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.
6 affiliations
- 1Vesper Bio Aps, Copenhagen, Denmark.
- 2Centre for Human Drug Research, Leiden, The Netherlands.
- 3Leiden University Medical Center, LUMC, Leiden, The Netherlands.
- 4PROMEMO, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
- 5Vesper Bio Aps, Copenhagen, Denmark. [email protected].
- 6Department of Biomedicine, Aarhus University, Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark. [email protected].
Abstract
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.
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BibTeX
@article{klem2026preclinical,
title = {{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.}},
author = {Louise Klem and Daniel Dumas and Imogen J Swift and Sofie L Frandsen and Ditte Nedergaard Mikkelsen and Laerke Fensbaek and Yalçin Yavuz and Okke Merton and Jesminne Castricum and Simone Prichardt and Graham M Wynne and Anders Riisager and Nina Schultz and Paul B Little and Ove Pedersen and Eva Thijssen and Anders Nykjaer and Philip Kremer and Mads Kjolby},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77638-2},
url = {https://europepmc.org/article/MED/42875454},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - 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.
AU - Louise Klem
AU - Daniel Dumas
AU - Imogen J Swift
AU - Sofie L Frandsen
AU - Ditte Nedergaard Mikkelsen
AU - Laerke Fensbaek
AU - Yalçin Yavuz
AU - Okke Merton
AU - Jesminne Castricum
AU - Simone Prichardt
AU - Graham M Wynne
AU - Anders Riisager
AU - Nina Schultz
AU - Paul B Little
AU - Ove Pedersen
AU - Eva Thijssen
AU - Anders Nykjaer
AU - Philip Kremer
AU - Mads Kjolby
PY - 2026
DA - 2026/09/14
JO - Nature communications
DO - 10.1038/s41467-026-77638-2
UR - https://europepmc.org/article/MED/42875454
AB - 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.
SN - 2041-1723
ER -