The U.S. Food and Drug Administration (FDA) accepted several modifications proposed by Bellerophon Therapeutics for its Phase 3 program to evaluate the efficacy and safety of INOpulse in patients with pulmonary arterial hypertension (PAH).
Under the new testing program, INOpulse may be ready for FDA review and possible approval years earlier than first anticipated.
INOpulse is a portable device that allows the continuous administration of inhaled nitric oxide (iNO) to ambulatory PAH patients in a controlled, fixed dose, dependent on body weight, and regardless of changes in respiration rate during exercise or sleep.
The original plan for the Phase 3 program included two studies, INOvation-1, involving 188 PAH patients and two treatment arms (placebo or iNO 75), and INOvation-2, with 282 PAH patients assigned to receive either placebo, iNO 50 or iNO 75. (INOvation-1, NCT02725372, is currently underway and recruiting PAH patients at eight testing sites across the U.S.)
With the approved modifications, the INOvation-2 study will now be replaced by a randomized withdrawal study involving about 40 patients from the INOvation-1 trial. This second study will include a four-month period in which patients receive treatment, followed by two months of withdrawal (no treatment).
The primary endpoint of the INOvation-1 study is changes in the six-minute walk distance (6MWD) test (a measure of exercise/function capacity) after four months of treatment. Patients showing an improvement of less or equal to 30 meters in this test, and who well tolerate inhaled nitric oxide, will be considered to enter the withdrawal study, in which they will be randomly assigned to receive a placebo (withdrawal) or continue treatment with iNO 75.
The withdrawal study’s objective is to understand whether or not clinical improvement during the treatment phase is due to iNO therapy. This will also help determine whether the 75 mcg/kg IBW/hr dose of iNO delivered through the INOpulse device for up to 24 hours a day can be considered an efficient treatment for PAH patients in need of long-term oxygen treatment (LTOT).
Both the INOvation-1 and withdrawal study will be carried out almost in parallel, which, according to Bellerophon, may reduce by at least two years the time until marketing of INOpulse, if it is approved by the FDA. Interim analyses will also be done halfway through the course of the studies, and if results prove successful, both may be stopped earlier.
Bellerophon believes these changes will provide better support to submit a New Drug Application (NDA) for the use of INOpulse in PAH patients on LTOT. The company anticipates that INOpulse may be approved as early as 2020.
“We are gratified that the FDA has agreed with the proposed modifications to our PAH Phase 3 program, which have the potential to make INOpulse available to PAH patients approximately two years earlier than otherwise would have been possible under the original Phase 3 program,” said Fabian Tenenbaum, Bellerophon’s president and CEO, in a news release.
“PAH is a rare disease and many patients continue to suffer from poor outcomes with currently available treatments. We believe INOpulse has the potential, if approved, to be an effective and well-tolerated treatment alternative for these patients.”