Ralinepag Achieves 55% Risk Reduction in PAH, With Vallerie McLaughlin, MD

Data from the phase 3 ADVANCE OUTCOMES trial presented at the American Thoracic Society (ATS) 2026 International Conference in Orlando, Florida, suggest ralinepag, an investigational once-daily oral prostacyclin receptor agonist, significantly reduced the risk of clinical worsening in patients with pulmonary arterial hypertension (PAH), including a largely pretreated population already receiving background combination therapy.1,2

The event-driven, randomized, double-blind study enrolled 687 patients with PAH and evaluated ralinepag versus placebo on top of standard of care. Ralinepag achieved a 55% reduction in risk of adjudicated clinical worsening events compared with placebo (hazard ratio [HR], 0.45; 95% CI, 0.33 to 0.62; P <.0001).2

“Ralinepag is highly potent. It's probably more potent than the currently available agents, and it's a once-daily agent, as opposed to twice daily,” Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the pulmonary hypertension program at the University of Michigan, said in an interview at ATS 2026. “We’re hoping that it would get higher levels of prostacyclin agonism in a patient and be potentially more effective.”

McLaughlin noted that prostacyclin pathway therapies remain foundational in PAH management, but clinical use has long been limited by tolerability and the need for careful dose adjustment. She described ralinepag as a potentially more patient-friendly approach that may allow for more effective prostacyclin pathway activation while maintaining individualized dosing strategies similar to existing clinical practice.

In addition to the primary endpoint, ralinepag demonstrated statistically significant improvements in key secondary outcomes. Investigators reported reductions in NT-proBNP levels from baseline to week 28 (24.3% reduction over placebo; P =.0013) and improvements in 6-minute walk distance (6MWD) (+20.4 m placebo-corrected difference; P =.0033). Additionally, ralinepag increased the odds of achieving clinical improvement by 47% (P =.015).2

The trial population included a high proportion of patients on background therapy, with many already receiving dual oral agents (80%). Despite this, ralinepag demonstrated benefit across multiple measures of disease progression, including time to hospitalization and other components of clinical worsening, suggesting additive efficacy in contemporary combination regimens.2

McLaughlin emphasized that these findings may have implications for treatment sequencing in PAH, particularly as clinicians increasingly escalate therapy earlier in the disease course. She suggested that once approved, a once-daily oral prostacyclin receptor agonist could be integrated as an additional option for patients already receiving endothelin receptor antagonists and phosphodiesterase type 5 inhibitors, potentially as a third- or later-line therapy depending on risk profile and disease trajectory.

The ADVANCE OUTCOMES study also included individualized dose titration without a ceiling, reflecting real-world prostacyclin management principles. McLaughlin indicated that this approach helps balance disease symptoms with medication adverse events.2

From a safety standpoint, findings were consistent with the known prostacyclin class profile, with no new safety signals identified. Adverse events were generally consistent with vasodilatory effects, and discontinuation rates were in line with expectations for this therapeutic class.2

United Therapeutics plans on submitting a new drug application for ralinepag to treat PAH to the US Food & Drug Administration by the second half of 2026.2

References

1. McLaughlin V, Ataya A, Albert J, et al. (Poster Board # 520) ADVANCE Outcomes: A Phase 3, Randomized Clinical Trial Evaluating Ralinepag for Pulmonary Arterial Hypertension. Poster presented at ATS 2026 in Orlando, Florida, on May 20.

2. United Therapeutics Corporation Announces ADVANCE OUTCOMES Study of Ralinepag Presented at ATS 2026. Unither.com. Published 2026. Accessed May 20, 2026. https://ir.unither.com/press-releases/2026/05-17-2026-191518923