Gantenerumab a monoclonal antibody did not meet the primary endpoint of slowing clinical decline in patients with early Alzheimer’s disease
Gantenerumab, a fully human monoclonal IgG1 antibody, failed to meet the primary endpoint of slowing clinical decline in people with early Alzheimer’s disease (AD) in two randomised, double-blind, placebo-controlled trials according to a release by the manufacturer Roche.
It has been estimated that currently, an estimated 6.2 million Americans aged 65 and older are living with Alzheimer’s dementia. Furthermore, the World Health Organisation has estimated that there are more than 55 million people with dementia worldwide and nearly 10 million new cases every year, with Alzheimer’s disease accounting for between 60 – 70% dementia cases. The amyloid cascade hypothesis of AD proposes that deposition of the amyloid-β peptide in the brain is a central event in disease pathology and several drugs have been developed, including gantenerumab which binds with high affinity to aggregated amyloid-β species and removes amyloid-β plaques.
The potential value of gantenerumab came from a small trial in 2012, which revealed that it resulted in a dose-dependent reduction in brain amyloid levels. However, these early findings were called into question after a 2017 randomised trial with the drug in patients with prodromal AD, i.e., mild cognitive impairment, over a 2-year period, was halted early for futility. Despite this, the manufacturer Roche embarked to two global phase III trials, GRADUATE I and II designed to evaluate the safety and efficacy of gantenerumab in people with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia over 27 months. The primary endpoint of both trials was the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 116 weeks, a tool that measures cognitive and functional change across six areas including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
Gantenerumab and Alzheimer’s disease outcomes
According to the press release, 1,965 participants across 30 countries were randomised 1:1 to receive gantenerumab or placebo by subcutaneous injection and titrated to reach a target dose of 510 mg which was administered every two weeks. The results showed that while there was a slowing of clinical decline in GRADUATE I of -0.31 (p = 0.095) and -0.19 (p = 0.29) in GRADUATE II of -0.31 (p=0.0954) from baseline on CDR-SB, neither decrease was statistically significant. Additionally, the level of beta-amyloid removal was also lower than expected.
Commenting on the findings, Levi Garraway, Roche’s Chief Medical Officer and Head of Global Product Development said, ‘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.’
Nevertheless, the press release reports that Roche remains committed to Alzheimer’s disease and is continuing to develop and deliver tests to enable early and accurate Alzheimer’s diagnosis and has a pipeline of investigational medicines for different targets, types and stages of the disease.