{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:54:02Z","timestamp":1782276842345,"version":"3.54.5"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Alzheimer\u2019s Disease (AD) is a prevalent neurodegenerative disorder which involves a complex pathobiology driven by amyloid-beta (A\u03b2) and tau pathologies, among other factors. A\u03b2 peptides are generated\n                      <jats:italic>via<\/jats:italic>\n                      \u03b2-secretase (BACE1) and \u03b3-secretase cleavage of amyloid precursor protein (APP). While long isoforms like A\u03b242 are neurotoxic and aggregation-prone, shorter isoforms (A\u03b238, A\u03b237) are non-amyloidogenic. \u03b3-secretase modulators (GSMs) shift production from longer to shorter peptides which is expected to slow down or halt (prevent) amyloid accumulation and its downstream effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The novel GSM nivegacetor was evaluated\n                      <jats:italic>in vitro<\/jats:italic>\n                      using cell lines overexpressing human wild-type APP, or human APP with the Swedish mutation K670N\/M671L (APPSwe). The\n                      <jats:italic>in vitro<\/jats:italic>\n                      selectivity of nivegacetor was tested on Notch-1, a representative gamma secretase substrate other than APP. Additionally, nivegacetor was profiled for its selectivity on a range of pharmacological targets.\n                      <jats:italic>In vivo<\/jats:italic>\n                      studies tested a dose-response and a time course of nivegacetor on soluble A\u03b2 levels in brain tissue of APPSwe transgenic mice. Furthermore, the impact of two ADAD mutations, PSEN1 E280A (Columbian) and PSEN2 N141I (Volga German), on nivegacetor\u2019s potency was tested. Moreover, nivegacetor was tested for possible effects on [\n                      <jats:sup>3<\/jats:sup>\n                      H]florbetaben binding to A\u03b2 plaque pathology in human AD brain tissue sections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nivegacetor lowered the production of A\u03b242 and A\u03b240 and concomitantly increased levels of A\u03b237 and A\u03b238\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      in mice. Nivegacetor did not inhibit Notch-1 and showed a favorable selectivity profile on a broad range of targets. When tested on two ADAD mutations, nivegacetor was equipotent on the PSEN1 E280A mutation and significantly less potent on the PSEN2 N141I mutation compared to wild-type gamma secretase. Nivegacetor did not interfere with the detection of amyloid plaques by [\n                      <jats:sup>3<\/jats:sup>\n                      H]florbetaben in human AD brain tissue, which is an important prerequisite for the use of florbetaben as a PET tracer in clinical trials.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Nivegacetor is a potent, orally bioavailable GSM with favorable properties and is currently under investigation as a clinical candidate in a Phase 2A clinical trial in individuals with prodromal and early sporadic AD, and in a Phase 2 clinical trial in individuals carrying the PSEN1 E280A ADAD mutation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1783414","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T09:16:40Z","timestamp":1779959800000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacology of nivegacetor (RG6289), a potent and selective gamma secretase modulator in clinical development for the treatment of Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Lothar","family":"Lindemann","sequence":"first","affiliation":[{"name":"Roche Pharma Research & Early Development, Neuroscience and Rare Diseases Translational Area, Discovery Neuroscience, F. 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