D28-20 ADVANCE Outcomes: A Phase 3, Randomized Clinical Trial Evaluating Ralinepag for Pulmonary Arterial Hypertension
V V Mclaughlin, A Ataya, J A Barbera, R L Benza, G Bohns Meyer, S Chang, R N Channick, J F Feenstra, S P Gaine, G Giannakoulas, C Sanchez Diaz, D Khanna, N H Kim, D J Lachant, R J Oudiz, I R Preston, N Sood, F Torres, J E Vachiery, T Pulido Zamudio, D Cella, M Escudero, V Lacasse, D T Solum, M J HumbertAbstract
Rationale
Ralinepag is a potent, once-daily, oral, highly selective IP receptor agonist. Ralinepag pharmacokinetics mimic parenteral prostacyclins and can provide continuous receptor engagement, with potential for sustained efficacy and improved tolerability. ADVANCE OUTCOMES (NCT03626688) was a multicenter, global, randomized, double-blind, placebo-controlled, morbidity and mortality study to evaluate the efficacy and safety of ralinepag in participants with pulmonary arterial hypertension (PAH).
Methods
In this event-driven study, participants with PAH were randomly assigned (1:1) to receive ralinepag or placebo, in addition to their standard of care PAH-specific background therapy. Dosing was individualized and titrated based on tolerability and clinical response. No dose ceiling was specified. The primary endpoint was 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 (FC), and health-related quality of life measures. Participant safety was monitored throughout the study. At the time of submission, treatment assignments and results remain blinded.
Results
The study completed enrollment in June 2025 with headline efficacy results expected in the first half of 2026. The full analysis dataset totals 687 participants from 30 countries distributed across five continents (Table 1). The population was primarily white (80%) with a mean age of 52 and a median time since diagnosis of 2.3 years. Sixty-two percent were classified as idiopathic or heritable PAH, 28.2% PAH due to connective tissue disease, 4.1% congenital heart defect, 3.1% drug/toxin induced, and 2.6% due to HIV infection. At baseline, participants had been receiving background PAH treatment for a median of 1.8 years (range, 0.09 to 22.7) and 80% of participants were receiving 2 background PAH therapies. Overall, the population exhibited low risk characteristics, including a mean (SD) 6MWD of 439 (105) m, low median (IQR) NT-proBNP of 214 (85, 523) pg/mL, and 71% were classified as WHO FC II. REVEAL 2.0 risk scores correspond to these characteristics, with a median (IQR) of 5 (3, 7) and 74% being considered low risk at baseline.
Conclusions
The full analysis population for the ADVANCE OUTCOMES study represents an opportunity to determine the effect of once-daily ralinepag on patient function, disease progression, and survival in a largely low-risk PAH population receiving two background therapies. Sponsored by United Therapeutics
This abstract is funded by: United Therapeutics