Phase 3 trial results show ralinepag significantly reduced the risk of worsening symptoms and improved exercise capacity in pulmonary arterial hypertension patients.
RT’s Three Key Takeaways:
- Clinical Worsening Reduction: Ralinepag achieved a 55% reduction in the risk of clinical worsening compared with placebo in patients with pulmonary arterial hypertension.
- Secondary Endpoint Gains: The study showed significant improvements in exercise capacity and a 24.3% reduction in N-terminal pro-B-type natriuretic peptide levels.
- Upcoming FDA Submission: United Therapeutics plans to submit a New Drug Application for the once-daily oral therapy to the Food and Drug Administration (FDA) in the second half of 2026.
Ralinepag reduced the risk of clinical worsening by 55% in patients with pulmonary arterial hypertension (PAH), meeting the primary endpoint of the phase 3 Advance Outcomes study, according to United Therapeutics.
The results were presented during the Breaking News: 2026 Clinical Trial Results in Pulmonary Medicine session at the American Thoracic Society (ATS) International Conference in Orlando. Ralinepag is an investigational once-daily oral prostacyclin receptor agonist that has not yet been approved by the FDA.
The study evaluated 687 patients, 80% of whom were already receiving dual background therapy and 70% of whom were considered WHO/NYHA Functional Class II at baseline. The 55% reduction in clinical worsening risk was consistent across all patient subgroups, including disease etiology, baseline exercise capacity, and background therapy use, according to the news release.
“In Advance Outcomes, ralinepag reduced the risk of clinical worsening, decreased NT-proBNP levels, and improved exercise capacity in lower risk, heavily pretreated PAH patients, underscoring the potential benefits of a once-daily prostacyclin receptor agonist,” said Vallerie V McLaughlin, professor of cardiovascular medicine and director of the pulmonary hypertension program at University of Michigan and chair of the Advance Outcomes steering committee.
Secondary endpoints also showed statistically significant improvements from baseline to week 28. Patients treated with ralinepag saw a 24.3% reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a critical biomarker for heart failure, compared with placebo. Additionally, the ralinepag group demonstrated a 20.4-meter placebo-corrected improvement in six-minute walk distance (6MWD).
“The Advance Outcomes study demonstrated that ralinepag was effective across disease etiologies of PAH, including connective tissue diseases such as systemic sclerosis, in which vascular remodeling and endothelial dysfunction can be accelerated,” said Derek Solum, senior director, product development at United Therapeutics.
The safety profile of the drug was consistent with known prostacyclin-related adverse events, and no new safety signals were identified during the study, according to the company.
Ralinepag is designed to target the prostacyclin pathway by activating receptors on pulmonary artery endothelial and smooth muscle cells to trigger the conversion of ATP to cAMP. Elevated intracellular cAMP levels are associated with vasodilation and the inhibition of vascular remodeling. The therapy demonstrates a six-fold higher binding affinity for the receptor than the active metabolite of selexipag, according to United Therapeutics.
“Based on the overwhelmingly positive results of the study, we believe that ralinepag could meaningfully improve the lives of people living with PAH upon FDA approval and redefine the PAH treatment landscape, where significant unmet needs from this devastating disease continue to persist,” said Martine Rothblatt, chairperson and chief executive officer of United Therapeutics, in a news release.
United Therapeutics intends to submit a New Drug Application for ralinepag to the FDA by the second half of 2026.
