United Therapeutics Corporation announced the conclusion of enrollment of the phase 3 ADVANCE OUTCOMES study evaluating the use of an extended-release formulation of ralinepag for the treatment of pulmonary arterial hypertension (PAH). The ADVANCE OUTCOMES study enrolled 728 participants. Clinical worsening events will be accrued through the end of 2025 and top-line data from the study is expected in the first half of 2026.

A previous phase 2 study of ralinepag in 61 PAH participants met its primary endpoint, showing a 29.8% reduction (p=0.03) in median pulmonary vascular resistance (PVR) after 22 weeks of treatment with ralinepag compared with placebo. After completing participation in the phase 2 study, 45 participants entered an open-label extension (OLE) study to assess the safety and tolerability of ralinepag for long-term use in patients with PAH. The OLE study reported that ralinepag continued to have a manageable side effect profile.

Moreover, two years after entering the OLE study, the study reported that ralinepAG significantly increased six-minute walk distance (6MWD) by a mean of 36.3 meters (p=0.004), and over 85% of study participants remained stable in their functional class from baseline. Additionally, hemodynamic measures taken either one or two years after entering the Ole study reported significant improvements (p=0.05) in both median PVR and mean pulmonary arterial pressure. Because the OLE portion of the phase 2 study was uncontrolled, these results need to be interpreted with caution.

Ralinepag is an investigational compound that is not approved for any use in any country. ADVANCE OUTCOMES is a global, multi-center, placebo-controlled phase 3 study evaluating an extended-release formulation of Ralinepag, an oral, selective, potent, once-daily IP receptor agonist intended to treat pulmonary arterial hypertension. The study includes participants on approved oral background PAH therapies.

Participants who complete the study have the opportunity to enroll in an open label extension study, ADVANCE EXTENSION. The primary endpoint of ADVANCE OUTCOMES is the time to the first clinical worsening event. Secondary endpoints of the study are change from Baseline through week 28 in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), six-minute walk distance, World Health Organization (WHO)/New York Heart Association (NYHA) functional class (FC), REVEAL risk score, heart rate recovery following completion of the six-minute walk test (6MWT), and health-related quality of life; proportion of subjects meeting NT-proBNP 440 meters, and WHO/NYHA FC I/II; time to all-cause mortality; time to first all-cause nonelective hospitalization; and safety and tolerability in subjects with PAH.