A Phase 2 Study of the Safety and Tolerability of Treprostinil Palmitil Inhalation Powder in Patients With Pulmonary Hypertension Associated With Interstitial Lung Disease

ABSTRACT Treprostinil palmitil (TP) inhalation powder (TPIP), an investigational formulation of the treprostinil prodrug TP, was designed to provide prolonged pulmonary vasodilation with once‐daily administration. In this phase 2 study (NCT05176951), adults with pulmonary hypertension associated with interstitial lung disease (PH‐ILD) were randomized 3:1 to receive TPIP ( n = 29) or placebo ( n = 10) for 16 weeks. TPIP was up‐titrated from 80 µg to each patient's maximum tolerated dose (≤ 640 µg). Study endpoints were safety and tolerability (primary); pharmacokinetics of TP and treprostinil (secondary); and clinical worsening, change from baseline in 6‐min walk distance (6MWD), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels (exploratory). Maximum TPIP dose (640 µg) once daily was achieved by 79.3% of patients. TPIP was well tolerated in this study, with a safety profile generally consistent with previously reported route‐specific treatment‐emergent adverse events (TEAEs) of inhaled treprostinil, such as cough and dyspnea. TEAEs occurred in 93.1% and 90.0% of patients on TPIP and placebo, respectively. Most TEAEs were mild or moderate in both groups. In patients on TPIP and placebo, TEAEs leading to treatment discontinuation occurred in 4 (13.8%) and 3 (30.0%) patients, respectively, and serious AEs occurred in 6 (20.7%) and 4 (40.0%) patients, respectively. Following the 640 µg TPIP dose, the treprostinil elimination half‐life was 7.1 h. In TPIP and placebo groups, clinical worsening was observed in 3 (10.3%) and 5 (50.0%) patients, respectively. Trends for improvement were observed in 6MWD and NT‐proBNP with TPIP treatment. These results suggest that TPIP may be a suitable once‐daily treatment for PH‐ILD.