PT2567 / Merck (MSD) - LARVOL DELTA

[VIRTUAL] Upregulation of Lysyl Oxidase Expression in Hypoxic Pulmonary Hypertension Is Complement-Dependent (ATS 2021) - "The present study demonstrates the specific contribution of the complement system to hypoxia-induced expression of lysyl oxidase (LOX), and therefore, potentially, to pulmonary vascular stiffening in PH."

Hypertension • Pulmonary Arterial Hypertension • Respiratory Diseases

Suppression of HIF2 signalling attenuates the initiation of hypoxia-induced pulmonary hypertension. (PubMed, Eur Respir J) - "A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4 days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5 weeks of hypoxia...EC HIF2α knockout prevented hypoxia-induced PH in mice.Inhibition of HIF2, not HIF1 can provide a therapeutic approach to prevent the development of hypoxia-induced PH. Future studies are needed to investigate the role of HIFs in PH progression and reversal."

Journal • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension. (PubMed, Eur Respir J) - "The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH...Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models...These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Immunology • Inflammation • Pulmonary Arterial Hypertension • EPAS1