PB1046: A long-acting VIP analogue

Vasoactive intestinal peptide (VIP) is a naturally occurring 28-amino acid neuropeptide with multiple pleiotropic effects, including vasodilatory, inotropic/lusitropic and antifibrotic effects, which are mediated by two G-protein coupled receptors: VPAC1 and VPAC2. VPAC receptors and nerve fibers containing VIP are widely distributed throughout the pulmonary vasculature, myocardial tissue, and systemic and coronary arteries. Several cardiopulmonary diseases – including pulmonary hypertension, fibrotic cardiomyopathies and heart failure – are associated with changes in VIP concentration or with alteration of affinity, density or physiological responsiveness of VIP receptors. Consequently, application of VIP-based therapies may have beneficial effects in the treatment of heart failure, hypertension, pulmonary arterial hypertension (PAH) and other cardiovascular diseases.

To date, the inherently poor in vivo stability and bioavailability of the native VIP peptide has precluded its use as a therapeutic. PhaseBio’s PB1046, a genetic fusion of an analogue of VIP to our ELP biopolymer, overcomes these limitations and demonstrates prolonged circulatory drug exposure and potent activity. PB1046 was designed to be relatively selective for binding to the VPAC2 receptor which can reduce potential gastrointestinal side effects believed to be associated with excessive activation of the VPAC1 receptor.

Based on positive data from preclinical models, PhaseBio conducted a phase 1 single ascending dose study of PB1046 in patients with essential hypertension. PB1046 administered subcutaneously was found to be well tolerated and demonstrated a prolonged, dose-dependent effect on blood pressure, which was used as an activity biomarker.

PB1046’s safety and tolerability at efficacious doses supported a second phase 1 single ascending dose study in patients with essential hypertension, in which PB1046 was administered intravenously to support use in an acute setting. PB1046 was safe and well tolerated at the single-dose exposure levels tested in the study.

PB1046 for Cardiopulmonary Diseases

PhaseBio is initially developing PB1046 to improve and prolong the lives of patients with PAH, a fatal rare disease with a clear unmet need for new treatments that reverse progression of the disease and improve long-term outcomes. PB1046 has been shown to be highly effective in a preclinical model of PAH.  A phase 2 study of PB1046 in patients with PAH is expected to start in the second half of 2017.

PB1046 is also expected to provide important clinical benefits to patients with multiple forms of cardiomyopathy and heart failure, including cardiomyopathy due to loss of dystrophin function, chemotherapy-induced cardiomyopathy, and heart failure with preserved or reduced ejection fraction.  Multiple preclinical studies have demonstrated significant benefit of PB1046 in each of these conditions due to its positive cardiac inotropic (contractility) and lusitropic (relaxation) effects without an increase in myocardial oxygen demand.  PhaseBio is currently evaluating the safety and tolerability of PB1046 in a phase 2a multiple ascending dose study 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. The disease is characterized by abnormal ion transport and viscous mucus secretions, leading to chronic lung infections. In normal epithelia, VIP stimulates CFTR processing / recycling and regulates chloride ion secretion. VIP peptide has the ability to rescue the CFTR protein with the most common mutation (F508del) in human nasal epithelial cells through enhanced membrane insertion and processing, restoring Clˉ secretion.

PhaseBio is conducting pre-clinical studies to confirm the potential of PB1046 and PB1120 as disease-modifying therapies in cystic fibrosis. Additional information can be found here: VIP-ELP Fusion Molecules PB1120 and PB1046 Correct F508del-CFTR Dysfunction.