Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with pulmonary hypertension associated with sarcoidosis (PH-Sarc).

Disease Overview

Sarcoidosis is characterized by the growth of inflammatory cells (granulomas) most commonly in the lungs or lymphatic tissues.  The cause of sarcoidosis is not known, but is believed to be an immune reaction to an unknown trigger such as infection or chemical in those that are genetically predisposed. Symptoms include fatigue, weight loss, joint aches and pains, dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry, hacking cough, or skin lesions. Up to 20% of sarcoidosis will also develop pulmonary fibrosis.

Possible treatments include steroids, methotrexate, chloroquine or azathioprine.  The efficacy of the antifibrotic therapies used for idiopathic pulmonary fibrosis have not been established for pulmonary fibrosis with sarcoidosis.  Lung transplantation is used in subjects with severe pulmonary fibrosis.

To learn more about this condition, visit the Foundation for Sarcoidosis Research.

Clinical Need

One of the long term outcomes of sarcoidosis is pulmonary hypertension.  The 5 year survival in subjects with pulmonary hypertension is only 59% compared to 96% survival in subjects without sarcoidosis.  Most patients with PH-Sarc also have pulmonary fibrosis, but not all. There are no approved therapies for PH-Sarc.

Mechanism of Action

Nitric oxide is normally produced in the blood vessel endothelium linings, working on the smooth muscle of the blood vessels to dilate or open the arteries. When nitric oxide enters the smooth muscle cells, it directly activates a chemical called soluble guanylate cyclase (sGC) in these cells. sGC produces another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP then causes the smooth muscle cells to relax, which in turn causes the blood vessels (arteries) to widen or dilate also known as vasodilation.

The INOpulse delivery system was designed to deliver nitric oxide in a targeted fashion allowing it to act primarily on the well-functioning part of the lung. The theory behind this delivery is that because inhaled nitric oxide is very short-acting and is deactivated quickly when it contacts blood, delivering it to well-ventilated parts of the lung will allow it to open up the blood vessels where good gas exchange is possible.

As with ILD with pulmonary fibrosis, inhaled nitric oxide may be beneficial in treatment of PH-Sarc by dual mechanisms. First, NO is a potent vasodilator thereby decreasing pressures in the pulmonary arteries and may improve right ventricular function. Second, inhaled nitric oxide is preferentially delivered to the well ventilated areas of the lung thereby matching ventilation to perfusion (V/Q matching) and improving oxygenation. This dual mode of action is not present with other PAH drugs since other PAH drugs do not preferentially dilate vessels in well ventilated areas of the lung.

Clinical Trials

We hypothesize inhaled nitric oxide reduces pulmonary vascular resistance without disturbing ventilation/perfusion of the lungs. A previous study of inhaled nitric oxide in PH-Sarc patients supports this hypothesis.

We are currently conducting a Phase 2 hemodynamic study in patients with pulmonary hypertension associated with sarcoidosis.

Find out more about this trial at clinicaltrials.gov.

References

1. Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS.  Chest 2001; 120:866
2. Patterson KC, Strek, MD.  An Am Thorac Soc 2013; 10 (4):362-370