FDA Accepts NDA for Ralinepag in Pulmonary Arterial Hypertension

The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for ralinepag, an investigational once-daily oral IP (prostacyclin) receptor agonist under review for pulmonary arterial hypertension (PAH).¹

Announced by parent company United Therapeutics Corporation on August 24, 2026, this filing is supported by phase 3 data from the ADVANCE OUTCOMES trial, in which ralinepag reduced the risk of clinical worsening by 55% compared with placebo in patients with PAH. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of June 24, 2027.¹

“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,” Martine Rothblatt, PhD, chairperson and chief executive officer of United Therapeutics, said 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.”¹

If approved, ralinepag would become the first once-daily oral prostacyclin agent available to patients with PAH, according to United Therapeutics. Existing oral, inhaled, and parenteral prostacyclin pathway agents require multiple daily doses or continuous delivery, leaving room for a simplified regimen. The NDA follows full publication of the ADVANCE OUTCOMES results in The Lancet.¹

ADVANCE OUTCOMES was a global, multicenter, randomized, double-blind, placebo-controlled, event-driven phase 3 study enrolling 687 patients with PAH. Participants received ralinepag or placebo in a 1:1 ratio on top of standard-of-care PAH-specific background therapy. Dosing was once daily, individualized and titrated based on tolerability and clinical response, with no specified dose ceiling.^1,2

The primary endpoint was time to first adjudicated clinical worsening event, encompassing death, non-elective hospitalization for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent, disease progression, or unsatisfactory long-term clinical response.^1,2

Ultimately, ralinepag achieved a statistically significant 55% reduction in the risk of a clinical worsening event compared with placebo. Results were consistent across prespecified subgroups, including disease etiology, six-minute walk distance (6MWD), World Health Organization Functional Class (WHO FC), NT-proBNP levels, and background therapy use.^1,2

Patients who completed the study had the option to enroll in an ongoing open-label extension, ADVANCE EXTENSION.¹

Ralinepag secondary endpoints and safety profile in ADVANCE OUTCOMES

Ralinepag also achieved statistical significance for key secondary endpoints, including reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker of heart failure severity, and improvement in 6MWD. Ralinepag improved the odds of achieving clinical improvement by 47% compared with placebo (P = .015), an additional secondary endpoint. Secondary endpoints also included changes in WHO/NYHA Functional Class, health-related quality of life measured by SF-36, and time to first all-cause nonelective hospitalization.^1,2

The safety profile of ralinepag was consistent with known prostacyclin-related adverse events, and no new safety signals were observed, according to United Therapeutics.¹

“In our clinical trial, ralinepag delayed disease progression, achieved clinical improvement, and provided durability of effect over many years,” Rothblatt said in a statement. “We attribute these robust results to its unique chemistry and multi-pathway effects, including vasodilation and anti-proliferative and anti-inflammatory activity.”¹

Ralinepag is not approved for any indication and remains investigational for PAH. Data from ADVANCE OUTCOMES were presented at the 2026 American Thoracic Society meeting and published in The Lancet.^1,2

References

1. United Therapeutics Corporation. United Therapeutics Corporation Announces FDA Filing Acceptance of New Drug Application for Ralinepag to Treat Pulmonary Arterial Hypertension. Published August 24, 2026. Accessed August 24, 2026. https://www.businesswire.com/news/home/20260824016096/en/United-Therapeutics-Corporation-Announces-FDA-Filing-Acceptance-of-New-Drug-Application-for-Ralinepag-to-Treat-Pulmonary-Arterial-Hypertension

2. 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. The Lancet. 2026;408(10554):521-531. doi:10.1016/s0140-6736(26)01011-1