Bellerophon Therapeutics recently announced the results from the final analysis (Part 2) of its Phase 2 long-term extension clinical trial on iNO/INOpulse drug-device combination product for the treatment of patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH).

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

Results from the Phase 2 long-term extension trial demonstrated a sustained clinical benefit in patients with PAH who were treated with INOpulse 75 mcg/kg ideal body weight per hour (iNO 75) therapy for a minimum of 12 hours daily in combination with Long-Term Oxygen Therapy (LTOT).

In Part 1 of the Phase 2 trial, these patients had a mean six-minute walk distance (6MWD, a measure of exercise capacity) improvement of 52.4 meters following 16 weeks of therapy. In Part 2 of the trial, following treatment for 16 to 32 months, those patients who remained on iNO 75 for a minimum of 12 hours daily in combination with LTOT maintained a mean increase in 6MWD of 55.2 meters.  These results supported the design of an already planned Phase 3 clinical trial.

After 16 weeks of blinded treatment in Part 1 of the trial, 65 patients were randomly assigned in Part 2 to receive either iNO 25 or iNO 75.  The long-term extension analysis of the data was conducted after patients had accomplished between 16 and 32 months of INOpulse therapy. The results were then compared to the assessments taken at baseline at Part 1. All patients in the trial were under at least one PAH therapy, and the majority were taking two or three PAH treatment drugs.

Results from the long-term extension analysis revealed:

• Patients on LTOT and iNO 75 who continued on INOpulse therapy for a minimum of 12 hours per day had a mean improvement of 55.2 meters in comparison with baseline (7 patients).
• Patients on LTOT and iNO 75 who continued on INOpulse therapy for fewer than 12 hours per day had a mean decrease of 18.0 meters in comparison with baseline (six patients).
• Patients in the treatment arm of iNO 25 dose, including those patients on LTOT, had a mean decrease of 43.7 meters from baseline (12 patients).

In terms of safety, there were no issues and no methemoglobin elevation or adjudicated pulmonary rebound cases were observed. There were two serious adverse events, possibly related, in patients who remained on iNO therapy.

These results confirmed previous tests where patients under LTOT and iNO 75 for a minimum of 12 hours daily had the greatest clinical benefit.

“The long-term analysis is very encouraging for PAH patients, as the data indicates a clinically significant and sustained benefit for patients on Long-Term Oxygen Therapy and the higher iNO 75 dose, when used for at least 12 hours per day,” said Jonathan Peacock, chairman and CEO of Bellerophon Therapeutics, in a news release. “The analysis supports the hypothesis generated from Part 1 of the Phase 2 study and is well aligned with the design of the Phase 3 program, for which we have agreement with the FDA through an SPA and with the European Medicines Agency, through a Scientific Advice Working Party.”

The planned U.S. and EU Phase 3 program will include two confirmatory trials in approximately 450 patients, in which one trial will have two treatment arms (iNO 75 and placebo) and one with three treatment arms (iNO 75, iNO 50, and placebo). The primary endpoint for each trial, which will run for two weeks, is the 6MWD after 16 weeks of treatment.

Time to Clinical Worsening (TTCW) is the secondary endpoint, pooled across both trials. The Phase 3 trials will use the second-generation INOpulse device, which is lighter and smaller, with improved user interface and better breath detection technology than the INOpulse DS device used in the Phase 2 trial.