55% Risk Reduction: Ralinepag’s ADVANCE OUTCOMES Results Signal New PAH Era

United Therapeutics Corporation announced positive top-line results from its pivotal phase 3 ADVANCE OUTCOMES study (NCT03626688), showing that oral ralinepag reduced the risk of clinical worsening events by 55% in patients with pulmonary arterial hypertension (PAH) compared to placebo. The hazard ratio was 0.45 (95% CI [0.33-0.62]; p<0.0001), demonstrating robust, durable efficacy in delaying disease progression.

In this event-driven, multicenter trial involving 687 PAH patients, 80% were on dual background therapy and 70% were WHO/NYHA Functional Class II at baseline.

Ralinepag, a highly selective IP receptor agonist, met its primary endpoint time to first adjudicated clinical worsening (death, nonelective PAH hospitalization, new parenteral/inhaled prostacyclin, disease progression, or unsatisfactory response) while showing statistically significant improvements in key secondary endpoints.

These included 47% increased odds of clinical improvement from baseline to Week 28 (p=0.015), gains in six-minute walk distance (6MWD), and reductions in NT-proBNP levels.

Benefits held consistent across subgroups, including time since diagnosis, etiology, baseline 6MWD, and background therapies, underscoring ralinepag’s broad potential. The drug was well-tolerated, with a safety profile aligned to known prostacyclin effects and no new signals.

“PAH is a progressive, life-threatening disease that has a devastating impact on patients’ lives. In the ADVANCE OUTCOMES study, ralinepag delayed disease progression in patients with PAH facing significant disease burden at baseline. Ralinepag’s potency and once-daily oral dosing make these outcomes highly relevant in real-world settings,” said Vallerie V. McLaughlin, M.D., Chair of the ADVANCE OUTCOMES Steering Committee and Director of the Pulmonary Hypertension Program at the University of Michigan.

United Therapeutics’ leadership reiterated the enthusiasm. “Our achievement in this pivotal trial is among the most important in our history and strengthens our decades-long commitment to advancing prostacyclin-based science,” stated Martine Rothblatt, Ph.D., Chairperson and CEO. Derek Solum, Ph.D., Senior Director of Product Development, added, “With its extended-release profile mimicking parenteral therapy, ralinepag provides disease-mitigating capabilities that target underlying PAH pathology.”

Ralinepag’s mechanism six-fold higher IP receptor affinity than selexipag’s metabolite, sustained occupancy, and potent cAMP elevation positions it for vascular protection via vasodilation and anti-remodeling effects. Prior phase 2 data showed significant pulmonary vascular resistance reductions.

The company plans full results presentation at an upcoming conference and an NDA submission to the FDA in H2 2026.

PAH Context

Affecting approx. 500,000 worldwide (50,000 in the US), PAH involves pulmonary artery pressure overload, right heart strain, and vascular changes, leading to high mortality. Diagnosis challenges limit treatment access despite rising prevalence.

Patients completing ADVANCE OUTCOMES can join the ADVANCE EXTENSION open-label study.

Reference

United Therapeutics Corporation Announces Ralinepag Achieved 55% Reduction in Risk of Clinical Worsening in Pivotal Pulmonary Arterial Hypertension Study, Delivering Exceptional, Highly Statistically Significant Efficacy, 02 March 2026, https://ir.unither.com/press-releases/2026/03-02-2026-113011187

A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients, ClinicalTrials.gov ID NCT03626688, https://clinicaltrials.gov/study/NCT03626688