Gantenerumab Not Found to Slow Clinical Decline in Early Alzheimer Disease

Gantenerumab did not meet the primary endpoint of a statistically significant slowing of clinical decline in patients with mild cognitive impairment (MCI) due to Alzheimer disease and mild Alzheimer dementia, according to results from the GRADUATE I and II studies. In terms of safety, gantenerumab was well-tolerated, including via subcutaneous administration.

Gantenerumab is an investigational fully human monoclonal IgG1 antibody. The drug is designed to target and bind to aggregated forms of beta-amyloid, including oligomers, fibrils and plaques, and activate immune cells in the brain to eliminate amyloid plaques and prevent further accumulation.

“So many of our families have been directly affected by Alzheimer’s, so this news is very disappointing to deliver,” said Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, in a press release. “We are profoundly grateful to the study participants, their care partners and study sites for their contributions to this research. 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.”

Patients enrolled in the study administered gantenerumab did experience reduced clinical decline in GRADUATE 1 and GRADUATE 2, respectively, from the baseline score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB); however, neither of these were deemed statistically significant.

The 2 global, double-blind, randomized, placebo-controlled clinical trials evaluated the safety and efficacy of gantenerumab in patients with MCI due to Alzheimer and mild Alzheimer dementia over 27 months. In total, 1965 study participants across 30 countries were randomized 1:1 to receive gantenerumab or placebo by subcutaneous injection titrated to reach a target dose of 510 mg administered every 2 weeks.

The data showed a relative reduction in clinical decline of 8% in GRADUATE 1 and 6% in GRADUATE 2 vs placebo. The CDR-SB measures cognitive and functional change across 6 areas including memory, orientation, judgment, and problem solving, community affairs, home and hobbies, and personal care.

A common radiological finding associated with amyloid-targeting therapies is amyloid-related imaging abnormalities (ARIA), and the incidence of ARIA-E (oedema or effusion) in the pooled gantenerumab arms was 25%. The majority of these are asymptomatic and very few lead to treatment discontinuation. Further, the incidence of ARIA-H (haemosiderin) was balanced across the gantenerumab and placebo groups.

Roche said it will continue developing tests to enable early and accurate diagnosis of Alzheimer disease and will continue investigating treatments for the different targets, types, and stages of the disease.

REFERENCE

Roche provides update on Phase III GRADUATE programme evaluating gantenerumab in early Alzheimer’s disease. Roche. November 14, 2022. Accessed November 15, 2022. https://www.roche.com/media/releases/med-cor-2022-11-14