Ralinepag Phase 3 PAH Trial Results

Once-daily oral ralinepag reduced the risk of a first clinical worsening event among adults with pulmonary arterial hypertension (PAH) in the phase 3 ADVANCE OUTCOMES trial, published in The Lancet. The population was predominantly pretreated and at low or intermediate-to-low risk.

The randomized, double-blind, placebo-controlled, event-driven trial assigned 728 participants, all of whom received at least one dose of ralinepag or placebo. Among the analyzed participants, 350 received ralinepag and 337 received placebo; 80% were receiving dual background PAH therapy, and 57% had idiopathic PAH.

The primary outcome was time to first adjudicated clinical worsening event, a composite of death from any cause; hospitalization for worsening PAH or right heart failure; initiation of parenteral or inhaled prostacyclin-pathway therapy; disease progression; or unsatisfactory long-term clinical response. Events occurred in 18% of the ralinepag group and 36% of the placebo group, corresponding to a hazard ratio of 0.45 (95% confidence interval, 0.33-0.62; P<.0001).

At week 28, ralinepag produced a placebo-corrected 20.41m improvement in 6-minute walk distance and a 24.3% lower model-estimated N-terminal pro-B-type natriuretic peptide concentration. Clinical improvement was nominally more likely with ralinepag (common odds ratio, 1.47; 95% confidence interval, 1.08-2.02; nominal P=.015). This result was interpreted nominally because hierarchical testing stopped after World Health Organization functional-class improvement did not differ significantly between groups.

Adverse events caused treatment discontinuation in 19% of the ralinepag group and 3% of the placebo group. Serious adverse events occurred in 28% and 31%, respectively, while adverse events leading to death occurred in 4% of each group. The investigators reported that the adverse-event profile was consistent with known prostacyclin-pathway effects and that no new safety signals were observed. They concluded that the findings supported ralinepag as an oral, once-daily treatment option while noting that the placebo-controlled trial could not establish comparative efficacy or tolerability versus other approved prostacyclin-pathway therapies.

Sources: McLaughlin VV, Solum D, Lachant D, et al. Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study. Lancet. Published online July 28, 2026. doi:10.1016/S0140-6736(26)01011-1

McLaughlin VV, Solum DT, Lachant DJ, et al. A82-03 ADVANCE Outcomes: a phase 3, double-blind, placebo-controlled clinical trial of ralinepag for the treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2026;212(Suppl_2):aamag286.013. doi:10.1093/ajrccm/aamag286.013