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# VES001, an oral sortilin inhibitor, raised plasma and CSF progranulin in healthy adults
- URL: https://www.coios.me/ves001-an-oral-sortilin-inhibitor-raised-plasma-and-csf/
- Published: 2026-10-17T09:02:11.000Z
- Updated: 2026-10-17T09:54:11.000Z
- Description: 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.
- Author: Daniel Ryan
- Tags: Tomorrow's world, Innovation in treatment, Dementia, #peer-reviewed, #new, #item, #source-2026-10, #score-58

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](https://doi.org/10.1038/s41467-026-77638-2?ref=coios.me)

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](https://pmc.ncbi.nlm.nih.gov/articles/PMC13669324/?ref=coios.me) (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](https://www.coios.me/d-treatment-innovation/)

Driver

[Dementia](https://www.coios.me/d-dementia/)