{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:04:27Z","timestamp":1773029067710,"version":"3.50.1"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Glycoprotein non\u2010metastatic melanoma protein B (GPNMB) was investigated as a pharmacodynamic (PD) biomarker for PIKfyve inhibition across translational studies ex\u00a0vivo, in\u00a0vitro, in animals, and in the clinic, demonstrating significant response to VRG50468 in cells, in\u00a0vivo in the central nervous system (CNS) and in peripheral fluids and tissues. VRG50468 is the active metabolite of VRG50635, a small molecule PIKfyve inhibitor pro\u2010drug in development for treating amyotrophic lateral sclerosis (ALS). Peripheral pharmacology was evaluated in peripheral blood mononuclear cells (PBMCs) from healthy volunteers ex\u00a0vivo and in\u00a0vitro and in PBMCs from mice given oral VRG50635. Central pharmacology was evaluated in\u00a0vitro using C9orf72 ALS patient\u2010derived induced pluripotent stem cell motor neurons and mouse primary neurons, and in\u00a0vivo in brains of mice given oral VRG50635. Two clinical studies in healthy adults examined plasma, PBMCs, and cerebrospinal fluid following oral VRG50635 for peripheral and central pharmacologic activity via GPNMB induction. PD GPNMB upregulation with VRG50468 was demonstrated across preclinical translational and clinical studies. A PD response to VRG50468 was observed ex\u00a0vivo in rodent and human PBMCs and in primary rodent neurons and motor neurons induced from stem cells of people with ALS. Repeated administration of VRG50635 to rodents and healthy human volunteers robustly induced GPNMB peripherally and in the CNS, which was concentration and time dependent in\u00a0vitro and dose and treatment duration dependent in\u00a0vivo, peripherally, and in CNS. GPNMB is a robust translatable PD biomarker for clinical trials with the PIKfyve inhibitor VRG50635.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>Clinical trial number: VGCS\u201050635\u2010001 and VGCS\u201050635\u2010003; identifier: NL81735.056.22 and NCT06286475<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cts.70489","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T02:46:15Z","timestamp":1771469175000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glycoprotein Non\u2010Metastatic Melanoma Protein B (\n                    <scp>GPNMB<\/scp>\n                    ): A Translational Pharmacodynamic Biomarker for\n                    <scp>PIKfyve<\/scp>\n                    Inhibition With\n                    <scp>VRG50635<\/scp>"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2894-7282","authenticated-orcid":false,"given":"Geraldine","family":"Gontier","sequence":"first","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace","family":"Kim","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond","family":"Gau","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningzhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6123-1505","authenticated-orcid":false,"given":"Swati","family":"Naphade","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alistair","family":"Stewart","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Galemmo","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Shook","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil","family":"Tarachandani","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9146-8324","authenticated-orcid":false,"given":"Irene","family":"Choi","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shane","family":"Raines","sequence":"additional","affiliation":[{"name":"2b Analytics  Wallingford Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Scannevin","sequence":"additional","affiliation":[{"name":"Verge Genomics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrieke W.","family":"Grievink","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars M. 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