{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:35:57Z","timestamp":1789763757320,"version":"4.0.1"},"reference-count":64,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,4,19]],"date-time":"2020-04-19T00:00:00Z","timestamp":1587254400000},"content-version":"vor","delay-in-days":109,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The search for drugs to treat Alzheimer's disease (AD) has failed to yield effective therapies. Here we report the first genome\u2010wide search for biomarkers associated with therapeutic response in AD. Blarcamesine (ANAVEX2\u201073), a selective sigma\u20101 receptor (SIGMAR1) agonist, was studied in a 57\u2010week Phase 2a trial (NCT02244541). The study was extended for a further 208\u00a0weeks (NCT02756858) after meeting its primary safety endpoint.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Safety, clinical features, pharmacokinetic, and efficacy, measured by changes in the Mini\u2010Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study\u2010Activities of Daily Living scale (ADCS\u2010ADL), were recorded. Whole exome and transcriptome sequences were obtained for 21 patients. The relationship between all available patient data and efficacy outcome measures was analyzed with unsupervised formal concept analysis (FCA), integrated in the Knowledge Extraction and Management (KEM) environment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Biomarkers with a significant impact on clinical outcomes were identified at week 57: mean plasma concentration of blarcamesine (slope MMSE:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.041), genomic variants SIGMAR1 p.Gln2Pro (\u0394MMSE:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.039; \u0394ADCS\u2010ADL:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.063) and COMT p.Leu146fs (\u0394MMSE:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.039; \u0394ADCS\u2010ADL:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.063), and baseline MMSE score (slope MMSE:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a0.015). Their combined impact on drug response was confirmed at week 148 with linear mixed effect models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Confirmatory Phase 2b\/3 clinical studies of these patient selection markers are ongoing. This FCA\/KEM analysis is a template for the identification of patient selection markers in early therapeutic development for neurologic disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.12013","type":"journal-article","created":{"date-parts":[[2020,4,19]],"date-time":"2020-04-19T22:39:48Z","timestamp":1587335988000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2\u201073) Phase 2a clinical study"],"prefix":"10.1002","volume":"6","author":[{"given":"Harald","family":"Hampel","sequence":"first","affiliation":[{"name":"Sorbonne University GRC n\u00b0 21, Alzheimer Precision Medicine (APM) AP\u2010HP, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital Boulevard de l'h\u00f4pital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coralie","family":"Williams","sequence":"additional","affiliation":[{"name":"Ariana Pharmaceuticals  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Etcheto","sequence":"additional","affiliation":[{"name":"Ariana Pharmaceuticals  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Goodsaid","sequence":"additional","affiliation":[{"name":"Regulatory Pathfinders LLC  San Juan Puerto Rico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Parmentier","sequence":"additional","affiliation":[{"name":"Ariana Pharmaceuticals  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Sallantin","sequence":"additional","affiliation":[{"name":"Laboratoire d'Intelligence Artificielle LIRMM, CNRS  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Anavex Life Sciences Corp.  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