ADVANCE OUTCOMES: Ralinepag Outperforms Placebo in Slowing Disease Progression in PAH

On March 2, 2026, United Therapeutics Corporation announced that its investigative prostacyclin (IP) receptor agonist ralinepag has met its primary endpoint of reducing worsening clinical events in patients with pulmonary arterial hypertension (PAH) in the phase 3 ADVANCE OUTCOMES study.1

Ralinepag, a highly selective and potent IP receptor agonist, utilizes multiple pathway effects, including vasodilatory, anti-proliferative, and anti-inflammatory. Ralinepag has exhibited 6-fold higher binding affinity than MRE-269, the active metabolite in selexipag, and has achieved sustained IP receptor occupancy similar to parental therapy. It restores prostacyclin signaling and activates IP receptors on pulmonary artery endothelial and smooth muscle cells, triggering downstream conversion of ATP to cAMP.1

“PAH is a progressive, life-threatening disease that has a devastating impact on patients’ lives,” Vallerie McLaughlin, MD, Kim A. Eagle MD endowed professor of cardiovascular medicine and director of the pulmonary hypertension program at the University of Michigan and chair of the ADVANCE OUTCOMES steering committee, said in a statement. “In the ADVANCE OUTCOMES study, ralinepag delayed disease progression in patients with PAH facing significant disease burden at baseline. Ralinepag’s potency and once-daily oral dosing make these outcomes highly relevant in real-world settings.”1

ADVANCE OUTCOMES was a pivotal multicenter, global, randomized, double-blind, placebo-controlled, event-driven phase 3 study evaluating the efficacy and safety of ralinepag in patients with PAH. The primary endpoint was time to first adjudicated clinical worsening event, which was defined as death, nonelective hospital admission for worsening PAH, initiation of inhaled prostacyclin pathway or parental agent for treatment of worsening PAH, disease progression, or unsatisfactory long-term clinical response.1

Key secondary endpoints included changes from baseline to week 28 in NT-proBNP, 6MWD, and WHO/NYHA FC; shift and proportion of patients with improved risk status, clinical improvement, or health-related quality of life; time to first all-cause nonelective hospitalization; time to all-cause mortality; heart rate recovery after completion of 6MWT; and safety and tolerability.1

Patients were eligible for enrollment if they were ≥18 years old and had a diagnosis of symptomatic PAH, as well as right heart catheterization performed at or within 3 years before screening, WHO/NYHA functional class II to IV symptoms, a 6-minute walk distance (6MWD) of ≥150 meters, or were taking PAH-specific background oral therapies, among other criteria. Patients were excluded if they presented with known HIV-associated PAH, ≥3 left ventricular dysfunction risk factors, more than mild lung disease on pulmonary function tests, or evidence of thromboembolic disease, among other criteria.2

A total of 687 patients were enrolled in the study and randomly assigned in a 1:1 ratio to either ralinepag or placebo, both in addition to standard of care PAH-specific background therapy. Once-daily dosing was individualized based on tolerability and response – no dose ceiling was specified.1

Ultimately, ralinepag demonstrated a 55% reduction in clinical worsening event risk (HR 0.45; 95% CI, 0.33-0.62; P <.0001). The drug also saw durable efficacy in delaying disease progression – 80% of patients were on dual background therapy, and 70% were considered WHO/NYHA functional class II at baseline. Ralinepag also improved 6MWD and NT-proBNP compared to placebo, with increased odds of achieving improvement by 47% from baseline to week 28.1

Investigators noted that these benefits were consistent across all patient subgroups, including time since diagnosis, baseline 6MWD, use of background therapies, and disease etiology. Additionally, ralinepag was well-tolerated and exhibited a safety profile consistent with known prostacyclin-related adverse events.1

“These results mark a significant advancement for PAH patients,” Derek Solum, PhD, senior director of product development at United Therapeutics and the lead for the global ADVANCE OUTCOMES program, said in a statement. “With its extended-release profile and pharmacokinetic characteristics that mimic the steady-state exposure of parental therapy, ralinepag provides disease-mitigating capabilities that target underlying PAH pathology and achieve impressive clinical benefits.”1

References

1. United Therapeutics. United Therapeutics Corporation Announces Ralinepag Achieved 55% Reduction in Risk of Clinical Worsening in Pivotal Pulmonary Arterial Hypertension Study, Delivering Exceptional, Highly Statistically Significant Efficacy. BusinessWire. March 2, 2026. Accessed March 2, 2026. https://www.businesswire.com/news/home/20260302493703/en/United-Therapeutics-Corporation-Announces-Ralinepag-Achieved-55-Reduction-in-Risk-of-Clinical-Worsening-in-Pivotal-Pulmonary-Arterial-Hypertension-Study-Delivering-Exceptional-Highly-Statistically-Significant-Efficacy

2. United Therapeutics. A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients. ClinicalTrials.gov Identifier: NCT03626688. Updated February 20, 2026. Accessed March 2, 2026. https://clinicaltrials.gov/study/NCT03626688