Safety, tolerability and efficacy of a novel sustained release analog of vasoactive intestinal peptide, PB1046, in patients with pulmonary arterial hypertension

Pulmonary arterial hypertensionPAHis a rarerapidly progressive and fatal disease that is characterized by pulmonary arterial remodelingsevere pulmonary hypertensionand progressive right heart failureThe prognosis of PAH is poor with an approximatemortality withinyear on modern therapyOver the past two decadesa number of medications for the treatment of PAH have been shown to improve patient symptoms and exercise capacityhowevernone of the current treatments are curative and long term prognosis remains poorThere remains a high unmet need for novel PAH targets and therapies that reverse the disease process and improve long term health outcomesVasoactive intestinal peptideVIPis aamino acid peptide hormone that activates VPACand VPACreceptors in the pulmonary vasculature and has been shown to relax pulmonary vascular smooth muscleneutralize pulmonary vasoconstrictorsand inhibit pulmonary vascular smooth muscle cell proliferationAdditionallyVIP improves right heart systolic and diastolic function and has broad anti inflammatory and anti fibrotic actionsVIP has been shown to be effective in reversing pulmonary vascular remodeling and prolonging survival in a murine model of PAHPBis a recombinant acid fusion protein comprising biologically active VIP at the N terminus and a physiologically inert repeating polymeric elastin like peptideELPat the C terminusThe fusion of VIP to the ELP moiety significantly increases in vivo exposure through sustained release from the injection siteextended circulatory half life and protection from enzymatic degradationPBis active as a fusion proteini ethe VIP moiety activates the receptor without a requirement to be cleaved or released from the ELP biopolymerPhaseBio has tested PBin a single dose Phasestudy in which the PK and PD enhancement of VIP via the ELP fusion was clearly demonstrated in the observed week long PBexposure profile and systolic blood pressure lowering effect after a single dose in essential hypertension patientsImportantlyPBdemonstrated a clean single dose safety tolerability profile across the expected therapeutic dose rangeIn this SBIR Fast Track proposalwe are applying for funding for the Phaseb and Phasestudies of PBin patients with PAHPhaseBio will investigate the multi dose safetyPKand PD of PBin an open labelnonplacebo controlledmulti dose Phaseb study of PBin PAH patients who have an implanted pulmonary arterial pressure monitorcardioMEMSIn this initial studyPBwill be administered as once weekly subcutaneously injections xweeks at a dose level previously tested and shown to be safe and well tolerated in subjects from the single dose Phasestudy and in an ongoing Phasemultiple ascending dose study in ambulatory heart failure patientsWhen the safetyPKand PD profile of PBare confirmed in PAH subjectsa randomizeddouble blindplacebo controlled Phasestudy of PBwill be initiated to investigate the potential beneficial effects of PBon exercise capacity and hemodynamics in symptomatic PAH patients Pulmonary arterial hypertensionPAHis a rarerapidly progressive and fatal disease that is characterized by pulmonary arterial remodelingsevere pulmonary hypertensionand progressive right heart failurePhaseBio is developing a novel drug for PAHPBwhich is a stablesustained release analog of vasoactive intestinal peptideThe studies in this proposal will verify the safetytolerability and efficacy of PBin two clinical studies in PAH patients