View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by AIR Universita degli studi di Milano The new england journal of medicine established in 1812 January 25, 2018 vol. 378 no. 4 Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease Lawrence S. Honig, M.D., Ph.D., Bruno Vellas, M.D., Michael Woodward, M.D., Mercè Boada, M.D., Ph.D., Roger Bullock, M.D., Michael Borrie, M.B., Ch.B., Klaus Hager, M.D., Niels Andreasen, M.D., Ph.D., Elio Scarpini, M.D., Hong Liu-Seifert, Ph.D., Michael Case, M.S., Robert A. Dean, M.D., Ph.D., Ann Hake, M.D., Karen Sundell, B.S., Vicki Poole Hoffmann, Pharm.D., Christopher Carlson, Ph.D., Rashna Khanna, M.D., Mark Mintun, M.D., Ronald DeMattos, Ph.D., Katherine J. Selzler, Ph.D., and Eric Siemers, M.D.​​ abstract BACKGROUND Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary The authors’ affiliations are listed in the tangles. The humanized monoclonal antibody solanezumab was designed to increase the Appendix. Address reprint requests to Dr. Honig at Columbia University Medi- clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the cal Center, Taub Institute for Research on synapses and precede the deposition of fibrillary amyloid. Alzheimer’s Disease and the Aging Brain, Columbia University College of Physi- METHODS cians and Surgeons, 630 W. 168th St. We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild (P&S Unit 16), New York, NY 10032-3795, dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) or at lh456@ cumc . columbia . edu. score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) N Engl J Med 2018;378:321-30. and with amyloid deposition shown by means of florbetapir positron-emission tomography DOI: 10.1056/NEJMoa1705971 Copyright © 2018 Massachusetts Medical Society. or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezu- mab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no sig- nificant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P = 0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on mag- netic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer’s disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.) n engl j med 378;4 nejm.org January 25, 2018 321 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI MILANO on January 25, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. The new england journal of medicine he neuropathological hallmarks and the Alzheimer’s Disease and Related Disor- of Alzheimer’s disease include extracellu- ders Association.7 The exclusion criteria have been Tlar plaques containing amyloid beta (Aβ) described previously.5,6 Unlike the EXPEDITION and intracellular neurofibrillary tangles contain- and EXPEDITION2 trials, the EXPEDITION3 trial ing hyperphosphorylated tau protein,1 along with included only patients with mild Alzheimer’s synaptic and neuronal losses.2 The Aβ hypothe- disease who had biomarker evidence of amyloid- sis of the mechanism of Alzheimer’s disease pro- related disease, determined by means of either poses that early pathogenesis of the disease re- florbetapir positron-emission tomography (PET) sults from the overproduction of or reduced scan or Aβ1-42 measurements in cerebrospinal clearance of Aβ, leading to the formation of fluid (CSF). oligomers, fibrils, and neuritic Aβ plaques.3,4 Patients were randomly assigned in double- Treatments that slow the production of Aβ or blind fashion to receive intravenous infusions of that increase the clearance of Aβ may slow the either solanezumab at a dose of 400 mg or pla- progression of Alzheimer’s disease. Solanezumab, cebo every 4 weeks for 76 weeks. Patients who a humanized immunoglobulin G1 monoclonal completed the double-blind period could partici- antibody that binds to the mid-domain of the pate in an optional 24-month open-label period. Aβ peptide, was designed to increase clearance Concomitant therapy, including treatments for from the brain of soluble Aβ, peptides that may symptoms of dementia (acetylcholinesterase in- lead to toxic effects in the synapses at a stage hibitors and memantine, alone or in combination) before the deposition of the fibrillary form of and nondrug treatments, was allowed in order the protein. to ensure that patients continued receiving the In two completed phase 3 clinical trials standard of care for Alzheimer’s disease. This (EXPEDITION and EXPEDITION2), solanezumab article includes only the results from the double- did not significantly reduce the decline in cogni- blind, placebo-controlled period of the trial. The tion or function (e.g., activities of daily living and primary objective of the trial was to test the hy- community involvement) in patients who had pothesis that solanezumab would slow the cogni- received a clinical diagnosis of mild-to-moderate tive decline of Alzheimer’s disease, as compared Alzheimer’s disease.5 However, in prespecified with placebo, in patients with mild dementia pooled secondary analyses, patients with mild due to Alzheimer’s disease. Alzheimer’s disease who were treated with solanez- umab had less cognitive decline by approximately Safety Assessments 34% and less functional decline by approximate- Key safety assessments included routine physical ly 18% than did patients who received placebo.6 and neurologic examinations, routine clinical We report the results of a third double-blind, laboratory assessment, and the collection of placebo-controlled phase 3 trial (EXPEDITION3), adverse-event data. Magnetic resonance imaging which enrolled only patients who had mild Alz- (MRI) was used to detect any evidence of amyloid- heimer’s disease, defined as a Mini–Mental State related imaging abnormalities for either hemor- Examination (MMSE) score of 20 to 26 (on a rhage or hemosiderin deposition (cerebral micro- scale from 0 to 30, with higher scores indicating hemorrhage or hemosiderosis) or edema or better cognition), and had biomarker evidence of effusions (vasogenic edema). Adverse events that cerebral beta-amyloid deposition. This trial was are associated with immunogenicity or antidrug intended to further investigate the secondary ef- antibodies were evaluated. Additional safety as- ficacy analyses from the earlier two trials. sessments are described in the protocol, avail- able with the full text of this article at NEJM.org. Methods Outcome Measures Patient Population and Trial Design The primary efficacy measure was the change This international trial included male and female from baseline to 80 weeks in the score on the patients, 55 to 90 years of age, who met the diag- 14-item cognitive subscale of the Alzheimer’s nostic criteria for probable Alzheimer’s disease Disease Assessment Scale (ADAS-cog14; scores according to the National Institute of Neuro- range from 0 to 90, with higher scores indicat- logical and Communicative Disorders and Stroke ing greater cognitive impairment).8,9 Key second- 322 n engl j med 378;4 nejm.org January 25, 2018 The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI MILANO on January 25, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Solanezumab for Dementia Due to Alzheimer’s Disease ary efficacy measures included scores on the fol- at and after baseline. All the tests of effects were lowing assessments: the MMSE10; the Alzheimer’s conducted at a two-sided alpha level of 0.05, un- Disease Cooperative Study (ADCS) Activities of less otherwise specified. Patients who did not Daily Living Inventory (ADCS-ADL; scores range have a postbaseline measure were not included from 0 to 78, with lower scores indicating greater in the analyses. Additional details, including in- functional impairment); the ADCS instrumental formation about the weighted imputation meth- subscale (ADCS-iADL), which assesses complex ods for missing data, are provided in the statisti- activities such as using public transportation, cal analysis plan (see the protocol). managing finances, or shopping (scores range Randomization of the patients was stratified from 0 to 56, with