Development of a novel disease modifying oral therapy for pulmonary arterial hypertension.

Abstract Vasculonics is developing a disease modifying compound, VN-1032, to reduce progressive vasculopathy of pulmonary arterial hypertension (PAH). PAH is a debilitating disease with a 2.8-year average survival and an average 5-year survival rate in 60% of patients receiving therapy. The current vasodilator therapies only reduce symptoms of the disease and do not impact disease progression. Preclinical research at Vasculonics has identified a novel drug-able molecule that selectively reduced Aryl hydrocarbon Receptor (AhR) activation and the vascular toxin asymmetric dimethylarginine (ADMA). Both AhR and ADMA play important role in the pathogenesis of PAH. Persistent activation of AhR and increased ADMA occur in PAH patients and preclinical models. Drugs such as Qing-Dai and dexfenfluramine which cause PAH in humans are activators of AhR pathway. These drugs recapitulated human like disease in animal models of PAH whereas the AhR gene deficient (AhR-/-) animals are protected from Qing Dai or dexfenfluramine. Based on multiple clinical and preclinical studies, AhR and ADMA have been recognized as important targets of therapy. However, drugs targeted to the mechanisms of AhR and ADMA in PAH are not available. Vasculonics has developed a novel chemical series that modulated AhR and ADMA. Innovative medicinal chemistry and lead optimization studies have produced VN-1032 as a lead molecule. In feasibility studies, VN-1032 inhibited the mechanisms involved in PAH including, inhibition of pulmonary artery smooth muscle cell proliferation, oxidative stress, inflammation and fibrosis. In vivo studies, VN-1032 produced robust efficacy in the Sugen-Hypoxia model of PAH progression. Thus, VN-1032 is a highly promising orally active disease modifying drug candidate for PAH. Our overarching goal now is to advance VN-1032 to IND enabling safety studies and IND filing. The goal of the SBIR phase 2 is to obtain critical preclinical safety and efficacy data to move VN-1032 to IND-enabling studies. In Aim 1, we will complete non-GLP safety assessment of VN-1032 by first testing it in dose escalation toxicology in rats and dogs followed by one week repeat dose toxicology studies in rats and dogs. In Aim 2, we will characterize a second compound to de-risk the technical strategy in Aim 1. Toxicity is the highest cause of drug failure in development. A readily available backup compound is critical for technical and commercial success of the program. In Aim 3, a dose-dependent efficacy study in a server disease model of PAH will be conducted. The dose response efficacy study will provide the “minimum efficacious dose, margin of safety and dose estimation” for the clinical studies. The 12- week duration efficacy study will demonstrate the efficacy in severe disease. The results of the safety and efficacy studies will advance VN-1032 to late stage GLP safety and GMP manufacturing for IND filing. Vasculonics has assembled a highly experienced drug development team to achieve the aims of this proposal and the subsequent IND-enabling and clinical studies. Our disease modifying novel therapy is expected to have a major impact on the survival and quality of life of PAH patients.