iNO is a selective pulmonary vasodilator. Clinical experience suggests iNO has potential to treat PAH.
A Phase 2 placebo-controlled trial of two dose of iNO in PAH patients who required at least one background PAH therapy was completed. After 16 weeks of blinded treatment (Part 1, n=80), patients entered the long-term extension phase (Part 2). In Part 2 the patients originally receiving iNO 75 mcg/kg (IBW/hr) or iNO 25 mcg/kg (IBW/hr) remained on their assigned treatment, while patients from the placebo group were randomized (double-blind) to either iNO 75 or 25 mcg/kg. Eleven patients randomized to iNO and 4 patients randomized to placebo in Part 1 did not enter Part 2. In Part 2, the primary endpoint was pulmonary vascular resistance (PVR), and a key secondary endpoint was six minute walk distance (6 MWD), both assessed as the change from the time of randomization to 25 mcg/kg or 75 mcg/kg iNO to 12 months. The primary analysis included all patients randomly assigned to 25 or 75 mcg/kg iNO (N=76), while exploratory analyses included an assessment by subgroups on (LTOT) and not on (non LTOT) long-term oxygen therapy.
During the 12 month interval from randomization to 25 mcg/kg or 75 mcg/kg iNO, 28 of 76 patients discontinued iNO without evaluation of PVR and 3 patients died. Twelve months after randomization, 6 of 37 (16%) patients who received iNO 25 mcg/kg and 9 of 39 (23%) patients who received iNO 75 mcg/kg had ≥ 20% reduction in PVR (Table 1), while 6 of 37 (16%) patients who received iNO 25 mcg/kg and 10 of 39 (26%) patients who received iNO 75 mcg/kg had ≥ 50 meter increase in 6MWD (Table 2). The tables suggest efficacy may differ according to LTOT status.
In patients with ≤ 32 months of exposure, serious adverse events (SAE) occurred in 5/32 in the 25 mcg/kg group and 12/33 in the 75 mcg/kg groups. Unexpectedly, drug-related SAEs occurred in 6 and 0 patients, respectively.
In this small Phase II trial without a long term control regimen, even though caution is needed when considering signals of efficacyespecially inexploratory subgroup analyses, the data suggest interest in further evaluation of the 75 mcg/kg group, potentially focusing on subjects on LTOT where adherence may be enhanced. The sponsor plans a phase III trial