{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:34:44Z","timestamp":1790127284774,"version":"4.0.1"},"reference-count":56,"publisher":"SAGE Publications","issue":"s1","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2024,10,18]]},"abstract":"<jats:p>Background: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer\u2019s disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-\u03b2 (A\u03b2) peptides into a toxic form of pyroglutamate A\u03b2 (pGlu-A\u03b2) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. Objective: Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-A\u03b2. Methods: Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. Conclusions: Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.<\/jats:p>","DOI":"10.3233\/jad-231126","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T10:51:26Z","timestamp":1729248686000},"page":"S79-S93","source":"Crossref","is-referenced-by-count":19,"title":["Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"101","author":[{"given":"Howard H.","family":"Feldman","sequence":"first","affiliation":[{"name":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Alzheimer\u2019s Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA"},{"name":"Shiley-Marcos Alzheimer\u2019s Disease Research Center, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the ADCS VIVA-MIND Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Messer","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Alzheimer\u2019s Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Statistics, East China Normal University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Sabbagh","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Galasko","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Alzheimer\u2019s Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA"},{"name":"Shiley-Marcos Alzheimer\u2019s Disease Research Center, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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