United Therapeutics Corporation has completed enrollment of its pivotal phase 3 ADVANCE OUTCOMES study, marking a significant milestone in the development of ralinepag, an investigational once-daily oral prostacyclin agonist for pulmonary arterial hypertension (PAH). The global, multi-center, placebo-controlled trial enrolled 728 participants and represents a potential breakthrough in PAH treatment if successful.
Study Design and Timeline
The ADVANCE OUTCOMES study is evaluating an extended-release formulation of ralinepag, an oral, selective, potent, once-daily IP receptor agonist. The study includes participants on approved oral background PAH therapies and will continue to accrue clinical worsening events through the end of 2025, with top-line data expected in the first half of 2026.
The primary endpoint focuses on time to the first clinical worsening event, while secondary endpoints include changes from baseline through week 28 in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), six-minute walk distance, World Health Organization (WHO)/New York Heart Association (NYHA) functional class, REVEAL risk score, heart rate recovery following completion of the six-minute walk test, and health-related quality of life.
Promising Phase 2 Results
Earlier phase 2 data demonstrated ralinepag's therapeutic potential in PAH patients. In a study of 61 PAH participants, ralinepag met its primary endpoint, showing a 29.8% reduction (p=0.03) in median pulmonary vascular resistance (PVR) after 22 weeks of treatment compared with placebo.
The long-term safety and efficacy profile was further evaluated in an open-label extension (OLE) study involving 45 participants from the phase 2 trial. After two years in the OLE study, ralinepag significantly increased six-minute walk distance by a mean of 36.3 meters (p=0.004), and over 85% of study participants remained stable in their functional class from baseline. Additionally, hemodynamic measures taken either one or two years after entering the OLE study reported significant improvements (p=0.05) in both median PVR and mean pulmonary arterial pressure.
Potential Treatment Paradigm Shift
"We are excited for the potential of ralinepag to be the first once-a-day oral prostacyclin agonist, which, if successful, could fundamentally change the PAH treatment paradigm, potentially leading over time to upfront use of oral prostacyclins as a first-line therapy alongside traditional ERA and PDE-5 oral products," said Derek Solum, Ph.D., Senior Director, Product Development at United Therapeutics and the lead for the ADVANCE OUTCOMES development program.
Addressing Significant Unmet Need
PAH is a life-threatening disease affecting the blood vessels in the lungs, characterized by increased pressure in the pulmonary arteries. The elevated pressure strains the right side of the heart as it pumps blood to the lungs, eventually leading to right heart failure and death. The disease is characterized by structural changes in blood vessel walls, aggregation of platelets, and alteration of smooth muscle cell function.
PAH affects approximately 500,000 individuals worldwide, with around 50,000 people affected in the United States. Despite increases in the number of people diagnosed with the disease, only a small fraction of patients with PAH are treated due to the rarity of the disease and the complexity of diagnosing it.
Ralinepag remains an investigational compound that is not approved for any use in any country. The company notes that results from the uncontrolled OLE portion of the phase 2 study need to be interpreted with caution.
