United Therapeutics (UTHR) Study result summary

Study design and population

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

• The primary endpoint was time to first adjudicated clinical worsening event, with 180 events targeted for study closure; secondary endpoints included NT-proBNP, 6MWD, WHO/NYHA FC, clinical improvement, hospitalization, mortality, risk score, HRQoL, and safety.

• Most participants were on dual background therapy (ERA and PDE5 inhibitor), with 80% on dual therapy and 70% in WHO/NYHA functional class II at baseline.

• Mean baseline 6MWD was about 439 meters, median age was 53 years, and 75.7% were female.

• Eligibility criteria aligned with current guidelines, ensuring broad applicability to clinical practice.

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.

• Significant reduction in time to disease progression (HR: 0.25, 95% CI: 0.12–0.51; p=0.0001), with a three-fold decrease in progression in the ralinepag group.

• Ralinepag increased odds of clinical improvement by 47% from baseline to Week 28, including in six-minute walk distance.

• Statistically significant improvements in 6MWD and NT-proBNP were observed.

• Benefits were consistent across all patient subgroups, including demographics, background therapies, risk categories, and geographic region.

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 observed; side effects were manageable and did not lead to high discontinuation rates.

• Discontinuations due to adverse events were under 10% in the active group, lower than in other pivotal trials.

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

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