The investigational once-daily oral prostacyclin reduced the risk of clinical worsening by 55% versus placebo in the Phase 3 ADVANCE OUTCOMES trial.
Written By: Nakum Mansi, PharmD
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration has accepted the New Drug Application (NDA) for ralinepag, an investigational therapy for pulmonary arterial hypertension (PAH), United Therapeutics announced today. The FDA has assigned a Prescription Drug User Fee Act target action date of June 24, 2027. Ralinepag remains investigational and has not been approved for any indication.
If approved, ralinepag would become the first and only once-daily oral prostacyclin for PAH, offering a potential differentiated treatment option for patients managing a progressive and life-threatening disease.
“Ralinepag has the potential to make an important difference for adults living with PAH a complex, progressive, and life-threatening disease that can severely impact daily life and lead to right heart failure,” said Martine Rothblatt, Ph.D., Chairperson and Chief Executive Officer of United Therapeutics, in a statement. “With the NDA now accepted for review, we are one step closer to offering PAH patients a new, once-daily oral treatment.”
Phase 3 ADVANCE OUTCOMES Data Supports Filing
The filing is supported by results from the pivotal Phase 3 ADVANCE OUTCOMES study (NCT03626688), a global, randomized, double-blind, placebo-controlled, event-driven trial evaluating ralinepag in 687 patients with PAH. Patients received once-daily ralinepag or placebo in addition to standard-of-care background therapy, with dosing individualized and titrated based on tolerability without a specified dose ceiling.
The study met its primary endpoint, with ralinepag demonstrating a statistically significant 55% reduction in the risk of clinical worsening compared with placebo (hazard ratio, 0.45; 95% CI, 0.33-0.62; p<0.0001). The primary endpoint was time to first adjudicated clinical worsening event, which included death, nonelective hospitalization for worsening PAH, initiation of parenteral or inhaled prostacyclin therapy, disease progression, or unsatisfactory long-term clinical response.
Ralinepag also achieved statistically significant improvements in key secondary endpoints. From baseline to Week 28, ralinepag reduced NT-proBNP by 24.3% versus placebo (p=0.0013) and improved six-minute walk distance by 20.4 meters versus placebo (p=0.0033). Additionally, ralinepag improved the odds of achieving clinical improvement by 47% (p=0.015). These findings were consistent across patient subgroups, including disease etiology, six-minute walk distance, World Health Organization Functional Class, NT-proBNP levels, and background therapy use.
Safety Profile Consistent with Class
The safety profile of ralinepag was consistent with known prostacyclin-related adverse events, with headache, diarrhea, nausea, and myalgia among the most commonly reported adverse events. No new safety signals were observed.
Patients who completed the ADVANCE OUTCOMES study had the option to enroll in an ongoing open-label extension study, ADVANCE EXTENSION (NCT03683186). The Phase 3 data were presented at the 2026 American Thoracic Society annual meeting and recently published in The Lancet.
Differentiated Receptor Pharmacology Supports Durable Efficacy
Ralinepag is a highly selective and potent prostacyclin (IP) receptor agonist with multiple pathway effects, including vasodilatory, anti-proliferative, and anti-inflammatory activity. It demonstrates six-fold higher binding affinity for the IP receptor than MRE-269 (selexipag’s active metabolite) and achieves sustained receptor occupancy similar to parenteral therapy. In a Phase 2 study (NCT02279160) ralinepag significantly reduced pulmonary vascular resistance compared with placebo in PAH patients on mono (41%) or dual combination (59%) background therapy. Ralinepag activates IP receptors on pulmonary artery endothelial and smooth muscle cells, triggering downstream conversion of ATP to cAMP. It is six- to eight-fold more potent at increasing in-vitro cAMP levels than the active metabolite of selexipag. Elevated intracellular cAMP promotes vasodilation and inhibits pathways involved in vascular remodeling.
PAH is a life-threatening disease affecting approximately 500,000 individuals worldwide, including about 50,000 in the United States. The condition is characterized by increased pressure in the pulmonary arteries, leading to right heart failure and death.
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About the Writer
Mansi Nakum (Linkedin) is a Pharm.D professional with a strong foundation in clinical pharmacy, evidence-based healthcare writing, and clinical data interpretation.
She has published work on Brugada syndrome and has a keen interest in guideline integration, multimodal therapy, pharmacogenomics, and antibiogram utilization.
As a healthcare writer, she focuses on translating clinical evidence into clear, accurate, and clinically relevant content, while continuously developing her expertise in evolving pharmacy practice.