Gantenerumab does not slow cognitive decline in early Alzheimer’s

1. In these two randomized parallel-group trials, the use of gantenerumab did not lead to slower cognitive decline over 116 weeks among persons with early symptomatic Alzheimer’s disease compared to placebo.

2. After 116 weeks, gantenerumab was associated with lower amyloid plaque burden than the placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The accumulation of aggregated amyloid-beta (Aβ) has been posited to play a significant role in the pathologic processes of Alzheimer’s disease. Monoclonal antibodies which target Aβ proteins have been developed but their efficacy in clinical trials has been equivocal. Gantenerumab, a human anti-Aβ IgG1 monoclonal antibody that removes Aβ via microglia-mediated phagocytosis, has been shown to have effects on biomarkers of Alzheimer’s disease and neurodegeneration. These two phase III trials aimed to determine the clinical and biological effects and safety of gantenerumab in the treatment of persons with early symptomatic Alzheimer’s disease. Overall, the studies showed there was no significant difference in clinical decline in the gantenerumab group versus the placebo group. The use of gantenerumab was associated with lower amyloid plaque burden, although the magnitude of plaque removal was less than expected based on previous studies. The generalizability of the findings in these trials is limited due to the lack of racial diversity in the trial population and comparisons between these trials and previous trials involving anti-amyloid antibodies are also limited due to significant differences in protocol.

Click to read the study in NEJM

Relevant Reading: Lecanemab in Early Alzheimer’s Disease

In-Depth [randomized controlled trial]: GRADUATE I and II were phase III, randomized, parallel-group trials that investigated the efficacy of gantenerumab in the treatment of early symptomatic Alzheimer’s disease. Persons 50 to 90 years of age with a Clinical Dementia Rating – Global Score (CDR-GS) of 0.5 or 1 and evidence of amyloid plaques on positron-emission tomography or cerebrospinal fluid (testing were selected, and excluded if they had other clinically significant findings on magnetic resonance imaging (MRI) which could cause cognitive impairment. Participants were randomly assigned in a 1:1 ratio to receive gantenerumab or placebo for 116 weeks and gantenerumab was administered at a prespecified dosing schedule. Participants also underwent regular MRI for assessment of amyloid-related imaging abnormalities (ARIA). The primary outcome was defined as the change in baseline in the score of the CDR-Sum of Boxes (CDR-SB) at week 116, with higher scores indicative of greater cognitive impairment. In total, 985 and 980 participants were enrolled in GRADUATE I and GRADUATE II respectively. In GRADUATE I, the primary outcome was 3.35 and 3.65 in the gantenerumab and placebo groups respectively (difference, -0.31; 95% Confidence Interval [CI], -0.66 to 0.05; p=0.10). In GRADUATE II, the primary outcome was 2.82 and 3.01 in the gantenerumab and placebo groups (difference, -0.19; 95% CI, -0.55 to 0.17; p=0.30). The difference in the adjusted mean (+/- standard error) amyloid level between the gantenerumab and placebo groups was -66.44 +/- 4.17 centiloids (95% CI, -74.71 to -58.16) and 56.46 +/- 3.98 centiloids (95% CI, -64.36 to -48.56) in GRADUATE I and GRADAUTE II, respectively. In summary, these trials demonstrated the use of gantenerumab in persons with early symptomatic Alzheimer’s disease was not associated with slower clinical decline at week 116.

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