Randy Bateman, MD, speaks with research technician Olatayo Ajenifuja about Alzheimer’s disease research. [Image courtesy of Matt Miller/Washington University School of Medicine]
A study published in the Lancet details the research from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) open-label extension study. The extension study, originally slated for three years, was cut short in mid-2023 following Roche/Genentech’s decision to discontinue gantenerumab development after the Phase 3 GRADUATE trials failed to meet their primary endpoint of slowing clinical decline. Despite this setback, participants with autosomal-dominant AD mutations who received higher doses over extended periods showed promising results.
While initial results from the blinded phase of this trial showed that gantenerumab substantially reduced brain amyloid plaques and altered Alzheimer’s biomarkers, no clear cognitive benefit emerged during the original study period
The Lancet study found that participants who received gantenerumab the longest (average 8.4 years) showed a 47% drop in the risk of developing symptomatic Alzheimer’s disease compared to controls (hazard ratio 0.53, 95% CI 0.29 to 0.97). While the initial analysis narrowly missed conventional statistical significance (p=0.07), supportive analyses that included additional participants strengthened the finding to statistical significance (p=0.04). This represents the first evidence from a clinical trial that long-term amyloid removal before symptom onset may delay the development of Alzheimer’s dementia. The effect was specific to those treated earliest and longest—participants who received gantenerumab for only two to three years showed no significant difference in cognitive outcomes compared to controls. The data suggests that robust and sustained amyloid removal beginning years before symptom onset is necessary for meaningful clinical benefit.
In the DIAN-TU open-label extension, gantenerumab’s safety largely mirrored that of other anti-amyloid antibodies, with roughly 30% of participants experiencing amyloid-related imaging abnormalities (ARIA), mostly mild brain edema or microhemorrhages detectable only on MRI scans. Two individuals developed more severe ARIA-E symptoms but recovered upon stopping treatment. The researchers noted no fatal or permanently disabling ARIA events. In the aforementioned GRADUATE Phase 3 trials, which led to an early termination of the DIAN-TU extension, participants had been on high-dose gantenerumab for about 2.6 years, rather than the planned three. To sustain amyloid clearance, most were subsequently transitioned to lecanemab, a newer anti-amyloid antibody that would win FDA approval for early Alzheimer’s.
Filed Under: Neurological Disease
