Adding the investigational selective prostacyclin receptor agonist ralinepag to background therapy helps reduce the risk of first clinical worsening in patients with pulmonary arterial hypertension (PAH), according to the phase III ADVANCE-OUTCOMES trial.
The primary outcome of a first clinical worsening event occurred in 18 percent of patients in the ralinepag group and 36 percent of those in the placebo group, corresponding to a 55-percent risk reduction (hazard ratio, 0.45, 95 percent confidence interval, 0.33–0.62; p<0.0001). [Lancet 2026;doi:10.1016/S0140-6736(26)01011-1]
First author Prof Vallerie McLaughlin from the University of Michigan Medical School in Ann Arbor, Michigan, US, and colleagues defined first clinical worsening event as a composite of death from any cause, admission to hospital due to worsening PAH or right heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response.
“The largest numerical between-group differences in components of the composite outcome were observed for disease progression (3 percent vs 11 percent), initiation of parenteral or inhaled prostacyclin-pathway therapy (3 percent vs 7 percent), and unsatisfactory long-term clinical response (4 percent vs 10 percent),” McLaughlin and colleagues said.
There was no meaningful difference in death (3 percent for both) or admission to hospital for worsening PAH or right heart failure (5 percent vs 6 percent), the authors added.
Significant reductions in N-terminal proB-type natriuretic peptide (NT-proBNP) and improvements in exercise capacity occurred alongside the decrease in clinical worsening events in the ralinepag group.
From baseline to week 28, NT-proBNP concentrations decreased by 4.3 percent with ralinepag but increased by 26.4 percent with placebo (p=0.0013). Additionally, the distance walked on the 6-min walk test (6MWT) increased by 8.24 m with ralinepag but decreased by 12.17 m with placebo (p=0.0033).
“The results suggest that further prostacyclin-pathway intensification can reduce clinical worsening even in a largely pretreated population with … predominantly low or intermediate-to-low risk, lower NT-proBNP concentrations, and higher 6MWT distance at baseline than in previous studies,” according to McLaughlin and colleagues.
Unmet need
The authors highlighted an unmet need in PAH, noting that morbidity and mortality rates remain very high, despite the availability of multiple approved therapies across the nitric oxide, endothelin, prostacyclin, and activin signalling pathways.
“As a prostacyclin receptor agonist, ralinepag is intended to activate prostacyclin signalling, which can promote vasodilation and might counter the proliferative and inflammatory mechanisms implicated in pulmonary vascular disease,” McLaughlin and colleagues said.
Compared with selexipag, an approved drug in the same class, ralinepag has a longer half-life and has been shown to be more potent than selexipag in nonclinical studies. [JHLT Open 2025;9:100270; Pulm Circ 2020;10:2045894020922814]
“Further research should clarify how ralinepag is best positioned among available PAH therapies, how tolerability during titration can be optimized, and whether longer-term treatment affects harder clinical outcomes,” the authors added.
ADVANCE-OUTCOMES
ADVANCE-OUTCOMES included 687 adults with PAH (median age 53 years, 76 percent female), which was diagnosed based on the 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) definition (mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and pulmonary vascular resistance of >2 Wood units). The mean 6MWT distance at baseline was 438.9 m, and 80 percent were on dual background PAH therapy.
The patients were randomly assigned to receive ralinepag (n=350) or placebo (n=337), initiated at a dose of 50 μg once daily and titrated weekly until the highest tolerated dose was reached. Median ralinepag dose was 250 μg at week 28 and 300 μg at week 52. Follow-up lasted a median of 85 weeks in the ralinepag group and 78.4 weeks in the placebo group.
Headache was the most common adverse event (AE), reported by 81 percent of patients in the ralinepag group and in 42 percent in the placebo group. Serious AEs occurred in 28 percent and 31 percent of patients, respectively. AEs led to treatment discontinuation in 19 percent of patients in the ralinepag group and in 3 percent in the placebo group and to death in 4 percent of patients in each group.