Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterised by elevated pulmonary vascular resistance that can lead to right ventricular failure and premature death. Ralinepag is an oral, once-daily, selective prostacyclin IP receptor agonist developed to treat PAH. We aimed to evaluate the efficacy and safety of ralinepag in patients with PAH. METHODS: ADVANCE OUTCOMES was a randomised, double-blind, placebo-controlled, event-driven, phase 3 trial of ralinepag in patients with PAH. Eligible patients were aged 18 years or older and PAH was diagnosed on the basis of the 2022 European Society of Cardiology and European Respiratory Society guidelines (mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and pulmonary vascular resistance of >2 Wood units). Patients were randomly assigned (1:1) to ralinepag or placebo, initiated at a dose of 50 μg once daily and titrated weekly until the highest tolerated individualised dose was reached. Randomisation was stratified by baseline 6-minute walk distance (6MWD), PAH aetiology, and oral background therapy. A block size of four was used within each combination of stratification factors. The sponsor, patients, and all personnel directly involved with the conduct of the study were masked to study drug identity and randomisation assignments. The primary outcome was time to first clinical worsening event, a composite of death from any cause, admission to hospital due to worsening PAH or right heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response. Efficacy analyses were done in the full analysis set and safety analyses in the safety set; both sets comprised 687 patients after exclusion of 41 randomly assigned and treated patients from sites in China (exclusions due to regulatory challenges and data integrity concerns). This study is registered with ClinicalTrials.gov (NCT03626688) and euclinicaltrials.eu (2023-509304-16-00) and is complete. FINDINGS: Patients were enrolled between Jan 24, 2019, and June 20, 2025. Of 1037 patients screened for eligibility, 728 were randomly assigned and received at least one dose of ralinepag or placebo; 687 were included in the full analysis and safety sets, of whom 350 received ralinepag and 337 received placebo. Median follow-up from randomisation to clinical worsening event, censoring, or study closure was 85·0 weeks (IQR 27·6-160·9) in the ralinepag group and 78·4 weeks (34·6-137) in the placebo group. At baseline, patients had a mean 6MWD of 438·9 m (SD 104·8) and 548 (80%) of 687 patients were receiving dual background PAH therapy. Overall, 64 (18%) of 350 patients in the ralinepag group and 121 (36%) of 337 patients in the placebo group had a first clinical worsening event (hazard ratio 0·45 [95% CI 0·33-0·62]; p<0·0001). The largest numerical between-group differences in components of the composite outcome were observed for disease progression, initiation of parenteral or inhaled prostacyclin-pathway therapy, and unsatisfactory long-term clinical response. Adverse event was the primary reason for treatment discontinuation in 65 (19%) of 350 patients in the ralinepag group and ten (3%) of 337 patients in the placebo group. Serious adverse events occurred in 98 (28%) patients in the ralinepag group and 104 (31%) patients in the placebo group. Adverse events leading to death occurred in 15 (4%) and 14 (4%) patients, respectively. INTERPRETATION: In patients with PAH receiving contemporary background therapy, ralinepag significantly reduced the risk of first clinical worsening compared with placebo, but was associated with more adverse-event-related treatment discontinuations. These results support the use of ralinepag as an oral, once-daily prostacyclin-pathway treatment option for PAH. FUNDING: United Therapeutics Corporation.