Preclinical and clinical investigation of VES001, an oral small molecule sortilin receptor inhibitor for the treatment of frontotemporal dementia: a first-in-human randomized placebo-controlled phase 1 trial

GRN haploinsufficiency reduces progranulin and causes frontotemporal dementia (FTD-GRN). VES001, an oral small-molecule sortilin inhibitor, increases progranulin without downregulating sortilin. Preclinically, VES001 bound sortilin selectively and elevated progranulin in plasma, cerebrospinal fluid (CSF), and hippocampal interstitial fluid of male rats. In a randomized, double-blind, placebo-controlled first-in-human phase 1 A study, 79 healthy adults (63/37% male/female; mean age 28 years) received VES001 or placebo as single ascending doses (10–990 mg) or multiple ascending doses for 7 days (180 mg once or twice daily, or 450 mg twice daily). Safety and tolerability, the primary endpoints, were met: no deaths, serious adverse events or treatment-related discontinuations; headache and fatigue were mild and not dose-related. Pharmacokinetics were dose-proportional, with blood–brain barrier penetration. Prespecified pharmacodynamic endpoints were met as single dosing increased plasma progranulin, and twice-daily dosing produced greater, sustained increases versus placebo in plasma (peak 49% change from baseline) and CSF (18% change from baseline). Although cohorts were small, dosing lasted 7 days, and participants were healthy, these findings establish pharmacological proof of mechanism for oral sortilin inhibition and support further development of VES001 as a potential disease-modifying therapy for FTD-GRN. EU CTR 2023-505847-38-00; ClinicalTrials.gov NCT06226064. Treatment for frontotemporal dementia due to GRN haploinsufficiency (FTD-GRN) are lacking. Here, in this preclinical and Phase 1 clinical trial, the authors show that VES001, an oral small molecule sortilin inhibitor, is safe and well tolerated, and increased progranulin levels.