Ralinepag, a selective prostacyclin IP receptor agonist, significantly reduced the risk of first clinical worsening compared with placebo in patients with pulmonary arterial hypertension (PAH) but was associated with more adverse-event-related treatment discontinuations, according to results of the ADVANCE OUTCOMES trial published July 28 in The Lancet.

ADVANCE OUTCOMES, conducted at 169 centers across 30 countries, enrolled 728 patients with PAH, defined as mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg and pulmonary vascular resistance >2 Wood units – with 687 patients included in the full analysis (median age, 53 years; 76% women). Mean baseline six-minute walk distance (6MWD) was 438.9 m, and 80% of all patients were receiving dual background PAH therapy.

Patients were randomized to either placebo (n=337) or once-daily ralinepag, starting at 50 µg and titrated weekly up to the highest tolerated dose (n=350) during a 16-week period.

At a median follow-up of 85 weeks with ralinepag and 78 weeks with placebo, the primary outcome – a first clinical worsening event – occurred in 64 patients (18%) vs. 121 patients (36%), respectively (hazard ratio, 0.45; p<0.0001). Events included death from any cause, hospitalization for worsening PAH or right heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response.

The largest between-group differences related to disease progression, initiation of prostacyclin-pathway therapy and clinical response, with no meaningful differences in all-cause death or hospital admission. Ralinepag patients also saw improved NT-proBNP levels and 6MWD.

Among patients, 65 in the ralinepag group (19%) and 10 in the placebo group (3%) discontinued treatment due to adverse events, with the most common reason being headache. Discontinuation in the ralinepag group was most frequent during the initial titration period. Other common adverse symptoms were diarrhea, nausea and myalgia, which investigators write are consistent with known prostacyclin-pathway effects.

Serious adverse events occurred in 98 patients (28%) in the ralinepag group and 104 (31%) in the placebo group, and adverse events leading to death occurred in 15 (4%) of ralinepag patients vs. 14 (4%) of placebo patients, with the most common causes being heart failure and sudden death.

"The results suggest that further prostacyclin-pathway intensification can reduce clinical worsening even in a largely pretreated population with relatively preserved baseline functional capacity," write trial investigators Vallerie V. McLaughlin, MD, FACC, et al. "Further research should clarify how ralinepag is best positioned among available PAH therapies, how tolerability during titration can be optimized, and whether longer-term treatment affects harder clinical outcomes."