PB1046: A long-acting VIP analogue

PB1046 is a subcutaneously-injected, sustained release analogue of the native human peptide vasoactive intestinal peptide (VIP) fused to our ELP biopolymer. VIP is a neurohormone that relaxes the muscles surrounding blood vessels, causing them to dilate, which results in improved blood flow. Native VIP exerts its function in the body by binding to two distinct receptors, VPAC1 and VPAC2. VPAC1 is found predominantly in the gastrointestinal tract, while VPAC2 is found predominantly in the myocardial wall and pulmonary arteries.

We designed PB1046 using our ELP technology to harness the positive therapeutic effects of native VIP while addressing the drawbacks that make native VIP inappropriate for use as a direct therapy. Native VIP is rapidly degraded, and, when injected into the body, is eliminated within minutes, limiting its therapeutic effect. High levels of native VIP also result in severe gastrointestinal problems due to VPAC1 activation. We have used our ELP technology to extend the half-life of VIP in PB1046 to approximately 60 hours. In addition, we designed PB1046 to be active predominantly on VPAC2 rather than VPAC1 in order to preferentially affect the lung and cardiac tissue and reduce the potential for gastrointestinal side effects associated with VPAC1 activation.

Several cardiopulmonary diseases are associated with changes in the levels of VIP peptide and its receptors, which may make PB1046 a beneficial treatment for pulmonary arterial hypertension (PAH), heart failure and other cardiomyopathies. We have received two orphan drug designations for PB1046 from the FDA, one for the treatment of PAH and a second for cardiomyopathy associated with Duchenne muscular dystrophy (DMD).

PB1046 for Pulmonary Arterial Hypertension

PhaseBio is developing PB1046 for the treatment of PAH, a progressive and life-threatening orphan disease with no known cure that is caused by abnormal constriction and adverse remodeling of the arteries, and is characterized by high blood pressure.

We are currently conducting a Phase 2b clinical trial of PB1046 in patients with PAH. We expect to report results from this trial in the first half of 2020.

Potential applications of PB1046 in other indications

The biological activities associated with VIP have the potential to provide therapeutic benefit to patients with other diseases. We believe that PB1046 provides a mechanism to bring these VIP-based therapies forward in the following indications:

• DMD-associated Cardiomyopathy. Cardiac dysfunction is a very common manifestation of DMD and a common cause of death for individuals with this condition. The ability of PB1046 to increase contractibility of cardiac muscles presents the possibility that it could provide therapeutic benefit to these patients. We observed that PB1046 slowed deterioration in cardiac function and preserved skeletal muscle function in a mouse model of DMD. In addition to direct effects on cardiac function, we believe decreased fibrosis also contributed to the positive effects of PB1046 on both cardiac and skeletal muscle in this model.
• Cystic Fibrosis. VIP has been shown to stimulate the processing of cystic fibrosis transmembrane regulator (CFTR), the protein defective in patients with cystic fibrosis (CF). In mice lacking the gene for VIP, CFTR is not located at the cell surface, where it is required to function properly, but accumulates within the cell. These mice have lung abnormalities that resemble CF, and treatment with VIP peptide restored CFTR to the cell surface and corrected the lung tissue abnormalities. Treatment with PB1046 of human epithelial cells containing the most common CFTR mutation found in patients with CF, F508del, has been observed to increase CFTR activity, providing further support that PB1046 may have potential as a treatment for patients with CF.