Ralinepag Reduced Clinical Worsening Risk by 55% in Phase 3 PAH Trial Published in The Lancet

United Therapeutics has reported publication of the full Phase 3 ADVANCE OUTCOMES trial results for investigational ralinepag in The Lancet, providing peer-reviewed evidence that the therapy significantly reduced disease progression in patients with pulmonary arterial hypertension (PAH). The company recently submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in June 2026, while ralinepag remains an investigational therapy.

Ralinepag Targets the Prostacyclin Pathway in PAH

Pulmonary arterial hypertension is a progressive and life-threatening disease characterized by elevated pressure in the pulmonary arteries, leading to right ventricular failure and premature death. Although combination therapy has improved outcomes, many patients continue to experience disease progression despite treatment.

Ralinepag is a highly selective, non-prostanoid prostacyclin (IP) receptor agonist administered once daily. By activating the prostacyclin pathway, it promotes pulmonary vasodilation while inhibiting vascular remodeling and inflammatory processes implicated in PAH progression. Compared with selexipag’s active metabolite, ralinepag demonstrates stronger IP receptor binding affinity and sustained receptor occupancy, providing continuous pharmacologic activity intended to mimic the steady exposure achieved with parenteral prostacyclin therapy.

Phase 3 ADVANCE OUTCOMES Demonstrated Durable Clinical Benefit

ADVANCE OUTCOMES (NCT03626688) was a global, randomized, double-blind, placebo-controlled, event-driven Phase 3 trial that enrolled 687 patients with PAH receiving standard background therapy. Approximately 80% of participants were already receiving dual background therapy, while 70% had World Health Organization (WHO) Functional Class II disease at baseline.

The study met its primary endpoint, with ralinepag reducing the risk of a first clinical worsening event by 55% compared with placebo (hazard ratio 0.45; 95% CI, 0.33-0.62; p<0.0001).

The therapy also achieved statistically significant improvements across several important secondary endpoints at Week 28:

• 24.3% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) versus placebo (p=0.0013)
• 20.4-meter placebo-corrected improvement in six-minute walk distance (p=0.0033)
• 47% higher odds of clinical improvement compared with placebo (p=0.015)

Investigators reported consistent treatment benefits across patient subgroups, including disease severity, functional class, time since diagnosis, baseline exercise capacity, NT-proBNP levels, and background therapies.

Safety Profile Remained Consistent with Prostacyclin Therapy

The overall safety findings aligned with the established prostacyclin pathway class.

The most frequently reported adverse events included headache, diarrhea, nausea, and myalgia. Importantly, investigators reported no new safety signals during the study, supporting the overall tolerability profile of long-term treatment. Patients completing the trial were eligible to continue into the ongoing ADVANCE EXTENSION (NCT03683186) open-label study.

Publication Strengthens the Clinical Evidence

Vallerie V. McLaughlin, MD, Chair of the ADVANCE OUTCOMES Steering Committee, said the findings demonstrate that adding prostacyclin pathway therapy reduced clinical worsening even in a predominantly pre-treated population with relatively preserved functional capacity. She noted that the results support ralinepag as a potential once-daily oral prostacyclin treatment option if approved by the FDA.

Martine Rothblatt, PhD, Chairperson and Chief Executive Officer of United Therapeutics, said publication in The Lancet highlights the need for additional therapies despite advances in PAH treatment and reinforces the potential of ralinepag to improve long-term outcomes for patients living with the disease.

Future Development

With publication in The Lancet and an NDA already under FDA review, ralinepag has reached a significant regulatory milestone. If approved, it could become a once-daily oral prostacyclin receptor agonist offering durable protection against clinical worsening for patients already receiving contemporary background therapy. Ongoing follow-up through the ADVANCE EXTENSION study is expected to provide additional long-term efficacy and safety data as regulators evaluate the application.

Reference

United Therapeutics Corporation Announces ADVANCE OUTCOMES Study of Ralinepag Published in The Lancet – United Therapeutics Investor Relations