Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease
Data from GRADUATE I (n=985; baseline CDR-SB score 3.7) and II (n=980; score 3.6) trials show use of gantenerumab was not associated with slower clinical decline at 116 weeks (change from baseline vs placebo = 3.35 vs 3.65; p=0.10 and 2.82 vs 3.01; p=0.30, respectively).
Source:
New England Journal of Medicine
SPS commentary:
Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer’s disease.
The primary outcome in the trials was the change from baseline in the score on the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116.
An editorial expresses surprise that these two phase 3 trials did not show significant benefits, given that gantenerumab is similar to aducanumab and lecanemab. It discusses methodological limitations of the trials and concludes that the gantenerumab trials add to the evidence of variable, small clinical effects of antiamyloid antibodies. It suggests that depending on the perspective, the results of the antibody trials to date either reinforce confidence in this therapeutic approach and its clinical meaningfulness or support a view that the effects are small, unreliable, and barely distinguishable from no effect. It adds that if a meaningful effect is not apparent after 1.5 to 2 years of treatment, there may be hope that it manifests in the future. It notes that the completion of preclinical prevention trials of lecanemab and donanemab, in which participants without cognitive impairment who have positive biomarkers of Alzheimer’s disease are receiving treatment for several years, is planned for 2027.