1/2 A Phase 2 Study of Elafin (Tiprelestat) for the Treatment of Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a disease of progressive obliteration of the lung vasculature that results from elastase mediated degradation of elastin, endothelial dysfunction, smooth muscle cell proliferation and chronic peri-and intravascular inflammation. These features can be a consequence of reduced bone morphogenetic protein receptor 2 (BMPR2) the most common mutation associated with PAH. While current PAH treatments largely aim to dilate unobstructed pulmonary arteries, there is an unmet need to find a therapy that is disease modifying in that it addresses these underlying cellular and molecular features of PAH. Our proposal tests the hypothesis that human recombinant Elafin (tiprelestat) is ideally suited for this role as it inhibits neutrophil elastase, suppresses cytokine mediated inflammation and activates BMPR2 signaling. Under the guidance of the US-FDA, we have developed a clinical development plan for Elafin. The main focus of our proposal as highlighted in Aim 1 is to establish the efficacy, safety and tolerability of daily subcutaneous Elafin in a 10-center Phase 2, 3-arm, randomized placebo controlled clinical trial. The primary endpoint of efficacy is change in pulmonary vascular resistance from baseline to 24 weeks with secondary efficacy endpoints of WHO functional class, six-minute walk distance (6MWD), N-terminal B-type natriuretic peptide, right ventricular function on echocardiography, EmPHasis-10 health-related quality of life score, and time to clinical worsening. Our lung CT imaging Core will use a new tool to assess changes in lung vascular volumes as an exploratory efficacy endpoint and we will assess Elafin pharmacokinetics as well as safety, and tolerability in PAH patients. While we anticipate that the pathological features targeted by Elafin will require continuous suppression, any change in remodeling should be sustained for a period of one month as opposed to an agent that functions primarily as a vasodilator. Thus, In Aim 2 we will conduct a blinded withdrawal of the Elafin or placebo at the end of the week 24 visit and will follow participants further for 4 weeks. We will then determine whether the change in clinical efficacy and lung vascular volumes observed between baseline and 24 weeks is sustained at 28 weeks. A sustained treatment would be an indication of Elafin’s capacity as a disease modifying therapy – a first in PAH. In Aim 3, we will develop biomarkers as target engagement of Elafin. These include neutrophil exosome elastase activity and elastase mediated neutrophil extracellular traps. Cytokine/chemokine levels indicate Elafin inhibition of NFkB and AP1. An unbiased approach incorporating advanced analytics and machine learning categorizes cytokine/chemokine profiles to support a response to treatment. Apelin levels will be monitored as reflective of Elafin mediated improved BMPR2 function. These features will be evaluated in relation to clinical outcomes. Exceptional clinical response to Elafin, lack of response, or significant adverse response will be interpreted in the light of anti-drug antibodies or genetic variants revealed by whole genome sequencing. We expect that the ‘triple threat’ of Elafin will reverse the course of progressive PAH. Project Number: 1UG3HL180990-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Roham Zamanian (+1 co-PI) | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $1,998,124 | Activity Code: UG3 | Study Section: Special Emphasis Panel[ZHL1 CSR-Z (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1UG3HL18099001