and dose-dependent reductions in brain Aβ SUVr and CSF p-Tau and t-Tau. These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration. Study Supported by: F.