RALINEPAG may offer once daily prostacyclin pathway targeting for patients with pulmonary arterial hypertension already receiving background therapy.
ADVANCE OUTCOMES, a global Phase III morbidity and mortality trial, has completed enrollment of 687 participants with pulmonary arterial hypertension (PAH) across 30 countries and five continents. The randomized, double blind, placebo controlled study is evaluating whether ralinepag, an oral, highly selective IP receptor agonist, can improve outcomes when added to standard PAH specific background therapy.
Ralinepag is designed to mimic the pharmacokinetics of parenteral prostacyclins and provide continuous receptor engagement. The trial’s central question is whether this oral approach can translate into sustained clinical benefit while maintaining tolerability in a population already receiving established PAH treatment.
ADVANCE OUTCOMES Trial Design
Participants were randomly assigned 1:1 to receive ralinepag or placebo in addition to their background PAH therapy. Dosing was individualized and titrated according to tolerability and clinical response, with no prespecified dose ceiling.
The primary endpoint is time to first adjudicated clinical worsening event. Secondary assessments include changes from baseline to Week 28 in N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), WHO Functional Class, and health-related quality of life measures. Safety monitoring continued throughout the study.
At the time of abstract submission, treatment assignments and results remained blinded. Headline efficacy results are expected in the first half of 2026.
Low Risk Baseline Profile Shapes Interpretation
The full analysis population had a mean age of 52 years, and 76% were female. Most participants were White (80.2%), with representation from the USA and Canada, Europe, South and Latin America, and Asia-Pacific. Median time since PAH diagnosis was 2.28 years.
Idiopathic or heritable PAH accounted for 62.0% of cases, followed by connective tissue disease at 28.2%. Smaller proportions had PAH related to congenital heart disease, drug or toxin exposure, or HIV infection.
Baseline characteristics suggest a largely low risk population. Mean 6MWD was 439 m, median NT-proBNP was 214 pg/mL, and 70.5% of participants were in WHO Functional Class II. The median REVEAL 2.0 risk score was 5, and 74% of participants were categorized as low risk. Most participants were already receiving two background PAH therapies, with a median treatment duration of 1.8 years.
These characteristics make ADVANCE OUTCOMES an important test of whether once daily ralinepag can influence patient function, disease progression, and survival in treated PAH patients who, at baseline, largely appeared clinically stable.
Reference
Vallerie V. Mclaughlin et al. ADVANCE Outcomes: A Phase 3, Randomized Clinical Trial Evaluating Ralinepag for Pulmonary Arterial Hypertension. ATS International Conference, 2026.
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