PB1046: A long-acting VIP analogue
PhaseBio’s PB1046 is a genetic fusion of an analogue of vasoactive intestinal peptide (VIP) to our ELP biopolymer. VIP is a naturally occurring neuropeptide with multiple pleiotropic effects mediated by the G-protein coupled receptors VPAC1 and VPAC2, which are distributed throughout the pulmonary vasculature, myocardial tissue, and systemic and coronary arteries.
PB1046 overcomes the inherently poor in vivo stability and bioavailability of the native VIP peptide and has demonstrated prolonged circulatory drug exposure. Moreover, PB1046 was designed to be relatively selective for binding to the VPAC2 receptor, which may reduce gastrointestinal side effects associated with excessive activation of the VPAC1 receptor.
Several cardiopulmonary diseases are associated with changes in the levels of VIP peptide and its receptors, which may make PB1046 a beneficial treatment for heart failure, pulmonary arterial hypertension (PAH) and fibrotic cardiomyopathies, among others.
PB1046 for Pulmonary Arterial Hypertension
PhaseBio is developing PB1046 for the treatment of PAH, a rare but fatal disease lacking treatments that effectively reverse disease progression and improve long-term patient outcomes. PB1046 has been shown to be highly effective in a preclinical model of PAH.
PhaseBio is currently conducting an exploratory, individually dose-titrated trial of PB1046 in subjects with PAH, and expects to initiate a larger, phase 2 study of PB1046 in patients with PAH in mid-2018.
PB1046 for Cardiomyopathy and Heart Failure
PB1046 has the potential to provide important clinical benefits in patients with multiple forms of cardiomyopathy and heart failure, including cardiomyopathy due to the loss of dystrophin function, chemotherapy-induced cardiomyopathy, and heart failure with preserved or reduced ejection fraction. Multiple preclinical studies have demonstrated the benefits of PB1046 in each of these conditions, due to the therapy’s ability to induce positive cardiac inotropic (contractility) and lusitropic (relaxation) effects without an increase in myocardial oxygen demand.
PhaseBio recently concluded a Phase 2a multiple ascending dose trial of PB1046 in patients with heart failure with reduced ejection fraction.
PB1046 for Cystic Fibrosis
Cystic fibrosis is an autosomal recessive disease caused by a mutation in the gene encoding the CFTR chloride channel, which leads to chronic lung infections. In normal epithelia, VIP stimulates CFTR processing / recycling and regulates chloride ion secretion.
PB1046 has been shown to rescue the CFTR protein with the most common mutation (F508del) in human nasal epithelial cells through enhanced membrane insertion and processing, restoring chloride ion secretion.
PhaseBio is conducting pre-clinical studies to confirm the potential of PB1046 as a disease-modifying agent in cystic fibrosis. Additional information can be found here: VIP-ELP Fusion Molecules PB1120 and PB1046 Correct F508del-CFTR Dysfunction.