Pulmonary arterial hypertension (PAH) is a serious condition in which the pressure in a patient’s pulmonary arteries becomes dangerously high. PAH begins when tiny arteries in the lungs, called pulmonary arterioles, become narrowed, blocked or destroyed.  This makes it harder for blood to flow through the lungs, and raises pressure within the arteries in the lungs.  As the pressure builds, the heart’s lower right chamber (right ventricle) must work harder to pump blood through the lungs, eventually causing the heart muscle to weaken and eventually fail.

Normal Heart vs Pulmonary Hypertension

PAH is an orphan indication, affecting 15 – 50 individuals/million in the US and Europe. Although management of PAH has improved significantly in the past 15 years, the mortality rate is still unacceptably high, with a 5-year survival rate of 60%.

The exact cause of PAH is not known; it may be idiopathic, and also may occur in the setting of other diseases such as connective tissue disease, or be hereditary.  Studies suggest that inflammation underlies the pathogenesis of PAH in some patients.  The lowest survival is seen in patients with immune-dysregulated/connective tissue associated PAH (CTD-PAH). Even patients achieving prolonged survival suffer significant morbidity and poor quality of life.  PAH is a progressive, life-threatening illness and potentially eligible for Orphan Designation in the US, EU, and Japan.

Currently approved therapies for the treatment of PAH include those acting on the nitric oxide pathway (PDE5 inhibitors, guanylate cyclase stimulator), the endothelin pathway (endothelin receptor antagonists), or prostacyclins.  These drugs target vasoconstriction.  While the development of these newer drugs has resulted in improvements in survival, they are palliative and do not address the inflammatory component of PAH.  PAH remains a progressive and life-threatening disease with an unmet medical need.

Pathogenesis of PAH

Researchers in Mark Nicoll’s laboratory at Stanford University have identified an inflammatory mediator, leukotriene B4 (LTB4), that has been identified in both animal models of PAH as well as human PAH.  A prominent pathological feature of PAH is accumulation of macrophages near the arterioles of the lung, and in both clinical PAH tissue and rat models of PAH, it has been demonstrated that the accumulated macrophages express high levels of LTA4H, the biosynthetic enzyme for LTB4.   Moreover, macrophage-derived LTB4 directly induces apoptosis in pulmonary artery endothelial cells (PAECs) and induces proliferation and hypertrophy of human pulmonary artery smooth muscle cells, both of which contributes to occlusion of the lumen and PAH.  Inhibition of LTB4 production, by inhibition of LTA4 hydrolase, had a very positive effect on both pressures as well as survival in animal models of PAH (Tian, W. et al., Sci Transl Med, 2013; 5: 1-14).

Eiger Bio has an exclusive license to this technology for targeting effects of leukotriene B4 (LTB4) to modulate inflammation and immune response in the lung, providing a potential preventative and therapeutic approach for treating PAH.  The technology was invented in the laboratory of Mark Nicolls, MD, Chief of Pulmonary and Critical Care Medicine at Stanford University.

Pathogenesis Figures

Figure A. Panel A is a sample of normal human lung, demonstrating no vascular occlusion (denoted by black).  Panel B-D are samples from PAH patients where occlusion of the pulmonary vasculature is observed (denoted by white arrows) with red and blue stains indicating LTB4 and other inflammatory cells.

Figure B.  Elevated LTB4 levels in serum in patients with PAH.