15 February 2020 by Raymond Benza

Case Study of Long-Term Safety, Tolerability, And Hemodynamic Response of Pb1046, A Sustained-Release Analogue for Vasoactive Intestinal Peptide (VIP), in an Adult Subject With Pulmonary Arterial Hypertension (PAH)

Background

PB1046 is an investigational neuropeptide, VIP, genetically fused to an elastin-like biopolymer, for treatment of PAH, with biologic effects mediated by two receptors, VPAC1 and VPAC2, belonging to the family B of G protein-coupled receptors. VPAC receptors are in the pulmonary and systemic circulation. The safety and accuracy of the CardioMEMS™ HF System, which monitors pulmonary artery (PA) pressure from a sensor implanted into the PA, have been previously documented, along with correlations with Swan-Ganz measurements and echocardiography.

Methods

The multi-dose safety, PK, and VIP-based pharmacodynamic effects of PB1046 were evaluated in an open-label, multi-dose Phase 1 pilot study in PAH patients who have a permanently implanted CardioMEMS™. PB1046 was administered weekly subcutaneously x 8 weeks (extended due to subjective improvements) at dose levels previously tested and shown to be safe.

Results

Three patients completed study with no related serious adverse events/symptomatic hypotension/syncope. PB1046 appears to be well tolerated with only mild injection site erythema. The available PK profile data confirmed the dose-related but less than dose proportional increase in study drug exposure profile observed in previous studies. CardioMEMS™ hemodynamic monitoring demonstrated reductions in mean PA pressure and total pulmonary resistance and increases in stroke volume and cardiac output without an increase in heart rate with PB1046. Long-term PB1046 therapy (over 18 months) in one subject demonstrated clinically meaningful improvements in all the hemodynamic parameters assessed, which were sustained for three months afterwards, suggesting a possible disease modifying effect of PB1046 (Figure 1) and will be presented.

Conclusions

The preliminary data for PB1046 support continued evaluation as a potential novel therapy for PAH patients that is safe and well tolerated. Improvements in hemodynamic parameters associated with PB1046 support the ongoing randomized, double-blind, parallel group Phase II PAH study assessing 16 weeks of PB1046 treatment for NYHA/WHO functional class II and III PAH patients.

Key Contributors

Raymond L. Benza, Sumita Paul, Murali Chakinala, Priscilla Correa, John Lee, and James White


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