Ralinepag's Benefit Spans Broad PAH Population, With Jean Elwing, MD

United Therapeutics' new drug application for ralinepag in pulmonary arterial hypertension (PAH) is under United States Food and Drug Administration (FDA) review, with a target action date of June 24, 2027, based on the phase 3 ADVANCE Outcomes trial.³ In the trial, ralinepag added to background PAH therapy reduced the hazard of a first adjudicated clinical worsening event by 55% versus placebo (HR, 0.45; 95% CI, 0.33-0.62; P <.0001). The effect was driven primarily by fewer disease progression events.¹

The 687 randomized participants had a median age of 53 years; 80.2% were White, 75.7% were female, and 79.8% were on dual background PAH therapy at baseline, with a mean PAH duration of 4.5 years. Approximately 70% were classified as WHO functional class II, reflecting a relatively stable, well-treated population rather than patients with advanced or treatment-refractory disease. Treatment decisions in this group are not limited to patients with advanced symptoms, since clinicians regularly manage patients who appear stable on therapy yet remain at risk for disease progression.¹

Placebo-corrected improvements in 6-minute walk distance and reductions in NT-proBNP favored ralinepag across all 4 baseline risk categories, though subgroup confidence intervals were wide and several crossed the null. Placebo-corrected 6-minute walk distance gains across subgroups ranged from about 15 m to 26 m, and NT-proBNP reductions ranged from about 18% to 28%. These functional and biomarker findings are complementary to the clinical worsening endpoint rather than a substitute for it.²

Jean Elwing, MD, professor of medicine in the division of pulmonary, critical care and sleep medicine at the University of Cincinnati College of Medicine, presented these findings at the CHEST 2026 Annual Meeting in Phoenix and spoke to HCPLive about where ralinepag could fit into the PAH treatment algorithm if approved.

HCPLive: How should clinicians weigh the 6MWD and NT-proBNP findings within these subgroups?

Jean Elwing, MD: The 6MWD and NT-proBNP findings provide supportive evidence alongside the primary clinical worsening results. In the overall ADVANCE Outcomes population, ralinepag improved 6MWD by a placebo-corrected 20.4 m at week 28 (P = .0033) and reduced NT-proBNP by 24.3% relative to placebo (P = .0013). In our subgroup analysis, the direction of improvement in both measures consistently favored ralinepag across all 4 baseline risk categories; placebo-corrected improvements in 6MWD ranged from approximately 15 to 26 m, while NT-proBNP reductions ranged from approximately 18% to 28%. These findings are encouraging, but the subgroup estimates have wider confidence intervals, and several include no difference, so we should avoid overinterpreting the magnitude of improvement within individual subgroups.

I also think it is important to recognize that 6MWD and NT-proBNP measure different aspects of disease; a patient with relatively preserved exercise capacity may have limited room for additional improvement in walking distance but may still benefit from treatment that reduces the likelihood of clinical worsening. For that reason, I would place the greatest emphasis on the clinical worsening endpoint, while viewing the functional and biomarker findings as complementary measures of treatment response.

HCPLive: What drove the reduction in clinical worsening events?

Jean Elwing, MD: The primary endpoint in ADVANCE Outcomes was time to first adjudicated clinical worsening event. The composite endpoint included all-cause death, nonelective hospitalization for worsening PAH, initiation of parenteral or inhaled prostacyclin therapy, disease progression, and unsatisfactory long-term clinical response. In the overall study, ralinepag reduced the hazard of a first clinical worsening event by 55% compared with placebo, with the treatment effect driven primarily by a reduction in disease progression events. This is clinically important because the endpoint captured several meaningful ways in which PAH can worsen, rather than relying exclusively on a change in exercise capacity or a biomarker.

Our CHEST subgroup poster focused on the composite clinical worsening endpoint across baseline risk categories and did not provide a breakdown of individual endpoint components within each subgroup. Therefore, while the analysis demonstrates a favorable treatment effect on overall clinical worsening, we cannot determine from this poster which specific components accounted for the treatment effect in each risk category. The important message is that ralinepag reduced the likelihood of clinically meaningful disease worsening in the overall population, with a consistent favorable direction of effect across the baseline risk groups studied.

HCPLive: This was a lower-risk population mostly on dual therapy. Who does it represent in practice?

Jean Elwing, MD: ADVANCE Outcomes included patients with established PAH who were receiving contemporary background therapy. Approximately 80% were receiving dual PAH therapy, about 70% were in WHO functional class II, the mean baseline 6MWD was approximately 439 m, and the mean duration since PAH diagnosis was 4.5 years. The study population therefore reflects an important group of patients we commonly see in clinical practice: individuals receiving established PAH treatment who may appear relatively stable but remain at risk for disease progression. This is particularly relevant because treatment decisions are not limited to patients with advanced symptoms or obvious clinical deterioration; we frequently evaluate patients who are doing reasonably well on therapy and must determine whether their current treatment is sufficient to maintain favorable long-term outcomes.

The findings suggest that patients with relatively preserved functional status and favorable risk characteristics may still benefit from additional prostacyclin-pathway treatment. At the same time, these results should not be generalized automatically to every PAH population, particularly patients with advanced disease, marked hemodynamic compromise, or treatment regimens that were not well represented in the study.

HCPLive: If approved, where would ralinepag fit in the treatment algorithm?

Jean Elwing, MD: If approved, ralinepag could provide an additional once-daily oral option targeting the prostacyclin pathway. Its potential role is particularly interesting in patients receiving background PAH therapy who remain at risk for clinical worsening, including some patients who have achieved favorable conventional risk criteria.

The ADVANCE Outcomes findings support the concept that additional prostacyclin-pathway treatment can provide benefit beyond established background therapy. Importantly, approximately 80% of participants in ADVANCE Outcomes were receiving dual background PAH therapy at baseline, suggesting that benefit was observed with contemporary standard-of-care treatment, and the subgroup analysis also raises the possibility that patients with relatively favorable baseline clinical characteristics may derive additional benefit. However, treatment selection must remain individualized; decisions about escalation should consider comprehensive risk assessment, right ventricular function, hemodynamics, clinical trajectory, tolerability, patient preferences, and the benefits and burdens of available therapies.

Ralinepag would not replace parenteral prostacyclin therapy in patients for whom intensive treatment is indicated, particularly those with high-risk features or advanced disease. Ultimately, its precise position in the treatment algorithm will depend on regulatory approval, the full efficacy and safety data, and how it compares with existing treatment options. The broader message from ADVANCE Outcomes is that we should continue to focus not only on achieving low-risk status, but also on maintaining favorable outcomes and reducing the risk of future disease progression.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools. Disclosures for Elwing include Acceleron, MerckActelion, Janssen, Aerovate, Altavant, Bayer, Gossamer Bio, Inhibikase, Liquidia, and United Therapeutics.

References

1. McLaughlin VV, Solum D, Lachant D, et al. Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study. Lancet. Published online July 28, 2026. doi:10.1016/S0140-6736(26)01011-1

2. Elwing JM, Solum D, Cella D, et al. Ralinepag treatment effects across risk profiles: results from ADVANCE Outcomes. Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ.

3. United Therapeutics Corporation. United Therapeutics reports the US FDA NDA acceptance for ralinepag to treat pulmonary arterial hypertension. Published August 24, 2026. Accessed October 23, 2026. https://ir.unither.com/~/media/Files/U/United-Therapeutics-IR/documents/press-releases/2026/ral-nda-acceptance-press-release.pdf