INOpulse – Cardiopulmonary Product

INOpulse is a portable device being developed by Bellerophon Therapeutics to treat lung diseases.

The device consists of a pulsative delivery system of nitric oxide (NO), an important agent for vasodilation. When given to a patient with pulmonary hypertension (PH) and constricted blood vessels in the lungs, inhaled nitric oxide (iNO) is absorbed by the smooth muscles and, through a series of biological mechanisms, helps to relax these muscles and achieve vasodilation, or the opening of blood vessels in the affected area. Consequently, blood pressure in the lungs and the strain on the right ventricle of the patient’s heart are reduced, and blood circulation becomes more normal.

Because it is portable, INOpulse is designed for daily use by patients as they go about daily life activities, inside and outside the home. The device is programmed to automatically adjust based on a patient’s breathing pattern, so that a constant and appropriate dose of iNO is delivered over time.

Bellerophon has three candidate INOpulse devices under development: One to treat pulmonary arterial hypertension (PAH), another for pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD), and a third for pulmonary hypertension associated with idiopathic pulmonary fibrosis (PH-IPF).

INOpulse and clinical trials

A Phase 2 clinical trial evaluated the use of pulsed iNO to treat patients with PH-IPF. A four-week, proof-of-concept study, it evaluated the ability of pulsed iNO to provide selective vasodilation (again, widening of blood vessels), as well as assess possible improvements in blood flow dynamics and exercise capacity in four PH-IPF patients.

Results were presented at the 113th American Thoracic Society (ATS) International Conference in May 2017, and showed that the study met its primary endpoint. An average 15.3 percent increase in blood vessel volume during acute inhalation of iNO was seen in patients, as well as a significant association between ventilation and vasodilation, demonstrating the ability of INOpulse to provide selective vasodilation to better-ventilated areas of the lungs. 

The results also showed that acute exposure to iNO led to an average 14 percent reduction in systolic pulmonary arterial pressure. After four weeks of treatment, patients also improved by an average of 75 meters in the six-minute walk distance (6MWD), a measure of exercise capacity. The study determined that iNO 30 mcg/kg is a potentially safe and effective dose. 

In another Phase 2 trial (NCT02734953), the INOpulse iNO system was seen to improve lung-pressure measurements in PAH patients.

Bellerophon reported positive data from the Phase 2 extension study of INOpulse and iNO treatment for PAH, establishing a clinical benefit for patients on long-term oxygen, whose disease was worsening despite being under at least one PAH therapy.

The company is continuing to evaluate data from its Phase 2 (NCT01457781) study  of INOpulse in patients with PAH, and is currently recruiting 188 PAH patients for its Phase 3 INOvation-1 trial (NCT02725372). This accelerated trial — taking place at about 90 sites across the U.S., and in Canada, Australia and select European countries — aims to determine the effectiveness, safety, and tolerability of INOpulse iNO treatment (75 mcg/kg), versus placebo, in PAH patients. Its primary goal is improvement at 18 weeks of treatment as measured by the 6MWD test, and initial results are expected to be released in late 2017. Final data is expected around mid-2018.

Based on these Phase 3 trial findings, and the results of a confirmatory withdrawal study that will recruit from patients enrolled in INOvation-1, the company expects to file a New Drug Application with the U.S. Food and Drug Administration (FDA), seeking approval to use INOpulse as a PAH treatment.

Bellerophon is also recruiting patients with PH-COPD and on oxygen therapy, (WHO group 3), for a Phase 1 clinical trial (NCT03135860) taking place in Belgium. The study will use high-resolution computed tomography (HRCT) to measure changes in functional pulmonary imaging parameters — the change in lobar blood volume after 4 weeks of treatment with iNO — assessing HRCT effectiveness in capturing those changes, and relate the findings to patient-reported outcomes and measures of changes in exercise tolerance.

During the ATS meeting in May, the company also presented initial results on the first four of 10 patients now enrolled in this PH-COPD study. The researchers found that four weeks of iNO treatment (using INOpulse device) led to better ventilation of patients’ lungs and a widening in blood vessels (vasodilation). Results also showed that all treated patients experienced a reduction in systolic pulmonary artery pressure.  Full study results are expected later in 2017.

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