Long-term use of gantenerumab in individuals with dominantly inherited Alzheimer’s disease (DIAD) may slow clinical decline, according to findings from an open-label extension (OLE) of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) platform trial.

While clinical effects were limited during short-term or partial amyloid removal, extended treatment appeared to be associated with delayed symptom onset, though the trial's early termination limits interpretation.

The OLE study, which was published in the Lancet followed DIAN-TU-001, a multicenter, randomized, double-blind phase 2/3 trial that compared solanezumab or gantenerumab against placebo in mutation carriers up to 15 years before or 10 years after their estimated symptom onset. Participants were eligible for the OLE if they completed the blinded study and had confirmed knowledge of their mutation status. All received subcutaneous gantenerumab at doses up to 1,500 mg every two weeks.
Out of 74 participants recruited between June 2020 and April 2021, 73 received treatment, but only 13 completed the full three years. Most discontinued due to the sponsor’s early termination of the trial, triggered by a prespecified interim analysis that indicated limited clinical benefit.

At the final analysis, long-term treatment led to a significant reduction in brain amyloid levels, measured by PiB-PET SUVR, with a mean decrease of –0.71 (95% CI –0.88 to –0.53, p< 0.0001). Safety findings were consistent with known risks of anti-amyloid antibodies: 53% of participants experienced amyloid-related imaging abnormalities, primarily microhemorrhages and edema, but no macrohemorrhages or treatment-related deaths were reported.

The authors, including principal investigator professor Randall J. Bateman of Washington University School of Medicine, noted that while the findings suggest potential benefit from sustained amyloid removal, the use of external controls and the OLE study design limit definitive conclusions. Further trials with longer durations and robust control groups are needed to confirm whether gantenerumab can delay progression in asymptomatic individuals at genetic risk for Alzheimer’s disease.

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