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Item new Peer-reviewed Added

VES001, an oral sortilin inhibitor, raised plasma and CSF progranulin in healthy adults

In a randomised placebo-controlled first-in-human trial, twice-daily oral VES001 for 7 days raised plasma progranulin by up to 49% and CSF progranulin by 18% from baseline.

VES001 is an oral small-molecule inhibitor of the sortilin receptor, developed for frontotemporal dementia caused by GRN haploinsufficiency (FTD-GRN). Preclinical work showed selective binding to human and rat sortilin without receptor downregulation. It also raised progranulin in plasma, CSF and hippocampal interstitial fluid of male rats. In a phase 1A randomised, double-blind, placebo-controlled trial, 79 healthy adults (63% male, mean age 28 years) received VES001 or placebo. Doses were single 10-990 mg or multiple doses over 7 days. There were no deaths, serious adverse events or treatment-related discontinuations; headache and fatigue were mild and not dose-related. Pharmacokinetics were dose-proportional, with CSF/plasma ratios of about 0.11-0.19. Twice-daily dosing raised plasma progranulin by 30% versus placebo and CSF progranulin by about 17%. Cohorts were small, dosing lasted only 7 days, and participants were healthy rather than GRN carriers. The p values were nominal, with no adjustment for multiple comparisons.

Why it is interesting: FTD-GRN currently has no disease-modifying treatment, and an oral route differs from the antibody and gene therapy approaches in trials. The study shows target engagement in the central nervous system.

Source
Nature Communications, 14 October 2026
Paper
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
Authors
Klem L, Dumas D, Swift IJ, Frandsen SL, Mikkelsen DN, Fensbaek L et al.
DOI
10.1038/s41467-026-77638-2
Full text
Open copy (open-access copy, PubMed Central)
Type
Peer-reviewed article
Design
Preclinical rat work plus randomised double-blind placebo-controlled phase 1 single and multiple ascending dose trial, n=79 healthy adults, 7-day dosing
Verdict
New finding
Driver
Innovation in treatment
Driver
Dementia

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