INOpulse for PAH

Bellerophon Therapeutics is developing the INOpulse delivery system for the treatment of patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH).

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.

Since blood vessels in the lungs of PAH patients are narrowed and because PAH patients sometimes have impaired release of naturally produced nitric oxide in their lungs, researchers have proposed the potential benefit of chronic administration of inhaled nitric oxide to PAH patients. Small studies published in medical literature support this potential, but larger definitive studies are needed.

Disease Overview

PAH is a rare, chronic, and currently incurable disease that causes the walls of the arteries of the lungs to tighten and stiffen. Estimates suggest that there are about 15,000 patients diagnosed with PAH in the United States and about 20,000 patients in Europe. In someone with PAH, the right side of the heart has to work harder to pump blood through narrowed arteries in the lungs, which can decrease blood flow through the body. Eventually, the extra stress causes the heart to enlarge and become less flexible, further compromising its ability to pump blood out of the heart, through the lungs, and into the rest of the body. Patients with PAH have symptoms ranging from dizziness and fainting to shortness of breath during exercise. This range of symptoms, combined with the rare nature of the condition, often makes diagnosis difficult, and many PAH patients are not diagnosed until the disease has progressed.

To learn more about this condition, visit the Pulmonary Hypertension Association.

Clinical Need

Although current therapies for PAH provide some benefit, there remains no cure, and some approved therapies can have significant systemic side effects, such as hypotension, hepatic dysfunction, and nausea. Despite the availability of approved medications, mortality remains a significant concern.

The INOpulse delivery system was designed specifically to continuously administer nitric oxide to spontaneously breathing ambulatory patients using a carefully controlled, fixed dose over time that is independent of changes in respiratory rate during exercise or sleep. The device delivers a pulsed dose of nitric oxide to ensure a constant dose over time in micrograms per kilogram of ideal body weight per hour (mcg/kg/IBW/hr). The INOpulse is configured to be highly portable and compatible with many available modes of oxygen delivery.

Clinical Trials

In October 2014, we completed a randomized, placebo-controlled, double-blind Phase 2 clinical trial of INOpulse for PAH. This was a Phase 2, placebo-controlled, double-blind, randomized, clinical study to determine safety, tolerability, and efficacy of pulsed iNO versus placebo as add-on therapy in symptomatic subjects with PAH.  The phase 2 data have shown the optimal benefit of INOpulse is in combination with long-term oxygen therapy (LTOT).  Based on the results of the Phase 2 trial, we have finalized our clinical development plans including phase 3 trial design in agreement with FDA and European Medicines Agency (EMA).  We initiated our Phase 3 clinical program for INOpulse for PAH in 2016.

Find out more about this trial at