The central goal of this translational P01 grant is to advance and apply the knowledge gained from Cycle I pre-clinical and clinical findings to the treatment of pulmonary arterial hypertension (PAH). Current therapies for PAH largely address the potential for dilatation of unobliterated pre-capillary pulmonary arteries and augmentation of right ventricular function but do not effectively target the extensively remodeled vasculature or the altered inflammatory or immune processes that contribute to this pathobiology. Project 3, Clinical Development of Elafin as a PAH Therapy addresses this unmet need by moving a very promising agent into the clinic while, at the same time, carrying out ancillary studies that will uncover an extensive biology of PAH related to altered innate and adaptive immunity. Elafin is a promising therapy for PAH because of its multiple functions as an inhibitor of neutrophil elastase, proteinase 3 and NF?B and as an activator of bone morphogenetic protein receptor (BMPR)2 signaling. Under the guidance of the NIH-SMARTT program and in collaboration with our industry partner, Proteo Biotech, we have developed a solid clinical development plan for Elafin focused on establishing its safety, tolerability, and efficacy in a step-wise fashion. This plan will be extensively discussed and reviewed with the United States Food and Drug Administration (US-FDA) at an anticipated pre-IND meeting in late Fall.
Aim 1 of Project 3 is to carry out a Phase I clinical trial utilizing the facilities of the new Stanford Clinical Research and Translation Unit (CRTU), the resources of the Stanford Center for Clinical Research (SCCR) in monitoring safety and tolerability, and the expertise of SRI International in carrying out pharmacokinetic, and immunogenicity studies. The Phase I clinical trial will be followed by an extended 180-day good laboratory practices (GLP) toxicity, pharmacokinetic, and immunogenicity study in the rat.
In Aim 2, we propose a small multi-center, randomized, placebo-controlled, double-blind Phase II clinical trial in PAH patients that will evaluate safety, tolerability pharmacokinetic and immunogenicity endpoints as well as indices of efficacy as judged primarily by reduction in pulmonary vascular resistance on right heart catheterization study. Other efficacy endpoints will include the six minute walk distance, NT-pro BNP and New York Heart Association Class. In conjunction with the Advanced Proteomic Phenotyping core, and Projects 1 and 2, we will determine the impact of Elafin on the immune/inflammatory signature of PAH in circulating blood cells using a novel hybrid cytometry-mass spectrometry time of flight technique (CyTOF). We will also elucidate the nature of the Elafin responder vs. non-responder by utilizing bioassays and gene expression studies in personalized induced pluripotent stem cells differentiated into endothelial cells.

Public Health Relevance

Despite therapeutic advances made during the last two decades, pulmonary arterial hypertension (PAH) remains an incurable disease with considerable morbidity and poor survival after 5 years. In this project, through Phase I and Phase II clinical trials, we evaluate the therapeutic feasibility and efficacy of Elafin, an agent that is an elastase inhibitor with broader anti-inflammatory properties that also reverses impaired vascular cell function by restoring properties of a deficient cell surface receptor, BMPR2. The project provides an opportunity to use novel technologies to address mechanisms of abnormal innate and adaptive immunity, autoimmunity, and inflammation that are the underpinnings of pulmonary vascular remodeling. The expectation based upon pre-clinical studies is that we will identify at least a subgroup of PAH patients that are highly responsive to this novel therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1)
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Xiao, Lei
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Stanford University
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