INOpulse for PH-COPD

Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with pulmonary hypertension associated with chronic Idiopathic Pulmonary Fibrosis (PH-IPF).

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.

IPF patients have low blood oxygen levels, a condition known as hypoxemia. When parts of the lungs are not well ventilated, as is often the case in PH-IPF, a protective mechanism known as protective hypoxic vasoconstriction can occur. This condition, where the body narrows certain blood vessels in poorly ventilated parts of the lung to send blood to better functioning parts of the lung, is the body’s mechanism to increase the amount of oxygen transferred to the blood. However, when this happens, the narrow arteries can put extra pressure on the heart. In addition, PH-IPF patients often have depressed production of the natural nitric oxide in the blood vessels of their lungs, which also causes them to narrow.

Research has suggested that inhaled nitric oxide may help open or dilate the blood vessels in the lungs of these patients. Dosing as a small pulse early in the patient’s breath may reduce the potential for adverse effects.

Disease Overview

IPF is 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 IPF is primarily a respiratory disease, it can also affect the pulmonary blood circulation, resulting in chronic pulmonary vasoconstriction and pulmonary hypertension. Pulmonary hypertension (PH) is a common complication in patients with late-stage IPF. PH-IPF has also shown to be associated with poor clinical outcomes when compared to similar IPF patients without PH.

To learn more about this condition, visit the IPF Foundation

Clinical Need

There is a significant and common unmet medical need for patients with PH associated with IPF that may be overlooked in everyday clinical practice because of the lack of available approved therapy. Also, drugs that are currently used to reduce pulmonary hypertension in PAH patients have been shown to potentially cause other problems, such as worsening hypoxemia, when used on patients with PH-IPF. This may be because these drugs act across a wide portion of the lungs’ blood vessels and can reverse the body’s protective mechanism of hypoxic vasoconstriction. 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.

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, while not reversing the body’s protective mechanism in other parts 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 (PHC) 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 initiated a clinical trial to evaluate both acute and chronic inhaled nitric oxide therapy in PH-IPF patients.

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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