Long-term gantenerumab Alzheimer's trial halted due to 'no regulatory path'

 Washington University School of Medicine led a study evaluating long-term gantenerumab treatment in individuals with dominantly inherited Alzheimer's disease (DIAD). Gantenerumab was associated with serious safety concerns, including a high incidence of brain bleeding and swelling, possibly leading to an early study termination.

Alzheimer's disease is a neurodegenerative disorder characterized by amyloid β plaque accumulation, which has been hypothesized to play a key role in disease progression. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) launched an initial prevention trial in 2012 to investigate anti-amyloid monoclonal antibodies, including gantenerumab, in asymptomatic and mildly symptomatic DIAD mutation carriers.

Previous studies showed that gantenerumab reduced amyloid plaques but did not significantly slow cognitive decline in symptomatic participants. These findings led to an open-label extension (OLE) study to determine whether higher doses of gantenerumab could fully remove amyloid plaques and delay clinical progression.

In the study, "Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease," published in The Lancet Neurology, researchers conducted an open-label extension following a randomized, double-blind, placebo-controlled, multicenter trial.

Participants had previously received gantenerumab, solanezumab, or placebo and were eligible for the OLE if they knew their genetic mutation status. Treatment sites were located across eight countries, including the United States, United Kingdom, Canada, France, Spain, and Australia.

Probability of progression in CDR Global and CDR-SB estimated from the Cox proportional hazards model. Credit: The Lancet Neurology (2025). DOI: 10.1016/S1474-4422(25)00024-9

A total of 73 participants received gantenerumab in the OLE. Thirteen completed the full three-year treatment period. Another 13 withdrew due to adverse events or disease progression. When the study was halted for safety reasons, 47 participants were still in the process of receiving treatment.

Amyloid-related imaging abnormalities were detected by MRI in 39 participants and included small brain bleeds (microhemorrhages), and swelling of brain tissue (cerebral edema). Two participants developed cortical blindness, requiring hospitalization before symptoms resolved.

Primary outcomes were to focus on amyloid plaque removal. Secondary outcomes included clinical dementia rating progression and biomarker changes in cerebrospinal fluid.

In a final ad hoc analysis of 55 participants, including some who discontinued early, amyloid plaque burden was significantly reduced, yet clinical measures did not show statistically significant improvements in cognitive function or dementia progression.

More information: Randall J Bateman et al, Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial, The Lancet Neurology (2025). DOI: 10.1016/S1474-4422(25)00024-9

Jonathan M Schott, Amyloid immunotherapy to prevent Alzheimer's disease: the wrong drug at the right time?, The Lancet Neurology (2025). DOI: 10.1016/S1474-4422(25)00066-3

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