Functional Respiratory Imaging (FRI) Markers Correlate With Clinical Endpoints in a Phase 2 Study of Treprostinil Palmitil Inhalation Powder in Patients With Pulmonary Hypertension Associated With Interstitial Lung Disease (PH-ILD)

Rationale: Vascular remodeling and loss of small pulmonary vessels on high-resolution computed tomography (HRCT) is described in PH. In an exploratory FRI analysis of a phase 2, double-blind, placebo-controlled trial in patients with PH-ILD (NCT05176951), patients in the TPIP arm showed a significant increase in the proportion of vascular volume in small arteries and a directional improvement in small-to-large artery volume ratio versus placebo. We hypothesized that observed changes in FRI markers would be associated with changes in clinical parameters. Methods: In this exploratory analysis, FRI markers were calculated for all patients with HRCT scans collected at baseline and week 16 (n=28). Volumes of small (≤5 mm 2 [BV5]) and large (≥10 mm 2 [BV10]) blood vessels in cross-sectional areas were analyzed. A deep-learning algorithm identified areas of high attenuation suspected as fibrosis; These were expressed as a percentage of total lung volume (HAA score). The Spearman rank correlation coefficient was calculated to evaluate the relationship between change from baseline (CFB) in FRI markers and clinical endpoints (CFB in 6-minute walk distance [6MWD] and NT-proBNP levels). Results: Change in FRI markers reflecting increased blood volume in small vessels consistently correlated with improved 6MWD and reduced NT-proBNP. An inverse relationship was observed between CFB in large vessels and 6MWD. An increase in the small-to-large vessel ratio was significantly associated with increased 6MWD and decreased NT-proBNP. Overall, increase in FRI markers of small arteries and veins combined showed stronger correlations with clinical parameters than markers of arteries alone. Decrease in HAA score was strongly associated with improved 6MWD and directionally correlated with decreased NT-proBNP. Conclusions: FRI markers of improved peripheral pulmonary vessel volume correlated favorably with positive shifts in clinical measures of cardiac ventricular stress (NT-proBNP) and exercise capacity (6MWD) in patients with PH-ILD. A similar relationship was demonstrated with reduced HAA scores. These findings support the use of quantitative HRCT parameters as markers of treatment response in pre-capillary PH. Further evaluation in a larger trial may provide additional insights. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany