United Therapeutics' Ralinepag Cuts PAH Clinical Worsening 55% in Phase 3 ADVANCE OUTCOMES

United Therapeutics said on March 2 that its investigational oral drug ralinepag met the primary endpoint of the pivotal Phase 3 ADVANCE OUTCOMES study in pulmonary arterial hypertension (PAH), cutting the risk of a clinical worsening event by 55% compared with placebo, HCPLive reported.

The company presented the topline results the same day in an investor webcast presentation. The data are company-reported and had not yet been presented at a medical meeting or published in a journal. The slides state that the use of ralinepag for PAH is investigational and has not been approved by the FDA.

Ralinepag is a once-daily, selective agonist of the prostacyclin (IP) receptor, the target of an established class of PAH treatments. HCPLive reported that the company describes it as having six-fold higher binding affinity than MRE-269, the active metabolite of selexipag, and sustained receptor occupancy similar to infused therapy.

Trial design and results

ADVANCE OUTCOMES was a multicenter, randomized, double-blind, placebo-controlled, event-driven study. A total of 687 patients were assigned 1:1 to ralinepag or placebo on top of their standard PAH background therapy, with once-daily doses individualized to tolerability and response and no dose ceiling. About 80% of patients were on dual background therapy and about 70% were in WHO functional class II at baseline, according to the presentation.

The primary endpoint was time to the first adjudicated clinical worsening event, defined as death, nonelective hospitalization for worsening PAH, starting an inhaled or infused prostacyclin drug, disease progression, or an unsatisfactory long-term clinical response. A first event occurred in 64 of 350 patients on ralinepag (18.3%) and 121 of 337 on placebo (35.9%), for a hazard ratio of 0.45 (95% CI, 0.33-0.62; p<0.0001).

Most of the difference came from disease progression (2.9% versus 10.7% as the first event), unsatisfactory long-term response (4.0% versus 9.8%) and starting inhaled or infused prostacyclin (2.9% versus 6.5%). Deaths as a first event (3.1% versus 3.0%) and PAH hospitalizations (5.4% versus 5.9%) were similar between groups. The company said the study also met secondary endpoints including change in NT-proBNP, six-minute walk distance and clinical improvement; HCPLive reported that investigators found the benefit consistent across patient subgroups.

"In the ADVANCE OUTCOMES study, ralinepag delayed disease progression in patients with PAH facing significant disease burden at baseline," said Vallerie McLaughlin of the University of Michigan, chair of the study's steering committee, in a statement quoted by HCPLive.

Safety

United Therapeutics said ralinepag was well tolerated, with a safety profile consistent with known prostacyclin-related adverse events and no new safety signals. The most common adverse events on ralinepag versus placebo were headache (81.1% versus 41.5%), diarrhea (58.3% versus 28.2%), nausea (45.1% versus 25.5%), myalgia (36.0% versus 10.7%) and jaw pain (35.7% versus 8.9%), according to the presentation.

The trial is registered as NCT03626688. Patients who completed it could enroll in an open-label extension.