Journal Article

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Formaglio, Maité, Masellis, Mario, Hannequin, Didier, Sánchez-Valle, Raquel, Berman, Sarah B., Jack, Clifford R., Dubois, Bruno, Wendelberger, Barbara A., Holdridge, Karen C., Mintun, Mark A., Clifford, David B., Cruchaga, Carlos, Hsiung, Ging-Yuek Robin, Mills, Susan L., Gordon, Brian A., Salloway, Stephen, Jayadev, Suman, Sims, John R., Kerchner, Geoffrey A., Wallon, David, Andersen, Scott W., Lah, James J., Giacobino, Caroline, Thomas, Ronald G., Brooks, William S., Perrin, Richard J., Bateman, Randall J., Coalier, Kelley A., Fontoura, Paulo, van Dyck, Christopher H., Berry, Scott M., Brosch, Jared R., Koeppe, Robert, Fagan, Anne M., Snider, B. Joy, Roberson, Erik D., McDade, Eric, Hitchcock, Janice M., Gauthier, Serge, Surti, G. Mustafa, Llibre-Guerra, Jorge J., Mummery, Catherine, Doody, Rachelle S., Aisen, Paul S., Baudler, Monika, Xiong, Chengjie, Wang, Guoqiao, Hassenstab, Jason, Li, Yan, Aschenbrenner, Andrew J., Pasquier, Florence, Snyder, Peter J., Masters, Colin L., Santacruz, Anna M., Honig, Lawrence S., Benzinger, Tammie L. S., Jimenez-Velazquez, Ivonne Z., Galasko, Douglas R., Yaari,

2021

Overview

Dominantly inherited Alzheimer’s disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4–7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses. Results from the phase 2/3 clinical trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease reveal no beneficial effects on cognitive measures despite a significant reduction in amyloid plaques and other key biomarkers in those treated with gantenerumab.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/308/2779/777 / 692/617/375/132/1283 / Abnormalities / Adult / Alzheimer Disease / Alzheimer Disease - drug therapy / Alzheimer Disease - genetics / Alzheimer Disease - psychology / Alzheimer's disease / Amyloid / Amyloid beta-Peptides / Amyloid beta-Peptides - cerebrospinal fluid / Antibodies, Monoclonal, Humanized / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - therapeutic use / Asymptomatic / Biomarkers / Biomarkers - cerebrospinal fluid / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Cerebrospinal fluid / Clinical trials / Cognitive ability / Disease Progression / Dose-Response Relationship, Drug / Drug therapy / Edema / Female / Humans / Infectious Diseases / Life Sciences / Male / Metabolic Diseases / Middle Aged / Molecular Medicine / Mutation / Neurodegenerative diseases / Neurosciences / Placebos / Senile plaques / Signs and symptoms / Tau protein