Gantenerumab and solanezumab — investigational drugs for prevention of Alzheimer’s disease — demonstrated no significant impact on cognitive decline in people with dominantly inherited Alzheimer’s disease (DIAD) in a phase 2/3 clinical trial published in Nature Medicine.
DIAD is a rare form of Alzheimer's disease (AD) — estimated to represent less than 1% of cases — in which patients carry genes that predispose them to the disease. Those with DIAD exhibit characteristics that facilitate the investigation of interventions in both the asymptomatic stages of AD and its symptomatic stages, to delay or slow disease progression. These include the development of Alzheimer’s dementia at a predictable age, the presentation of pathological signs of the disease years before symptom onset, and the low likelihood of experiencing other conditions that contribute to cognitive decline.
Randall Bateman and colleagues assigned 144 people with DIAD to treatment with either gantenerumab or solanezumab or a placebo control for up to seven years. Although both drugs engaged their targets, neither was shown to significantly slow or prevent AD compared with results obtained with the placebo. The therapeutic potential of these treatments, however, remain unclear, given that the asymptomatic placebo group showed no cognitive decline. Furthermore, although the observed absence of cognitive or clinical benefit is a potential roadblock in the journey toward the development of effective drugs against AD, significant reductions in many biological features of AD in patients treated with gantenerumab suggest potential utility in the early treatment of DIAD.
The authors conclude that this trial has emphasized the need for improved and more-sensitive cognitive measures in asymptomatic populations, and the use of higher doses over longer timescales to augment drug-target engagement.
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