Treatment with the monoclonal antibody (mAb) gantenerumab (Genentech, South San Francisco, CA; Roche, Basel, Switzerland) was associated with a lower amyloid plaque burden in people with early Alzheimer disease (AD), but it did not slow cognitive decline after 116 weeks. These findings are from the phase 3 GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) clinical trials which were published in The New England Journal of Medicine.
Gantenerumab is a fully human, anti-Aβ immunoglobulin G1 (IgG1) mAb that is delivered subcutaneously. It has a higher affinity for aggregated Aβ than any mAb previously tested for the treatment of AD. The phase 3 GRADUATE I and GRADUATE II clinical trials included 985 and 980 participants, respectively, aged 50 to 90 years with mild cognitive impairment or mild dementia due to AD and evidence of amyloid plaques based on PET or cerebrospinal fluid (CSF) testing.
- Participants were randomized to receive either gantenerumab or placebo by subcutaneous injection once every 2 weeks.
- The primary outcome was change in Clinical Dementia Rating (CDR) scale Sum of Boxes (SB) score from baseline to week 116.
- Changes from baseline in CSF or PET scan amyloid levels also were measured.
In terms of results:
- At week 116, participants in GRADUATE I treated with gantenerumab showed a change from baseline in CDR-SB score of 3.35, while the placebo-treated participants showed a change of 3.65 (difference, -0.31; 95% CI, -0.66 to 0.05; P=.10).
- In GRADUATE II, the change from baseline was 2.82 with gantenerumab and 3.01 with placebo (difference, -0.19; 95% CI, -0.55 to 0.17; P=0.30). The difference in clinical decline was not statistically significant.
- Gantenerumab-treated participants in GRADUATE I and GRADUATE II showed a difference in amyloid level of -66.44 and -56.46 centiloids respectively, compared to placebo, and 28% and 26.8% of participants in GRADUATE I and GRADUTE II respectively reached amyloid-negative status.
- In both trials, participants treated with gantenerumab showed lower CSF levels of phosphorylated tau 181 (p-tau181) and higher levels of Aβ42, and 24.9% of participants who received gantenerumab presented with amyloid-related imaging abnormalities with edema (ARIA-E).
“We are profoundly grateful to the study participants, their care partners and study sites for their contributions to this research,” said Levi Garraway, MD, PhD, Chief Medical Officer and Head of Global Product Development at Genentech. “While the GRADUATE results are not what we hoped, we are proud to have delivered a high quality, clear and comprehensive Alzheimer’s dataset to the field, and we look forward to sharing our learnings with the community as we continue to search for new treatments for this complex disease.”
The findings from the GRADUATE I and GRADUATE II clinical trials highlights the importance of research into the relationship between Aβ and clinical decline in AD.