INOpulse for PH-ILD

Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with pulmonary hypertension associated with Interstitial Lung Disease (PH-ILD).

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.

Disease Overview

Interstitial lung disease (ILD) is a general category that includes many different lung conditions.  All interstitial lung diseases affect the interstitium, a lace-like network of tissue that extends throughout both lungs.  ILDs are a chronic progressive disease of destruction of the airways and lung tissue. This results in scarring, thickening of the lung tissue causing insufficient ability for the lungs to oxygenate blood to be delivered to the body, caused by imbalance in mediators and chronic inflammation. While ILD is primarily a respiratory disease, it can also affect the pulmonary blood circulation, resulting in vascular remodeling and pulmonary hypertension. Chronic elevation of the pulmonary artery pressures puts stress on the right ventricle and can lead to ventricular failure.

One of the largest and most serious subset of ILDs is IPF (Idiopathic Pulmonary Fibrosis). IPF patients have a life expectancy of only 3-5 years after diagnosis.  There is no cure, and extremely few, or specific therapies to treat IPF.

To learn more about this condition, visit the IPF Foundation

Clinical Need

Pulmonary hypertension (PH) is a common complication in patients with late-stage IPF and other ILDs. PH associated with IPF, which is the most widely studied, has also shown to be correlated with poor clinical outcomes when compared to similar IPF patients without PH. This significant and unmet medical need for patients with PH associated with IPF and other ILDs, may be overlooked in everyday clinical practice because of the lack of available approved therapy. To date the drugs that are currently used to reduce pulmonary hypertension in PAH patients have not been effective in clinical trials when these drugs are used for patients with ILD.

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.

Inhaled nitric oxide may be beneficial in treatment of PH with IPF and other ILDs 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. Previous studies of inhaled nitric oxide in IPF patients have supported the hypothesis.

In a previous study by Yoshida et al., PH-IPF patients (10 subjects) were monitored with Right Heart Catheterization (RHC) for hemodynamic changes. Each patient was monitored for 10 minutes each on room air, room air with nitric oxide, oxygen alone, and nitric oxide with oxygen. The results showed a significant decrease in pulmonary pressure and a significant increase in oxygenation for the combination of nitric oxide and oxygen when compared to oxygen alone.

In another study by Blanco et al., PH-IPF patients (7 subjects) received inhaled nitric oxide both at rest and during exercise for 20 minutes. During both rest and exercise, hemodynamic measurements showed a significant decrease in pulmonary artery pressure on inhaled nitric oxide compared to air, with greater vasodilation during exercise than at rest.

We have completed a clinical trial to evaluate both acute and chronic inhaled nitric oxide therapy in PH-IPF patients. The results showed that iNO results in regional dilatation of blood vessels in the lung in the well-ventilated areas.  In addition, there were improvements in hemodynamics with acute use of iNO and meaningful improvements in exercise capacity over 4 weeks of chronic use.

We are planning a larger Phase 2b study in a wider population of pulmonary fibrosis patients at both low and intermediate/high risk of pulmonary hypertension.

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  1. Yoshida M, Taguchi O, Gabazza EC, Yasui H, Kobayashi T, Kobayashi H, Maruyama K, Adachi Y, Eur Respir J 1997;10:2051-2054
  2. Isabel Blanco, Jesús Ribas, Antoni Xaubet, Federico P. Gómez, Josep Roca, Robert Rodriguez-Roisin, Joan A. Barberà. Journal of Applied Physiology Published 1 March 2011 Vol. 110 no. 3, 638-645