Vesper Bio ApS announced positive topline results from its Phase Ib/IIa SORT-IN-2 clinical study evaluating VES001, the first oral therapy being tested for frontotemporal degeneration (FTD). The study demonstrated that VES001 led to a greater than 95% mean increase in progranulin levels in cerebrospinal fluid compared to baseline at the highest dose tested in asymptomatic carriers with FTD caused by mutations in the progranulin gene (GRN).
The results represent a significant milestone for treating FTD-GRN, a genetic variant that accounts for approximately 25% of familial FTD cases. Since individuals with FTD-GRN typically have progranulin concentrations around half that of people without GRN mutations, the observed increase represents a normalization of progranulin levels to healthy ranges.
Study Design and Participants
The open-label, single-arm study included six individuals from the Netherlands and the UK who carry GRN mutations but remain asymptomatic. All participants received daily oral doses of VES001 following a stepped dosing regimen: a lower dose for 28 days, followed by a higher dose for 56 days. The study was conducted at two clinical centers: the Erasmus University Medical Centre in Rotterdam and the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility at University College London.
The data showed dose-dependent increases in progranulin protein levels in both plasma and cerebrospinal fluid, confirming target engagement and validating Vesper's selective sortilin inhibition approach.
Safety Profile and Mechanism of Action
VES001 demonstrated a favorable safety and tolerability profile throughout the three-month daily dosing regimen. Only a few mild adverse events were reported, with no severe adverse events or discontinuations due to treatment-related effects observed during the study period.
The drug works as a competitive sortilin inhibitor that selectively prevents degradation of progranulin while preserving sortilin levels and functions crucial for neuronal health. This approach contrasts with antibody-mediated degradation of sortilin and represents the first validation of restoring normal progranulin levels in this patient population without affecting other essential sortilin functions.
Clinical Significance and Expert Perspectives
"Progranulin is vital for maintaining neuronal health. However, progranulin levels in asymptomatic people with GRN mutations are typically half that of people without such mutations," said Mads Kjolby, Co-Founder and Chief Medical Officer at Vesper Bio. "Based on these topline Phase Ib/IIa data, we believe VES001 has the potential to normalise progranulin levels not only in asymptomatic individuals with GRN mutations, but in symptomatic people too, without affecting other sortilin functions crucial for neuronal health."
Professor Jonathan Rohrer, Principal Investigator at the trial's UK sites from the Dementia Research Centre at UCL Queen Square Institute of Neurology, emphasized the treatment's preventive potential: "This is the first oral therapy being tested in FTD. The increase of progranulin levels back to normal levels in these asymptomatic mutation carriers – who know they will develop symptoms in the next 10 to 20 years – speaks to the future potential of this treatment to prevent people ever developing symptoms of FTD."
Next Steps and Development Timeline
The SORT-IN-2 study, supported by the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration through the TreatFTD programme, will provide full results in Q1 2026. Vesper Bio plans to advance VES001 into Phase IIb/III clinical trials to evaluate efficacy on clinical progression and biomarker endpoints in symptomatic FTD-GRN patients.
Jacob Falck Hansen, Chief Executive Officer at Vesper Bio, stated: "These data represent an important milestone for Vesper Bio and the FTD community. The strong clinical results validate our targeted approach. It gives us great confidence in further developing our selective sortilin inhibitor VES001 with potential to become the first approved treatment for FTD-GRN."
Separately, Vesper Bio announced successful completion of long-term, pivotal toxicology studies of VES001 in animals, supporting the compound's continued development.
Disease Background
Frontotemporal degeneration is a group of brain disorders causing degeneration in the frontal and temporal lobes, impacting behavior, judgment, communication, and daily living activities. FTD represents the most common cause of dementia in people under age 60 and is often misdiagnosed as Alzheimer's disease. FTD-GRN, caused by mutations in the progranulin gene resulting in low progranulin levels, accounts for approximately one quarter of familial FTD cases.
