Vesper Initiates Phase 1b/2a SORT-IN-2 Trial of VES001 in Genetically Mutated Frontotemporal Dementia

Mads Fuglsang Kjølby

A new phase 1b/2a proof-of-concept trial (NCT06705192), dubbed SORT-IN-2, will assess the therapeutic potential of investigational VES001 as a potentially disease-modifying therapy for patients with mutations in their progranulin-coding gene (GRN), the root cause for frontotemporal dementia (FTD). The trial, initiated in recent days, is expected to complete dosing for all participants by mid-2025.¹

The open-label study, expected to take place at Erasmus University Medical Center in The Netherlands, follows a multiple ascending dose (MAD) design within a single cohort, investigating 2 distinct dose levels (360 mg and 900 mg), consecutively over a 3-month period. In the study, investigators will use change in progranulin GRN levels in cerebrospinal fluid (CSF) and plasma at day 28 and day 84 relative to baseline as the primary outcome measure. Notably, the study will not include genetic testing for GRN mutations, relying instead on previously confirmed mutation data from participants' medical histories.

VES001 targets sortilin, a receptor that depletes progranulin by binding and degrading it, reducing extracellular levels. By normalizing progranulin levels with convenient daily oral dosing, the belief is that VES001 could offer a promising, patient-friendly treatment approach to a population that currently lacks approved therapies.

"The aim of this study is to further demonstrate the safety and tolerability of VES001 and confirm whether VES001 has a positive effect on progranulin levels in the cerebrospinal fluid and blood plasma of these patients," Mads Fuglsang Kjølby, co-founder and interim chief medical officer at Vesper, said in a statement. "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. Based on the data from our successful First-in-Human trial, we believe VES001 will normalise progranulin levels, and thus has great potential to slow or even arrest FTD(GRN) disease progression."

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Participants eligible for the study must be asymptomatic carriers of the GRN mutation, confirmed through prior genetic testing and documented historical records. They must have a BMI between 18 and 32 kg/m², weigh at least 50 kg, and be in good physical health, as assessed through medical history, physical exams, lab tests, and ECGs. Female participants of childbearing potential must agree to effective contraception and have a negative pregnancy test, while male participants must use barrier contraception and refrain from donating sperm. All participants should be able to communicate effectively in Dutch or English and comply with study requirements.

Individuals will be excluded if they have active or chronic diseases, neurological conditions, significant cognitive impairment, recent malignancy, or abnormal lab results. Those with untreated hypertension, abnormal ECG readings, or a history of cardiac issues are ineligible. Additional exclusions include positive tests for infections like HIV, significant back issues that could complicate lumbar punctures, and conditions affecting coagulation or platelet count. Participants with a history of seizure, significant head trauma, or cognitive decline are also excluded.

"It is an incredible achievement by the Vesper team that we have been able to progress VES001 so quickly into this next clinical trial phase. We are committed to bringing this important new oral treatment option to families living with FTD, where there is no approved therapy available today. We are all striving for a future free from FTD for patients and their families," Paul Little, chief executive officer at Vesper, said in a statement.

VES001 was first evaluated in a phase 1 study of healthy volunteers, with final results from the multiple-ascending dose portion released in September 2024. In a cohort of 78 healthy volunteers, the therapy was considered safety and tolerated across multiple doses, with no serious or treatment-emergent adverse events reported. These findings reaffirmed data seen in the single-ascending dose stage announced earlier in the year, where the agent demonstrated excellent pharmacokinetics and distribution to relevant parts of the brain. Importantly, data from the SAD portion showed a significant and robust increase in the levels of progranulin, demonstrating target engagement.^2,3

REFERENCES
1. Vesper Bio initiates Phase Ib/IIa proof of concept study of VES001 in asymptomatic patients with gene mutations that cause frontotemporal dementia (FTD). News release. Vesper Bio. January 7, 2025. Accessed January 9, 2025. https://www.prnewswire.com/news-releases/vesper-bio-initiates-phase-ibiia-proof-of-concept-study-of-ves001-in-asymptomatic-patients-with-gene-mutations-that-cause-frontotemporal-dementia-ftd-302344029.html
2. Vesper Bio announces successful Phase I study for potentially disease-modifying treatment for frontotemporal dementia. News release. Vesper Bio. September 4, 2024. Accessed January 9, 2025. https://www.prnewswire.com/news-releases/vesper-bio-announces-successful-phase-i-study-for-potentially-disease-modifying-treatment-for-frontotemporal-dementia-302236963.html
3. Vesper Bio announces completion of single ascending dose stage in trial of its lead candidate VES001, a potentially disease-modifying treatment for fronto-temporal dementia. News release. Vesper Bio. May 30, 2024. Accessed January 9, 2025. https://www.prnewswire.com/news-releases/vesper-bio-announces-completion-of-single-ascending-dose-stage-in-trial-of-its-lead-candidate-ves001-a-potentially-disease-modifying-treatment-for-fronto-temporal-dementia-302158331.html