United Therapeutics Reports Pivotal Phase 3 ADVANCE OUTCOMES Study of Ralinepag Achieves Primary Endpoint, Showing 55% Reduction in Risk of Clinical Worsening in Pulmonary Arterial Hypertension
United Therapeutics Corporation, a public benefit corporation dedicated to developing transformative therapies for patients with life-threatening conditions, announced today that its long-term pivotal Phase 3 ADVANCE OUTCOMES study met its primary endpoint, demonstrating significant clinical benefit for patients with pulmonary arterial hypertension (PAH). In the study, ralinepag reduced the risk of a clinical worsening event by 55% compared with placebo, with a hazard ratio of 0.45 (95% confidence interval [CI]: 0.33–0.62; p<0.0001), marking a major milestone in the treatment of this progressive and life-threatening disease.
PAH is a rare but severe condition characterized by high blood pressure in the arteries of the lungs, leading to progressive right heart failure and premature mortality. Despite advances in treatment, many patients continue to experience disease progression, highlighting the urgent need for effective therapies that can delay clinical worsening and improve functional outcomes. Ralinepag, an oral, once-daily prostacyclin receptor agonist, represents a promising addition to the PAH treatment landscape, particularly for patients already receiving background therapy.
The ADVANCE OUTCOMES study enrolled a diverse population of patients with PAH, including 80% who were receiving dual background therapy and 70% classified as World Health Organization (WHO)/New York Heart Association (NYHA) Functional Class II at baseline. This patient population reflects the real-world complexity of PAH, encompassing individuals with varied disease etiology, duration since diagnosis, and baseline functional capacity. The robust design and size of the study provided a comprehensive evaluation of ralinepag’s efficacy and safety across these subgroups.
In addition to the primary endpoint of risk reduction for clinical worsening events, ralinepag demonstrated statistically significant benefits in key secondary endpoints. Patients receiving ralinepag showed improvements in six-minute walk distance (6MWD), a standard measure of exercise capacity in PAH, as well as reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker associated with heart strain and disease severity. Furthermore, ralinepag increased the odds of achieving clinical improvement from baseline to Week 28 by 47% compared with placebo (p=0.015), illustrating the therapy’s potential to meaningfully improve both functional capacity and overall clinical status.
The benefits of ralinepag were consistently observed across all patient subgroups, including variations in disease etiology, time since diagnosis, baseline 6MWD, and background therapy use. This consistency underscores the robustness of the treatment effect and suggests broad therapeutic relevance, reinforcing ralinepag’s potential to address a wide range of patients with PAH.
Safety and tolerability were carefully evaluated in the ADVANCE OUTCOMES study. Ralinepag was generally well-tolerated, with adverse events consistent with known prostacyclin-related effects. Importantly, no new safety signals were observed, supporting the favorable risk-benefit profile of the therapy in this patient population.
“Pulmonary arterial hypertension is a progressive and life-threatening disease that has a profound impact on patients’ lives, affecting daily function and long-term survival,” said Vallerie V. McLaughlin, M.D., Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine and Director of the Pulmonary Hypertension Program at the University of Michigan, who also serves as Chair of the ADVANCE OUTCOMES Steering Committee. “In the ADVANCE OUTCOMES study, ralinepag effectively delayed disease progression in patients facing significant disease burden at baseline. Its potency, combined with once-daily oral dosing, makes these outcomes highly relevant in real-world clinical settings, offering a potentially transformative option for patients living with PAH.”
Martine Rothblatt, Ph.D., Chairperson and Chief Executive Officer of United Therapeutics, emphasized the strategic importance of this achievement for the company. “United Therapeutics was founded on the principle that we could bring transformative therapies to people living with PAH. The results from this pivotal trial represent one of the most significant milestones in our history, reinforcing our decades-long commitment to advancing prostacyclin-based science. The strength and consistency of these findings give us optimism that ralinepag could meaningfully improve long-term outcomes for patients, and if approved, could usher in a new era of PAH treatment, addressing persistent unmet medical needs. We are deeply grateful to the study participants and investigators whose dedication made these results possible.”
Derek Solum, Ph.D., Senior Director of Product Development at United Therapeutics and lead for the global ADVANCE OUTCOMES program, highlighted the pharmacologic advantages of ralinepag. “With its extended-release profile and pharmacokinetic characteristics that mimic the steady-state exposure of parenteral prostacyclin therapy, ralinepag provides disease-mitigating capabilities that directly target the underlying pathology of PAH. These features, combined with impressive clinical efficacy, make ralinepag a potentially transformative therapy for patients.”
Looking forward, United Therapeutics plans to present the full results from the ADVANCE OUTCOMES study at an upcoming international scientific conference, allowing clinicians and researchers to evaluate the comprehensive data and further understand the clinical implications of ralinepag therapy. The company also intends to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for ralinepag in the second half of 2026, marking a significant step toward regulatory approval and broader patient access.
In conjunction with the announcement, United Therapeutics will host a public webcast on March 2, 2026, at 8:30 a.m. Eastern Time. The webcast will provide additional insights into the study outcomes, the clinical relevance of ralinepag, and the company’s plans for advancing this therapy. Interested parties can access the webcast through the United Therapeutics website at https://ir.unither.com/events-and-presentations. A rebroadcast will also be available for one year at the same location.
The successful completion of the ADVANCE OUTCOMES study and the substantial reduction in risk for clinical worsening highlight ralinepag’s potential to fill a critical gap in PAH management. With its once-daily oral administration, favorable safety profile, and robust clinical efficacy, ralinepag represents a significant advancement in the field and offers hope for improved outcomes for patients facing this challenging disease.
United Therapeutics continues to focus on innovative therapies for PAH, reinforcing its mission to develop transformative treatments that address the unmet medical needs of patients worldwide. The results from ADVANCE OUTCOMES underscore the company’s commitment to improving the lives of individuals living with PAH, providing a potential new standard of care for this progressive and debilitating condition.
