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

Summary

In 687 analyzed patients with PAH, 18% of those receiving ralinepag versus 36% receiving placebo experienced a first clinical worsening event. Ralinepag reduced the risk of clinical worsening by 55% (HR 0.45, 95% CI 0.33-0.62; P<0.0001), although adverse-event-related treatment discontinuation was more frequent with active treatment.

Key Findings

• First clinical worsening occurred in 18% of ralinepag-treated patients versus 36% with placebo.
• Ralinepag reduced the risk of first clinical worsening by 55% (HR 0.45, 95% CI 0.33-0.62; P<0.0001).
• Treatment discontinuation due to adverse events occurred in 19% with ralinepag versus 3% with placebo.

Clinical Implications

Ralinepag may be considered as an oral add-on prostacyclin-pathway option for adults with PAH, with treatment selection balancing reduced disease progression against prostacyclin-related adverse effects and discontinuation risk.

Limitations

• The primary endpoint was a composite outcome, and the largest numerical differences were driven by disease progression and treatment escalation rather than mortality.
• Adverse events led to substantially more treatment discontinuations with ralinepag.
• Follow-up was limited to the trial period, so long-term survival and durability remain less certain.

Future Directions

Future studies should define the optimal placement of ralinepag within combination therapy, identify patients most likely to benefit, and evaluate long-term effects on right ventricular function, hospitalization, and mortality.