Solanezumab in‐depth outcomes
Authors: Farlow Martin R. , Bateman Randall J. , Aschenbrenner Andrew J. , Benzinger Tammie L.S. , Clifford David , Coalier Kelley , Cruchaga Carlos , Fagan Anne M. , Goate Alison M. , Gordon Brian A. , Hassenstab Jason , Jack Clifford R. , Koeppe Robert A. , McDade Eric , Mills Susan , Morris John C. , Salloway Stephen P. , Santacruz Anna , Snyder Peter J. , Wang Guoqiao , Xiong Chengjie , Snider B. Joy , Mummery Catherine J. , Surti Ghulam M. , Hannequin Didier , Wallon David , Berman Sarah , Lah James J. , Jiménez‐Velazquez Ivonne Z. , Roberson Erik D. , van Dyck Christopher H. , Honig Lawrence S. , Sanchez‐Valle Raquel , Brooks William S. , Gauthier Serge , Masters Colin L. , Galasko Doug R. , Brosch Jared R. , Hsiung Ging‐Yuek Robin , Jayadev Suman , Formaglio Maïté , Masellis Mario , Clarnette Roger , Pariente Jeremie , Dubois Bruno , Pasquier Florence , Andersen Scott W. , Holdridge Karen C. , Mintun Mark A. , Sims John R. , Yaari Roy ,   DIAN‐TU Study Team
Published: December 2020

AbstractBackgroundSolanezumab is a monoclonal antibody targeting soluble forms of β‐amyloid protein important in the pathogenesis of Alzheimer’s disease (AD). Three previous 18‐month double‐blind placebo‐controlled trials of low‐dose solanezumab in late‐onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly‐inherited mutation‐associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.MethodMutation‐carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 – 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double‐blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN‐MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale‐Revised, the Digit Symbol Substitution Test total score from the WAIS‐R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN‐MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β‐amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre‐specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.ResultThe topline efficacy, safety and biomarker results will be reported.ConclusionThis study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti‐amyloid therapy in sporadic AD.