Phase 3 Trial of New Oral Drug for Pulmonary Arterial Hypertension: Ralinepag Reduces Risk of Clinical Worsening by 55%

Pulmonary arterial hypertension causes vascular resistance in the lungs to rise continuously, placing an increasing burden on the right side of the heart. Even when patients are already receiving multiple standard treatments, further delaying hospitalization, disease progression, or treatment escalation remains a central clinical challenge. A phase 3 study published in *The Lancet* showed that the oral prostacyclin receptor agonist ralinepag achieved positive results on this key objective.

ADVANCE OUTCOMES was a randomized, double-blind, placebo-controlled trial that analyzed 687 patients with pulmonary arterial hypertension. In addition to their existing standard therapy, participants took extended-release ralinepag or placebo once daily. Approximately 80% were already receiving two background therapies, and 70% were in World Health Organization functional class II at the start of the trial, indicating that although most patients remained physically active, their disease risk had not disappeared.

The primary endpoint was the first independently adjudicated clinical worsening event, including death, unplanned hospitalization due to worsening pulmonary arterial hypertension, initiation of injectable or inhaled prostacyclin therapy, disease progression, and an unsatisfactory long-term response. Events occurred in 64 of 350 participants in the ralinepag group and 121 of 337 participants in the placebo group. The hazard ratio was 0.45, corresponding to a 55% relative risk reduction, with a 95% confidence interval of 0.33 to 0.62.

Some secondary endpoints also moved in the same direction. At 28 weeks, ralinepag reduced NT-proBNP, a marker of cardiac stress, by 24.3% compared with placebo, while the adjusted difference in six-minute walking distance increased by 20.4 meters. However, these data primarily demonstrate delayed disease worsening and improvements in functional measures and cannot be directly interpreted as proof of prolonged overall survival.

Ralinepag selectively activates the prostacyclin IP receptor, thereby promoting pulmonary vasodilation and potentially inhibiting vascular wall remodeling. Its once-daily oral formulation is intended to provide a more convenient way to target the prostacyclin signaling pathway. However, its actual clinical value must also be weighed against tolerability. Common adverse reactions included headache, diarrhea, nausea, and muscle pain, broadly consistent with the known effects of this drug class. However, 19% of participants in the ralinepag group discontinued treatment because of adverse events, compared with 3% in the placebo group. Serious adverse events occurred in 28% and 31% of participants, respectively.

The study data also have an important limitation: because of regulatory and data-integrity concerns, the paper excluded 41 treated participants at trial centers in China, leaving 687 participants in the final efficacy and safety analysis population. This decision adds complexity to the interpretation of the results and to regulatory review. In addition, the trial was funded by United Therapeutics, and further attention will need to be paid to the review of the complete data and to longer-term real-world performance.

United Therapeutics submitted a new drug application to the U.S. Food and Drug Administration in June 2026. Ralinepag remains an investigational drug and has not been approved for any indication. Therefore, although the phase 3 trial provides strong evidence supporting an additional oral treatment option, whether it ultimately enters clinical practice and which patients it may be suitable for will still depend on regulators’ overall assessment of efficacy, tolerability, and data quality.