{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:58:38Z","timestamp":1793825918931,"version":"4.6.1"},"reference-count":102,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    p75 neurotrophin receptor (p75\n                    <jats:sup>NTR<\/jats:sup>\n                    ) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75\n                    <jats:sup>NTR<\/jats:sup>\n                    with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200\u2009mg LM11A-31 and 400\u2009mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug\u2013placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75\n                    <jats:sup>NTR<\/jats:sup>\n                    with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrialsregister.eu\/ctr-search\/search?query=eudract_number:2015-005263-16\">2015-005263-16<\/jats:ext-link>\n                    ; ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03069014\">NCT03069014<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-02977-w","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T06:02:06Z","timestamp":1715925726000},"page":"1761-1770","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4502-7170","authenticated-orcid":false,"given":"Hayley R. 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E.M.R. is a compensated scientific advisor to Alzheon, Aural Analytics, Cognition Therapeutics, Denali, Enigma, Retromer Therapeutics and Vaxxinity and a cofounder and advisor of ALZPath. K.B. has provided consultation to Abbvie, AC Immune, AriBio, ALZpath, BioArctic, Biogen, Eisai, Lilly, Ono Pharma, Prothena, Roche Diagnostics and Siemens Healthineers. K.B. has participated in a data safety monitoring board or advisory board for Julius Clinical and Novartis. K.B. has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics. K.B. is a cofounder of and has stock in Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. J.L.C. has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, Aprinoia, Artery, Biogen, Biohaven, BioXcel, Bristol-Myers Squib, Cassava, Cerecin, Eisai, GAP Foundation, Janssen, Karuna, Lighthouse, Lilly, Lundbeck, EQT (formerly LSP), Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, Oxford Brain Diagnostics, PharmatrophiX, Prothena, ReMYND, Roche, Sage Therapeutics, Scottish Brain Science, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity and Wren pharmaceutical, assessment and investment companies. F.M.L. and S.M.M. are listed as inventors on patents related to LM11A-31 that are assigned to the University of North Carolina, University of California, San Francisco and the Department of Veterans Affairs. They are also entitled to royalties distributed by UC and the VA per their standard agreements. F.M.L. is a principal of and has financial interest in PharmatrophiX, a company focused on the development of small-molecule ligands for neurotrophin receptors, with licensing of several related patents. M.W. is the vice president for research and development of NeuroScios. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}