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      A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

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          Abstract

          Background

          Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD).

          Methods

          In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose.

          Results

          Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints.

          Conclusions

          The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy.

          Trial registration

          ClinicalTrials.gov, NCT01224106. Registered on October 14, 2010.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13195-017-0318-y) contains supplementary material, which is available to authorized users.

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          Most cited references12

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          Alzheimer's disease.

          Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
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            Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials

            Background Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer’s disease (AD). Methods Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale and the Disability Assessment for Dementia. Results A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event. Conclusions These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed. Trial registration Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143; registered 2 May 2008. Electronic supplementary material The online version of this article (doi:10.1186/s13195-016-0189-7) contains supplementary material, which is available to authorized users.
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              Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.

              Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.

                Author and article information

                Contributors
                ostrowitzki.susanne@gene.com
                robert.lasser@medday-pharma.com
                edorflinger@gmail.com
                p.scheltens@vumc.nl
                f.barkhof@vumc.nl
                tania.nikolcheva@roche.com
                elizabeth.ashford@roche.com
                sylvie.retout@roche.com
                carsten.hofmann@roche.com
                paul.delmar@roche.com
                gregory.klein@roche.com
                mirjana.andjelkovic@roche.com
                bruno.dubois@psl.aphp.fr
                mboada@fundacioace.com
                kaj.blennow@neuro.gu.se
                luca.santarelli@therachon.com
                paulo.fontoura@roche.com
                Journal
                Alzheimers Res Ther
                Alzheimers Res Ther
                Alzheimer's Research & Therapy
                BioMed Central (London )
                1758-9193
                8 December 2017
                8 December 2017
                2017
                : 9
                : 95
                Affiliations
                [1 ]ISNI 0000 0004 0534 4718, GRID grid.418158.1, Product Development, , Neuroscience, Genentech Inc., ; South San Francisco, CA USA
                [2 ]MedDay Pharmaceuticals, Boston, MA USA
                [3 ]Formerly Roche Translational & Clinical Research Center, New York, NY USA
                [4 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, VU University Medical Center, ; Amsterdam, The Netherlands
                [5 ]ISNI 0000000121901201, GRID grid.83440.3b, Institute of Neurology, UCL, ; London, UK
                [6 ]Roche Pharma Research and Early Development, NORD, Basel, Switzerland
                [7 ]GRID grid.419227.b, Roche Products Limited, ; Welwyn Garden City, UK
                [8 ]Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center, Basel, Switzerland
                [9 ]Clinical Pharmacology and Bioanalytical R&D, Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
                [10 ]Alzheimer Institute and ICM, UMR-S975, Salpêtrière University Hospital, AP-HP, Pierre and Marie Curie University, Paris, France
                [11 ]Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
                [12 ]Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
                [13 ]Formerly Roche Pharma Research and Early Development, NORD, Basel, Switzerland
                Article
                318
                10.1186/s13195-017-0318-y
                5723032
                29221491
                333a64d4-0d42-4e27-abb4-a2e12ea1a5b3
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 July 2017
                : 30 October 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007013, F. Hoffmann-La Roche;
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Neurology
                gantenerumab,alzheimer’s disease,scarlet road
                Neurology
                gantenerumab, alzheimer’s disease, scarlet road

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