Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study.

Summary

In the phase 3 ADVANCE OUTCOMES trial, 687 patients with pulmonary arterial hypertension receiving contemporary background therapy were randomized to ralinepag or placebo. A first clinical worsening event occurred in 18% of ralinepag-treated patients versus 36% receiving placebo, corresponding to a hazard ratio of 0.45, although treatment discontinuation due to adverse events was more frequent with ralinepag.

Key Findings

• Among 687 analyzed patients, first clinical worsening occurred in 18% with ralinepag versus 36% with placebo.
• Ralinepag reduced the risk of first clinical worsening with a hazard ratio of 0.45 (95% CI 0.33-0.62; p<0.0001).
• Adverse events led to treatment discontinuation in 19% of ralinepag-treated patients versus 3% of placebo-treated patients.

Clinical Implications

Ralinepag can be considered as an oral, once-daily prostacyclin-pathway treatment option for pulmonary arterial hypertension patients on background therapy. Clinicians should balance its reduction in clinical worsening against adverse effects, particularly those leading to treatment discontinuation.

Limitations

• The primary endpoint was a composite outcome containing heterogeneous clinical events.
• Forty-one randomized and treated patients from sites in China were excluded because of regulatory and data-integrity concerns.
• The trial was sponsor-funded, and adverse-event-related discontinuation was substantially higher with ralinepag.

Future Directions

Further studies should define which pulmonary arterial hypertension phenotypes derive the greatest benefit, evaluate long-term survival and quality-of-life effects, and clarify optimal integration with combination therapy while minimizing treatment discontinuation.