Once-Daily Oral Ralinepag Lowers Clinical Worsening Risk in Pretreated PAH

Key Takeaways

• Among adults with pulmonary arterial hypertension (PAH), most of whom were on dual background therapy, once-daily oral ralinepag was associated with a 55% lower risk of first clinical worsening than placebo.
• The benefit was driven mainly by disease progression, escalation to parenteral or inhaled prostacyclin therapy, and unsatisfactory clinical response, not by death or hospitalization.
• Adverse events led to discontinuation in 19% of patients on ralinepag vs 3% on placebo, most often during dose titration.

Prostacyclin-pathway therapy is an established target in PAH. Evidence has been limited, however, for adding an oral, once-daily prostacyclin receptor agonist in a largely pretreated, lower-risk population.

Investigators conducted the randomized, double-blind, placebo-controlled phase 3 ADVANCE OUTCOMES trial at 169 centers in 30 countries. The full analysis included 687 adults with PAH, with a median age of 53 years; 76% were women. PAH was defined as mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and pulmonary vascular resistance >2 Wood units. Mean baseline 6-minute walk distance (6MWD) was 438.9 m, about 70% of patients were in WHO functional class II, and 80% received dual background therapy. Patients were assigned to placebo (n = 337) or ralinepag (n = 350). Ralinepag was started at 50 µg once daily and titrated weekly to the highest tolerated dose over 16 weeks. The primary outcome was time to first adjudicated clinical worsening, a composite of:

• death
• hospitalization for worsening PAH or right heart failure
• initiation of parenteral or inhaled prostacyclin-pathway therapy
• disease progression
• unsatisfactory long-term clinical response

Median follow-up was 85 weeks with ralinepag and 78 weeks with placebo. A first clinical worsening event occurred in 64 patients (18%) on ralinepag vs 121 (36%) on placebo (hazard ratio 0.45; 95% confidence interval [CI] 0.33–0.62; P < .0001). At week 28, 6MWD improved by 20.4 m relative to placebo, and NT-proBNP fell by 24.3% relative to placebo. Hierarchical testing stopped at WHO functional class, so later secondary outcomes, including clinical improvement, were interpreted nominally.

Treatment discontinuation due to adverse events occurred in 65 patients (19%) on ralinepag vs 10 (3%) on placebo. Headache was the most common reason. Diarrhea, nausea, and myalgia were also common. Serious adverse events occurred in 28% vs 31% of patients, and adverse events leading to death in 4% of each group.

Death and hospitalization did not differ meaningfully between groups. The population was largely lower risk, with relatively preserved functional capacity. Ralinepag was compared with placebo, not with other prostacyclin-pathway agents. The investigators said further research should clarify where ralinepag fits among available therapies, how to improve tolerability during titration, and whether it affects harder outcomes. Ralinepag remains investigational.

The authors concluded that ralinepag reduced clinical worsening in a largely pretreated PAH population, supporting it as an oral, once-daily prostacyclin-pathway option.