3 minOn March 2, United Therapeutics announced that its investigational next-generation selective prostacyclin (IP) receptor agonist, Ralinepag, achieved significant success in the pivotal Phase 3 clinical trial, ADVANCE OUTCOMES.
According to the results, Ralinepag reduced the risk of clinical worsening in patients with pulmonary arterial hypertension (PAH) by 55%. With the potential to become the first and only once-daily oral prostacyclin therapy with pharmacokinetic properties comparable to intravenous administration, Ralinepag may redefine the treatment paradigm for PAH. United Therapeutics plans to submit a New Drug Application (NDA) to the U.S. FDA in the second half of 2026.
About the ADVANCE OUTCOMES Trial
ADVANCE OUTCOMES is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study that enrolled a total of 687 patients with PAH.
Primary Endpoint:
Compared with placebo, Ralinepag reduced the risk of a first clinical worsening event—including death, unplanned hospitalization, or initiation of intravenous or inhaled therapy—by 55% (HR = 0.45; 95% CI: 0.33–0.62; p < 0.0001).
Key Secondary Endpoints
Clinical Improvement:
After 28 weeks of treatment, patients receiving Ralinepag demonstrated a 47% higher likelihood of achieving clinical improvement (p = 0.015).
Biomarkers and Exercise Capacity:
Patients showed a significant reduction in NT-proBNP levels (a biomarker of heart failure), along with a meaningful improvement in 6-minute walk distance (6MWD).
Safety Profile
In this study, 80% of patients were already receiving dual background therapy, and 70% had baseline WHO/NYHA functional class II status. These data indicate that Ralinepag provides substantial incremental benefit on top of contemporary standard-of-care treatments.
Ralinepag was generally well tolerated, with a safety profile consistent with known prostacyclin-class therapies. Common adverse events included headache, nausea, and diarrhea, and no new safety signals were identified.
Potential Impact on the Competitive Landscape
The prostacyclin pathway in the PAH market is currently dominated by oral therapies such as Selexipag (brand name Uptravi), as well as inhaled and intravenous treatment options.
Compared with Selexipag, Ralinepag demonstrates stronger receptor affinity. Studies indicate that Ralinepag has approximately six-fold higher binding affinity for the IP receptor than the active metabolite of Selexipag, and is 6–8 times more potent in promoting intracellular cAMP production—a key mechanism underlying vasodilation and anti-proliferative effects.
Ralinepag utilizes an extended-release formulation, with a half-life of 20–24 hours, enabling once-daily oral dosing and potentially improving patient adherence. In contrast, Selexipag typically requires twice-daily dosing.
If approved, Ralinepag is expected not only to challenge the market share of Uptravi but also to shift treatment strategies earlier in the disease course, potentially delaying the need for more costly intravenous or inhaled therapies.
