United Therapeutics (UTHR) Study result summary

Study design and patient population

• Phase III ADVANCE OUTCOMES was a global, randomized, double-blind, placebo-controlled trial evaluating ralinepag in 687 PAH patients, with 1:1 randomization and individualized dosing.

• The primary endpoint was time to first adjudicated clinical worsening event; secondary endpoints included NT-proBNP, six-minute walk distance, WHO/NYHA functional class, clinical improvement, hospitalization, mortality, risk score, HRQoL, and safety.

• 80% of participants were on dual background therapy (ERA and PDE5 inhibitor), and most were functional class II with a mean disease duration of 4.5 years.

• Median age was 53 years; 75.7% were female, and 80.2% were White.

• Eligibility criteria aligned with current ERS/ESC guidelines and World Symposium recommendations.

Efficacy results

• Ralinepag reduced the risk of clinical worsening events by 55% compared to placebo (HR 0.45, 95% CI: 0.33–0.62; p<0.0001).

• Clinical worsening occurred in 18.3% of ralinepag patients vs. 35.9% of placebo.

• Statistically significant improvements were observed in secondary endpoints, including six-minute walk distance, NT-proBNP, and clinical improvement.

• Benefits were consistent across all patient subgroups, including baseline 6MWD, etiology, background therapy, age, sex, and geography.

• Disease progression events were three times less frequent in the ralinepag group, with a 75% reduction in risk of disease progression.

Safety and tolerability

• Ralinepag was well-tolerated; adverse events were consistent with known prostacyclin effects: headache (81.1%), diarrhea (58.3%), nausea (45.1%), myalgia (36.0%), chills, and jaw pain (35.7%).

• No new or unexpected safety signals were identified; side effects were manageable and did not lead to high discontinuation rates.

• Discontinuation due to adverse events was less than 10% in the active group, lower than other pivotal trials.

• Ralinepag's once-daily dosing and favorable pharmacokinetics contributed to improved tolerability.

• Over 1,000 patient-years of observation revealed no new safety concerns.