Abstract Details

Gantenerumab is a subcutaneous fully-human monoclonal antibody that binds to aggregated amyloid-beta species, including oligomers, fibrils, and plaques.

GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27-month, global, Phase III, randomized, placebo-controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).

Eligible participants (50–90 years) with early AD were randomized 1:1 to receive subcutaneous gantenerumab or placebo, administered at the study site or at home. A universal titration scheme for all participants receiving gantenerumab, irrespective of apolipoprotein E ε4 (APOEε4) genotype, allowed participants to reach a target dose of 510 mg gantenerumab every 2 weeks. This titration maximizes gantenerumab exposure while balancing amyloid removal and amyloid-related imaging abnormalities (ARIA) risk for all individuals. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR-SB; higher scores indicate greater impairment). Secondary confirmatory and exploratory efficacy endpoints, tau and amyloid positron emission tomography, cerebrospinal fluid and plasma biomarkers, were also assessed.

GRADUATE I and II enrolled 985 and 980 participants, respectively. Change from baseline in CDR-SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% CI –0.66 to 0.05) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17). The difference between gantenerumab and placebo groups in amyloid reduction at Week 116 was –66.57 (standard error [SE] 4.13) centiloids for GRADUATE I and –56.52 (SE 3.96) centiloids for GRADUATE II. ARIA-edema (ARIA-E) occurred with gantenerumab; ARIA-E were manageable and mostly asymptomatic.

Gantenerumab did not slow decline in participants with early AD. Clinical benefit may require sufficient amyloid plaque removal; however, the parameters remain to be defined.