The two phase 3 trials, GRADUATE I and II, explored the potential of gantenerumab, a monoclonal antibody targeting amyloid-beta, in slowing cognitive decline in individuals with early-stage Alzheimer's disease. The findings were published in The New England Journal of Medicine.
These trials involved a total of 1,965 participants aged 50 to 90 with mild cognitive impairment or mild dementia linked to Alzheimer's disease. The primary focus was the change in the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB) score at week 116. The results indicated a lower amyloid plaque burden in participants receiving gantenerumab. However, the treatment did not exhibit a significant impact on the rate of cognitive decline.

In the GRADUATE I trial, the change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with the placebo, showing a non-significant difference of –0.31 (95% confidence interval [CI], –0.66 to 0.05; P=0.10). Similarly, in the GRADUATE II trial, the difference was –0.19 (95% CI, –0.55 to 0.17; P=0.30).
Also, at week 116, the gantenerumab group exhibited a notably lower amyloid level on PET scans compared to the placebo group. Amyloid-negative status was achieved in 28.0% and 26.8% of participants in the two trials, further highlighting the antibody's potential impact.
Despite these positive findings, concerns are up regarding the safety of gantenerumab. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of participants receiving gantenerumab, with symptomatic ARIA-E reported in 5.0% of cases.
While gantenerumab demonstrated efficacy in reducing amyloid plaque burden, the trials did not establish a significant association with slower clinical decline. The results underscore the complexity of Alzheimer's disease and the ongoing challenges in developing effective treatments. The findings can possibly open avenues with continued research, emphasizing the need for innovative strategies to combat this pervasive and debilitating condition.
Source:
Bateman, R. J., Smith, J., Donohue, M. C., Delmar, P., Abbas, R., Salloway, S., Wojtowicz, J., Blennow, K., Boada, M., Watson, D., Woodward, M., Thanasopoulou, A., … Doody, R. S. (2023). Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease. In New England Journal of Medicine (Vol. 389, Issue 20, pp. 1862–1876). Massachusetts Medical Society. https://doi.org/10.1056/nejmoa2304430