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).

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

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.