Genentech Provides Update on Phase III GRADUATE Program Evaluating Gantenerumab in Early Alzheimer’s Disease
– Phase III GRADUATE studies did not meet their primary endpoints of slowing clinical decline in people with early Alzheimer’s –
– The level of beta-amyloid removal by gantenerumab was lower than expected –
– Topline data will be presented at the Clinical Trials on Alzheimer’s Disease Conference –
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“So many of our families have been directly affected by Alzheimer’s, so this news is very disappointing to deliver,” said
Study participants treated with gantenerumab showed a slowing of clinical decline in GRADUATE I and GRADUATE II of -0.31 (p=0.0954) and -0.19 (p=0.2998), respectively, from baseline score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB); however, neither was statistically significant. This represents a relative reduction in clinical decline of 8% in GRADUATE I and 6% in GRADUATE II compared with placebo. The CDR-SB measures cognitive and functional change across six areas including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.
The level of beta-amyloid removal, the protein that builds up to make plaques in the brains of people with Alzheimer's, was lower than expected with gantenerumab treatment.
Amyloid-related imaging abnormalities (ARIA) are a common radiological finding associated with amyloid-targeting therapies. The incidence of ARIA-E (edema or effusion) in the pooled gantenerumab arms was 25%, with the vast majority being asymptomatic and very few leading to treatment discontinuation. The incidence of isolated ARIA-H (haemosiderin) was balanced across the gantenerumab and placebo arms.
About the GRADUATE I and II studies
The Phase III GRADUATE I and II studies were two global, double-blind, randomized, placebo-controlled clinical trials evaluating the safety and efficacy of the investigational anti-amyloid monoclonal antibody gantenerumab in people with mild cognitive impairment (MCI) due to Alzheimer’s and mild Alzheimer’s dementia over 27 months. 1,965 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 two weeks. The primary endpoint was the change from baseline score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 116 weeks. The CDR-SB measures cognitive and functional change across six areas including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. There were 17 secondary endpoints including change in disease severity assessed using various neuropsychological and functional assessment tools (e.g., MMSE, ADAS-Cog, etc.), assessment of therapeutic levels of gantenerumab, incidence of adverse events, disease biomarkers and scans. A full list is available at www.clinicaltrials.gov.
Gantenerumab is a fully-human monoclonal IgG1 antibody, an investigational medicine that is subcutaneously administered and designed to target and bind to aggregated forms of beta-amyloid including oligomers, fibrils and plaques, and activate immune cells in the brain (microglia) to clear amyloid plaques and prevent further accumulation. Gantenerumab was discovered in collaboration with MorphoSys.
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