Clinical Pearls & Morning Reports
Published November 15, 2023
Bateman et al. conducted two randomized, placebo-controlled phase 3 trials (GRADUATE I and II) to determine the clinical and biologic effects and safety of gantenerumab in persons with early symptomatic Alzheimer’s disease, defined as mild cognitive impairment or mild dementia due to Alzheimer’s disease. Read the NEJM Original Article here.
Q: What is gantenerumab?
A: Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ, including oligomers, fibrils, and plaques. It removes Aβ through microglia-mediated phagocytosis, promotes amyloid plaque clearance, and has been shown to have effects on biomarkers of Alzheimer’s disease and neurodegeneration.
Q: Did gantenerumab reduce the amyloid plaque burden in the trials by Bateman et al.?
A: The amyloid level on positron-emission tomography at week 116 among participants receiving gantenerumab was lower than the level among those receiving placebo. The mean (±SD) amyloid level at week 116 was 40.68±27.39 and 104.44±33.15 centiloids in the gantenerumab and placebo groups, respectively, in the GRADUATE I trial and 44.85±26.67 and 99.52±27.72 centiloids in the gantenerumab and placebo groups, respectively, in the GRADUATE II trial.
A: In these trials, there was no significant difference between the gantenerumab group and the placebo group in the primary clinical outcome, the change from baseline in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) score at week 116. In the GRADUATE I trial, the estimated mean change from baseline in the CDR-SB score at week 116 was 3.35 in the gantenerumab group and 3.65 in the placebo group (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10). In the GRADUATE II trial, the change was 2.82 in the gantenerumab group and 3.01 in the placebo group (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30).
A: The incidence of ARIA-E overall was 24.9% with gantenerumab and 2.7% with placebo, and the incidence approximately doubled with each APOE ɛ4 allele present. Most cases of ARIA-E were asymptomatic; 5.0% of the participants receiving gantenerumab had ARIA-E temporally associated with central nervous system symptoms, whereas only 0.2% of the participants receiving placebo had symptomatic ARIA-E. The most common symptoms associated with ARIA-E were headache and dizziness. In the gantenerumab group, there were cases of serious symptomatic ARIA-E (in 11 participants), ARIA-E that led to permanent discontinuation of gantenerumab (in 2 participants), and ARIA-E that led to permanent discontinuation of the trial (in 4 participants), but no deaths were associated with ARIA-E.