United Therapeutics reports ralinepag PAH data showing 55% reduction in clinical worsening

US-based pharma co United Therapeutics announced that ralinepag, an oral prostacyclin receptor agonist, met the primary endpoint in the Phase III ADVANCE OUTCOMES study in pulmonary arterial hypertension (PAH). The ralinepag clinical worsening reduction of 55% versus placebo positions the molecule as a potential first once-daily oral prostacyclin for PAH, a disease area where United Therapeutics has built its franchise over more than two decades.

Trial specifics

The ADVANCE OUTCOMES study was a multicenter, global, randomized, double-blind, placebo-controlled, event-driven Phase III trial enrolling 687 adults with PAH. Patients were randomized 1:1 to receive ralinepag or placebo on top of standard-of-care PAH background therapy. Dosing was once daily, individualized and titrated according to tolerability and clinical response, with no specified dose ceiling. At baseline, 80% of patients were receiving dual background therapy and 70% were classified as WHO/NYHA Functional Class II.

The primary endpoint was time to first adjudicated clinical worsening event – defined as death, nonelective hospitalization for worsening PAH, initiation of parenteral or inhaled prostacyclin-pathway therapy for worsening PAH, disease progression, or unsatisfactory long-term clinical response. Ralinepag reduced this risk by 55% compared with placebo (hazard ratio 0.45, 95% CI 0.33–0.62; p<0.0001).

Among secondary endpoints, statistically significant improvements were observed in six-minute walk distance and NT-proBNP levels, details not disclosed. The odds of achieving clinical improvement from baseline to Week 28 were 47% higher with ralinepag than placebo (p=0.015). The company reported that benefits were consistent across subgroups, while the safety profile was described as consistent with known prostacyclin-related adverse events. Patients completing the study had the option to enroll in an ongoing open-label extension, ADVANCE EXTENSION.

United Therapeutics said it intends to submit a New Drug Application for ralinepag to the US FDA by the second half of 2026 and plans to present full results at an upcoming international conference.

Research context

Ralinepag is a selective agonist of the prostacyclin (IP) receptor, a G protein-coupled receptor whose activation increases intracellular cyclic AMP in pulmonary artery smooth muscle and endothelial cells. This signaling cascade promotes vasodilation, inhibits smooth muscle proliferation, and exerts anti-inflammatory and antiplatelet effects.

PAH is characterized by endothelial dysfunction and a deficiency in endogenous prostacyclin, making restoration of IP receptor signaling a well-validated therapeutic strategy. According to United Therapeutics, ralinepag demonstrates six-fold higher binding affinity for the IP receptor than MRE-269, the active metabolite of selexipag, and achieves sustained receptor occupancy that the company compares to parenteral prostacyclin therapy. In a prior Phase II study, ralinepag reduced pulmonary vascular resistance versus placebo in patients on mono or dual background therapy.

PAH affects approximately 500,000 individuals worldwide and remains a progressive, fatal condition despite the availability of therapies targeting three established pathways: endothelin, nitric oxide, and prostacyclin. Current PAH treatment guidelines recommend combination therapy, yet long-term outcomes remain poor. The prostacyclin pathway is served by several approved agents, but oral options have been limited in potency and pharmacokinetic profile relative to parenteral formulations such as intravenous epoprostenol and subcutaneous treprostinil.

The most direct competitor to ralinepag in the oral prostacyclin PAH space is selexipag (Uptravi), developed by Actelion (now part of Johnson & Johnson). Selexipag is the only currently approved oral selective IP receptor agonist for PAH, having received US FDA approval in 2015 based on the GRIPHON Phase III trial, which demonstrated a 40% reduction in the composite of morbidity and mortality events. Ralinepag’s reported 55% risk reduction in a broadly comparable composite endpoint, albeit in a different trial population and era of background therapy use, will invite direct comparison once full data are available.