Vesper Bio is developing a rich pipeline of first-in-class small molecule Vps10p modulators for a number of significant unmet medical needs. Alongside our lead program VES001 for FTD, we are leveraging our deep domain expertise in Vps10p biology to explore multiple additional Vps10p targets with high disease relevance, in a number of therapy areas and indications.
A novel sortilin antagonist for FTD(GRN)
VES001 is in phase I clinical trials and being developed for patients with autosomal dominant Frontomporal dementia starting in 2023.
VES001 is a proprietary small molecule, orally available, CNS -barrier penetratant, sortilin antagonist
VES001 selectively binds sortilin and disrupts protein-protein interaction with progranulin at the cell membrane. This means that VES001 acts as a progranulin uptake inhibitor. We have
demonstrated dose-dependent elevation in extracellular progranulin in a manner that does not disrupt the intracellular mileu.
Frontotemporal dementia (FTD) is one of the more prevalent forms of presenile dementia after Alzheimer’s disease accounting for 5–10% of all dementia patients (Graff-Radford and Woodruff, 2007). While the majority of FTD cases are sporadic, approximately 10–40% of patients have a positive family history consistent with a strong genetic component to the disease. The primary neuropathological hallmark of FTD is degeneration of the brain’s frontal and temporal lobes as well as accumulation of proteinaceous inclusions found within neurons and glial cells. FTD subtypes have been established depending on the proteins found in these inclusions.
Symptoms of FTD include:
Behavioural/personality changes (impulsiveness, apathy, compulsiveness)
Primary progressive aphasia
In many cases, FTD patients display abnormal motor function and coordination including parkinsonism and motor neuron disease. Symptom onset is typically before age 60 and in most cases is associated with a life expectancy of 7-10 years post symptom onset.
There are no FDA-approved treatments for FTD, with the only available treatments targeting behavioural symptoms of the disease.
Genetic analysis of chromosome 17q21 led to the identification of 70 pathogenic mutations within progranulin that cause FTD. These mutations essentially result in a haploinsufficiency of the protein. The frequency of GRN mutations is estimated to be up to 11.7% of the total FTD population, and up to 25% of familial cases. FTD-GRN has an incidence of 3 to 15 per 100,000 of population aged 45-64.
Sortilin protein interactions at the cell surface are well understood and we have demonstrated that our compounds disrupt apoptotic signals associated with disease states.