Sortilin Antagonist VES001 Meets Primary End Point in Phase 1 Study of Frontotemporal Dementia

Mads Fuglsang Kjølby

New findings from a phase 1 study of healthy volunteers showed that all end points were successfully met with treatment of Vesper Bio’s VES001, a potentially disease-modifying treatment for frontotemporal dementia with mutations in the progranulin gene (FTD-GRN). The company has completed a clinical trial application seeking to advance the investigational agent into a phase 2a proof-of-concept trial in a relevant patient population, with dosing expected to begin in Q4 2024.¹

In the 2-part study, topline data from the 7-day multiple ascending dose (MAD) portion reaffirmed findings seen in the single-ascending dose (SAD) stage, announced earlier this year. Using a cohort of 78 healthy volunteers, VES001 was considered safe and tolerated across multiple doses, with no serious or treatment-emergent adverse events reported. VES001, a patient friendly, first-in-class, brain penetrant, oral treatment which targets progranulin deficiency, an underlying cause of FTD, demonstrated strong target engagement, evidenced by an increased and accumulating level of progranulin in the volunteers dosed once or twice daily in the MAD stage.

"Vesper Bio is proud of its status as a world leader in sortilin biology. The data generated in our Phase I trial of VES001 demonstrate the potential of sortilin inhibition as a therapeutic approach to the treatment of frontotemporal dementia, and potentially other neurodegenerative diseases," Mads Fuglsang Kjølby, chief medical officer at Vesper, said in a statement.¹

To date, there are no approved disease-modifying treatments for FTD-GRN, which is estimated to account for a quarter of familial FTD cases. VES001, a small molecule sortilin inhibitor, is designed to bind to the sortilin receptor and stop progranulin from binding, thereby helping to maintain and normalize progranulin levels. Sortilin and progranulin play critical roles in FTD. Mutations in the GRN gene reduce progranulin levels, leading to neurodegeneration. Sortilin, a receptor, helps regulate progranulin’s cellular transport and availability. Disruption in this pathway contributes to FTD pathology by impairing neuronal survival.

READ MORE: Synaptic Agent Fosgonimeton Falls Short in Phase 2/3 LIFT-AD Trial of Mild-to-Moderate Alzheimer Disease

VES001, an agent designed to cross the blood-brain barrier, exhibited “excellent” pharmacokinetics and distribution to plasma and the targeted central nervous system compartment in the phase 1 trial. The company noted that data from this study will be published in due course and when modelled on to the target population, represent a substantial normalization of progranulin concentration after 7 days of dosing.

"At Vesper, we are motivated by our patients and their relatives, who inspire our mission to develop innovative therapies that can help fight this awful disease," Paul Little, chief executive officer at Vesper, said in a statement.¹ "These promising clinical data coupled with VES001's patient friendly profile bring us one step closer to transforming patient outcomes in frontotemporal dementia."

As mentioned, the company announced the completion of its SAD portion of the phase 1 trial earlier this year. All told, the data demonstrated the safety and tolerability of VES001 across the full range of doses tested and showed the agent has excellent pharmacokinetics and distribution to relevant parts of the brain. Importantly, patients who received the investigational treatment experienced a significant and robust increase in the levels of progranulin, demonstrating target engagement.²

Despite increased industry interest in FTD, there has still been little therapeutic success to show for. In 2023, Wave Life Sciences discontinued its investigational agent WVE-004 after it failed to show clinical benefit in a phase 1b/2a study (NCT04931862) of patients with C9orf72-associated amyotrophic lateral sclerosis (C9-ALS) and FTD.³ Later that year, data from the phase 2 INFRONT-2 study (NCT03987295) showed that treatment with latozinemab (Alector), an investigational monoclonal antibody, had no significant impact on disease progression among patients with C9orf72-associated FTD despite increasing progranulin expression.⁴

REFERENCES
1. Vesper Bio announces successful Phase I study for potentially disease-modifying treatment for frontotemporal dementia. News release. Vesper Bio. September 4, 2024. Accessed September 6, 2024. https://www.prnewswire.com/news-releases/vesper-bio-announces-successful-phase-i-study-for-potentially-disease-modifying-treatment-for-frontotemporal-dementia-302236963.html
2. 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 September 6, 2024. 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
3. Wave Life Sciences announces topline results from phase 1b/2a FOCUS-C9 study of WVE-004 for C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia. News release. May 23, 2023. Accessed September 6, 2024. https://www.globenewswire.com/news-release/2023/05/23/2674200/0/en/Wave-Life-Sciences-Announces-Topline-Results-from-Phase-1b-2a-FOCUS-C9-Study-of-WVE-004-for-C9orf72-associated-Amyotrophic-Lateral-Sclerosis-and-Frontotemporal-Dementia.html
4. Carter L, Ljubenkov P, Seelaar H, et al. Twelve-month results in FTD-C9orf72 participants from INFRONT-2: a phase 2 study of latozinemab (AL001) in FTD. Presented at: Clinical Trials on Alzheimer’s Disease conferece; Oct 24-27, 2023; Boston, MA. POSTER LB27.