Range of Clinical Trials Testing INOpulse System for PAH, PH-linked Lung Diseases, Bellerophon Announces

INOpulse is advancing in a number of clinical trials as a potential treatment of pulmonary hypertension (PH) associated with several lung diseases, Bellerophon Therapeutics reported in a recent announcement.

The company is currently developing INOpulse to treat PH associated with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), sarcoidosis, as well as for patients with pulmonary arterial hypertension (PAH).

INOpulse is an inhaled nitric oxide (iNO) therapy, designed to lower blood pressure in the lungs by acting as a potent vasodilator to relax and open blood vessels. It is administered through a tube in the nose using a portable device about the size of a paperback book, which automatically adjusts nitric oxide pulses to the patient’s breathing pattern.

“All three of our target indications, PH-ILD, PH-COPD, and PH-Sarcoidosis, represent significant unmet medical needs with mean survival as low as two years from diagnosis. INOpulse’s unique targeted vasodilation differentiates it from current vasodilators and offers the potential for it to be the first approved therapy in these indications,” Fabian Tenenbaum, CEO of Bellerophon, said in a press release.

The company announced preliminary results of its Phase 3 INOvation-1 trial (NCT02725372), assessing the potential and safety of INOpulse in PAH patients against placebo, in October. Data showed that treatment reduced pulmonary vascular resistance by 18 percent, compared to placebo, and  improved patients’ heart function, exercise capacity (measured by six-minute walk distance, 6MWD), and levels of a biomarker of right ventricular failure NT-ProBNP.

But evaluation of early findings by an independent Data Monitoring Committee concluded that benefits in exercise capacity — measured by the 6MWD test and the trial’s primary goal — after 16 weeks of treatment were not sufficient to demonstrate INOpulse’s effectiveness.  Based on this analysis, the committee recommended stopping the trial.

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“Although our INOvation-1 trial for INOpulse in PAH did not achieve its primary endpoint of 6MWD, we believe that the collective results from the trial support the cardio-pulmonary benefits of iNO,” Tenenbaum said. “The results showed clinical benefit in hemodynamics and right ventricular function consistent with currently marketed PAH therapies.”

Treated patients “not on prostanoids or multiple background therapies” also had better 6MWD scores, Tenenbaum added, results that “support the potential benefit that INOpulse can provide in PH-ILD, PH-COPD and PH-Sarcoidosis, where patients are not on any background PAH medications.”

Supported by positive results in an analysis of two patients in a Phase 1 study (NCT02267655) focused on PH associated with pulmonary fibrosis (a type of ILD), Bellerophon launched a Phase 2b trial (NCT03267108) in patients with PH-ILD.

The study has already enrolled 40 patients at U.S. sites, who will be given iNO 30 mcg/kg or placebo for eight weeks. Top-line results here are expected in January 2019. Since, the company decided to expand the trial, the release states.

Two groups of pulmonary fibrosis patients on long-term oxygen therapy and with or at risk of associated PH will be recruited to test the safety and effectiveness of two higher doses (45 and 75 mcg/kg) of iNO against placebo for 16 weeks.

Enrollment in these additional groups is set to start this month or next (information is available here), and results are expected to be announced later in 2019.

“The additional cohorts will allow us to assess higher doses of inhaled nitric oxide (iNO), along with longer duration of treatment, enabling us to plan for a potential pivotal Phase 3 program,” Tenenbaum said.

INOpulse was also evaluated in PH-COPD in a trial (NCT03135860; COPD-007 study), which included 10 patients with COPD who received 30 mcg/kg of iNO. The trial showed that this treatment strategy could induce a decrease of about 19.9% in systolic pulmonary arterial pressure (sPAP), with significant improvements in ventilation and vasodilation. Researchers also reported clinically meaningful benefits in exercise capacity at both two and four weeks of treatment, relative to baseline values.

Bellerophon and the U.S. Food and Drug Administration (FDA) reached an agreement on the design of a new Phase 2b study in PH-COPD.

This double-blind, placebo-controlled study will take place in the U.S. starting next year, and is expected to enroll about 90 PH-COPD patients. Treatment efficacy will be determined by changes in 6MWD compared to placebo, and other secondary endpoints, including right ventricular function and oxygen saturation.

Collected data will help define patient population, clinical endpoints, and study size for a future pivotal INOpulse Phase 3 study in COPD patients, the company said.

Another Phase 2 trial (NCT03727451) evaluating INOpulse in patients with PH-sarcoidosis is expected to open this year.

This open-label and dose-escalation study plans to enroll about 16 people, who will be treated with 30, 45, 75, or 125 mcg/kg iNO for up to 16 weeks, to determine the optimal dose for the open-label extension study that will follow. Efficacy will be determined by right heart catheterization and assessment of several outcome measures, including changes in cardiac function, pulmonary vascular resistance, and exercise capacity relative to baseline.

“We expect to initiate a Phase 2a trial to evaluate the hemodynamic benefit of INOpulse in PH-Sarcoidosis by year-end 2018, with results expected in 2019,” Tenenbaum said.