A82-03 ADVANCE Outcomes: A Phase 3, Double-blind, Placebo-controlled Clinical Trial Of Ralinepag For The Treatment Of Pulmonary Arterial Hypertension

Rationale

Ralinepag, a highly selective, potent, once-daily oral prostacyclin (IP) receptor agonist with multiple pathway vascular targets, including vasodilatory, anti-proliferative, and anti-inflammatory properties, was developed to treat patients with pulmonary arterial hypertension (PAH). Ralinepag pharmacokinetics demonstrate sustained plasma concentrations similar to parenteral therapy conferring continuous IP receptor occupancy. ADVANCE OUTCOMES (NCT03626688) was a global, multicenter, randomized, double-blind, placebo-controlled, event-driven study to assess the efficacy and safety of ralinepag in participants with PAH.

Methods

Participants were randomized 1:1 to receive ralinepag or placebo in addition to their standard of care or PAH-specific background therapy. There was no dose ceiling for ralinepag; dosing was individualized and titrated according to tolerability and clinical response. The primary end point was the time to first adjudicated clinical worsening event (CWE). Protocol-defined CWEs included death (all causes), nonelective hospitalization (≥24 hours) for conditions related to worsening PAH, initiation of parenteral/inhaled prostacyclin, disease progression (≥15% decrease in six-minute walk distance (6MWD) and worsening functional class (FC) or initiation of additional PAH therapy), and unsatisfactory long-term clinical response (receiving study drug for ≥28 weeks with sustained FC III/IV symptoms and decrease in 6MWD). Key secondary end points evaluated at Week 28 included change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), change in 6MWD, and clinical improvement. Safety was monitored via adverse events, hospitalizations, and clinical laboratory and electrocardiogram parameters.

Results

The final analysis data set included 687 participants; 350 participants were randomly assigned to ralinepag and 337 participants to placebo. Overall, the mean (SD) age of participants was 52.0 (14.9) years, 75.7% were female, 80.2% were White, and participants had a median time since PAH diagnosis of 2.29 years. Most had either idiopathic PAH (57.1%) or CTD-associated PAH (28.2%). The median (range) time on background therapy was 1.9 (0.09-22.7) years; 79.8% were receiving dual oral background PAH therapy. At Baseline, 70.5% were classified as FC II with a mean (SD) 6MWD of 439 (105) m and a median (IQR) NT-proBNP of 213 (85, 522) pg/mL. In the ralinepag group, the mean (SD) dose at Week 28 was 336.5 (264.5) mcg and the mean (SD) overall exposure was 104.3 (88.4) weeks. Clinical worsening occurred in 18% (n = 64) of the ralinepag group and 36% (n = 121) of the placebo group (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62; p < 0.0001) (Figure 1). These findings were consistent across all patient subgroups, including time since diagnosis, disease etiology, baseline 6MWD, WHO FC, NT-proBNP levels, and use of background therapies. At Week 28, ralinepag treatment resulted in statistically significant improvements in 6MWD (+20.4 m placebo-corrected difference; p = 0.0033), NT-proBNP (24.3% reduction over placebo; p = 0.0013), and 47% greater odds of achieving clinical improvement (p = 0.015). Ralinepag treatment was well-tolerated; the safety profile was consistent with known prostacyclin-related adverse events. No new safety signals were observed.

Conclusions

Ralinepag resulted in a statistically significant 55% reduction in the risk of clinical worsening compared with placebo, underscoring the durable efficacy of once-daily oral ralinepag in a largely low-risk, heavily pretreated, and contemporary PAH population. These results support the benefit of a convenient, well tolerated oral prostacyclin pathway agent for the treatment of PAH.

Sponsored by United Therapeutics.

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