INOpulse for PH-COPD

Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD).

Mechanism of Action

Nitric oxide (NO) 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.

COPD patients with advanced disease often 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 COPD, 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, COPD patients often have depressed production of the natural nitric oxide in the blood vessels of their lungs, which also causes them to narrow.

Researchers have suggested that inhaled nitric oxide could help open or dilate the blood vessels in the lungs of these patients. Further, they proposed that dosing as a small pulse early in the patient’s breath could reduce the potential for adverse effects.

Disease Overview

COPD is a chronic progressive disease caused by chronic inflammation and destruction of the airways and lung tissue. While COPD is primarily a respiratory disease, the chronic exposure to toxins in tobacco smoke and resulting lack of oxygen may cause changes in the pulmonary circulation, resulting in chronic pulmonary vasoconstriction and pulmonary hypertension. Pulmonary hypertension, or PH, is a common complication in patients with late-stage COPD. PH-COPD has also shown to be associated with poorer clinical outcomes in patients with this condition when compared to similar patients without PH. However, a causal link between higher pulmonary pressures and worsened health outcomes has not yet been proven.

To learn more about this condition, visit the COPD Foundation.

Clinical Need

There is a significant and common unmet medical need for patients with PH associated with COPD 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-COPD. 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.

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.

This concept has shown benefit in an open-label randomized control study in a small number of subjects. We are now evaluating this in a larger clinical trial using a new device and dosing regimen and plan to conduct additional studies with the goal of getting this drug-device combination approved, by health regulatory agencies around the world, for use by patients with PH-COPD on long-term oxygen therapy.

Clinical Trials

A Phase 2, randomized, controlled, open-label, comparative study in 32 subjects with PH associated with COPD was conducted in Austria and sponsored by Messer Austria GmbH. Subjects were randomized to receive either oxygen alone (17 subjects) or oxygen with pulsed inhaled nitric oxide (15 subjects) for 3 months. Pulsed delivery of nitric oxide showed no treatment-limiting long-term effects on lung function, methemoglobin levels, or incidence of adverse events after 3 months of therapy. Importantly, there were reductions in pulmonary arterial pressures and improvements in cardiac output. We have obtained an exclusive license to this data and have incorporated the findings into our clinical development program.

We completed a Phase 2 acute dose ranging trial with the INOpulse DS device in July 2014. Given the nature of the condition, we required that all participants in the trial be on long-term oxygen therapy (LTOT).

Find out more about this trial at

We have initiated a chronic use clinical trial in PH-COPD evaluating the effect on exercise capacity.


Vonbank K, Ziesche R, Higenbottam TW, et al. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax. 2003;58(4):289-293.