SUMMARY

• Company sponsored studies designed to investigate the safety and efficacy of UPTRAVI in the treatment of interstitial lung disease (ILD), or pulmonary hypertension associated with ILD have not been performed.
• A search of the internal database identified limited information from the pivotal GRIPHON (PGI2 Receptor agonist In Pulmonary arterial HypertensiON) study, which investigated the long-term efficacy, safety and tolerability of UPTRAVI in adult patients with symptomatic pulmonary arterial hypertension (PAH).¹ Of the 1156 patients enrolled, 16 (2.8%) in the UPTRAVI group and 22 (3.8%) in the placebo group had ILD listed as a previous or concomitant disease at baseline.² Of note, patients with moderate or severe restrictive lung disease were excluded from enrollment.^1,3,4 Subgroup analysis designed to determine overall efficacy and/or safety outcomes in this specific patient population was not undertaken.
• An analysis of data from the United States (US)-based SPHERE (SelexiPag: tHe usErs dRug rEgistry) registry (Data cut: December 20, 2019; N=500), an observational study designed to provide information on the disease characteristics, clinical outcomes, and dosing regimens of patients treated with UPTRAVI in routine clinical practice, revealed that 60 (12%) of patients had interstitial lung disease. However, details concerning outcomes of patients with comorbid ILD in the SPHERE registry are not available.⁵
• A search of the scientific literature retrieved 1 case series⁶  and 3 case reports^7-9, describing the administration of UPTRAVI to treat PAH in patients with comorbid ILD.

CLINICAL DATA

Information From GRIPHON

GRIPHON is a randomized, multicenter, double-blind, placebo-controlled, event-driven, phase 3 study that evaluated long-term efficacy, safety and tolerability of UPTRAVI in patients with symptomatic PAH. The study enrolled 1156 patients who were randomized 1:1 to receive UPTRAVI or placebo. The primary endpoint was a composite of death or a complication related to PAH (hospitalization for worsening PAH, worsening of PAH resulting in the need for lung transplantation or balloon atrial septostomy, initiation of parenteral [subcutaneous or intravenous] prostanoid therapy or chronic oxygen therapy, disease progression defined as a ≥15% decrease in 6-minute walk distance [6MWD], and either worsening of functional class [FC] or need for additional PAH therapy) up to the end of treatment period plus 7 days. Safety was assessed throughout the treatment period and up to 7 or 30 days after the last intake of UPTRAVI or placebo.¹

The total number of patients in GRIPHON with a previous or concomitant disease at baseline denoting ILD was 2.8% (n=16) in the UPTRAVI group and 3.8% (n=22) in the placebo group.² Of note, patients with moderate or severe restrictive lung disease, defined as a total lung capacity <60% of predicted, were excluded from enrollment.^1,3,4 A subgroup analysis designed to determine overall efficacy and/or safety outcomes in this specific patient population with previous or concomitant ILD was not undertaken.²

Information From SPHERE

SPHERE was a US-based, multicenter, prospective, observational drug registry that enrolled patients actively treated with UPTRAVI, which was designed to provide information on the disease characteristics, clinical outcomes, and dosing regimens of patients treated with UPTRAVI in routine clinical practice.⁵

At an interim data analysis (data cut: December 20, 2019; N=500), 60 (12%) of patients had comorbid interstitial lung disease.⁵

Details concerning outcomes in these patients with comorbid ILD in the SPHERE registry are not available.

Information From Case Series

Dagher et al (2025)⁶ conducted a retrospective case series involving 8 patients with connective tissue disease associated with PAH (CTD-PAH) and scleroderma. All patients were naïve to prostacyclin therapy and had confirmed ILD. The study evaluated outcomes over a 16-week period of UPTRAVI treatment. At baseline, the median age of the patients was 51.5 (range, 48–62) years. All patients were receiving background therapy for PAH, including phosphodiesterase type 5 inhibitors (PDE-5i) and endothelin receptor antagonists (ERA). At the time of PAH diagnosis, the average mean pulmonary arterial pressure (mPAP) was 47 mmHg, and the mean pulmonary vascular resistance (PVR) was 8.6 Wood units (WU).

Patients started UPTRAVI at a dose of 200 mcg twice daily. After an 8-week titration period, all patients reached a maintenance dose of 1600 mcg twice daily. During titration, common adverse events (AEs) included headaches and nausea. No patient discontinued UPTRAVI during the 16-week follow-up.⁶ 

At 16 weeks, there was an average increase of 101.8 meters (m) in the 6MWD, which was statistically significant (P<0.05), increasing from a baseline average of 306 m to 407 m. All patients showed a decrease in N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels; however, this reduction was not statistically significant for the group (P=0.1048).⁶ 

Overview of Identified Information From Other Studies

Relevant information identified from 3 case reports^7-9 describing the administration of UPTRAVI to treat PAH in patients with comorbid ILD is summarized in Table: Case Reports Describing the Administration of UPTRAVI to Treat PAH in Patients With Comorbid ILD.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 8 July 2025.