New data from the ADVANCE Outcomes trial, presented at the European Respiratory Society (ERS) Congress 2026 in Barcelona, Spain, held September 5 to 9, detail the baseline characteristics and clinical improvement outcomes behind ralinepag, an investigational oral prostacyclin (IP) receptor agonist whose new drug application (NDA) for pulmonary arterial hypertension (PAH) the FDA accepted for review last month.1
PAH is a progressive disease leading to right ventricular failure and death, and mortality remains high despite treatment advances, according to the study investigators.1 ADVANCE Outcomes (NCT03626688) is a global, randomized, double-blind, placebo-controlled, event-driven trial evaluating ralinepag added to background PAH-specific therapy in participants with WHO Group 1 PAH.1 Ralinepag is a potent, once-daily oral IP receptor agonist with high selectivity and 6-fold higher binding affinity for the IP receptor than the prostacyclin analog MRE-269.1
“In our clinical trial, ralinepag delayed disease progression, achieved clinical improvement, and provided durability of effect over many years,” said Martine Rothblatt, PhD, chairperson and chief executive officer of United Therapeutics.2
ADVANCE Outcomes baseline characteristics and trial design
ADVANCE Outcomes randomized 687 participants with PAH in a 1:1 ratio to ralinepag (n = 350) or placebo (n = 337) added to background PAH-specific therapy, with dosing individualized and titrated without a prespecified ceiling.1 The trial population reflected a contemporary, pretreated PAH cohort: 79.8% of participants were receiving dual background therapy, 70.5% were WHO Functional Class II, and mean baseline 6-minute walk distance (6MWD) was 439 m (SD, 105).1
The primary endpoint was time to first adjudicated clinical worsening event, and key secondary endpoints included change in NT-proBNP, 6MWD, and a composite clinical improvement outcome requiring at least 2 of 3 criteria: an increase in 6MWD of 10% or more (or 30 m or more), improvement to or maintenance of WHO Functional Class I or II, or a decrease in NT-proBNP of 30% or more.1 These findings build on the phase 3 ADVANCE Outcomes data supporting the ralinepag NDA, which the FDA accepted for review in August 2026 with a Prescription Drug User Fee Act target action date of June 24, 2027.2
Ralinepag clinical improvement and safety outcomes
Ralinepag reduced the risk of a clinical worsening event by 55% compared with placebo (hazard ratio, 0.45; 95% CI, 0.33-0.62; P < .001).1 At week 28, participants receiving ralinepag had 47% greater odds of achieving the composite clinical improvement outcome than those receiving placebo (P = .015).1 Ralinepag also produced significant improvements in NT-proBNP (24.3% reduction over placebo; 95% CI, -36.1% to -10.3%; P = .001) and 6MWD (20.4 m placebo-corrected increase; 95% CI, 6.81 to 34.02; P = .003).1
Ralinepag was generally well tolerated, and no new safety signals were observed relative to the known prostacyclin-related adverse event profile.1 Common adverse events were consistent with the prostacyclin drug class, including headache, diarrhea, nausea, and myalgia.1 Results were also consistent across prespecified subgroups, including disease etiology, 6MWD, WHO Functional Class, NT-proBNP levels, and background therapy use.2
If approved, ralinepag would become the first once-daily oral prostacyclin agent available to patients with PAH, according to United Therapeutics.2 Patients completing ADVANCE Outcomes had the option to enroll in an ongoing open-label extension, ADVANCE Extension, and the trial results have also been published in The Lancet.2
contemporary pulmonary arterial hypertension population: insights from the ADVANCE Outcomes study. Abstract 131722. Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.
