Phase 3 PAH trial of ralinepag fully enrolled, results expected in 2026
728 people with PAH to test the daily oral treatment against a placebo
A Phase 3 clinical trial testing the experimental daily oral treatment ralinepag in people with pulmonary arterial hypertension (PAH) has completed enrollment.
The ADVANCE OUTCOMES trial (NCT03626688) enrolled 728 people with PAH who were on oral background therapies. Participants are being randomly assigned to receive ralinepag at doses up to 400 micrograms per day, or a placebo. The study is testing whether ralinepag is better than the placebo at delaying the time to clinical worsening events such as death, unplanned hospitalization due to worsening PAH, or disease progression.
Data will be collected until the end of this year, and top-line results from the study are expected in the first half of 2026, according to United Therapeutics, which is developing ralinepag after acquiring rights to it from Arena Pharmaceuticals.
“Our philosophy and mission drive us to relentlessly seek ways to improve patient care and achieve better treatment outcomes,” Derek Solum, PhD, senior director of product development at United, said in a company press release. “We are grateful for the participants and clinical investigators who have participated in this pivotal study to help us pursue our mission.”
Secondary outcome measures in the trial, assessed from the start of the study through week 28, include change in levels of a biomarker of heart failure, six-minute walk distance (a common measure of exercise capacity in people who can walk), heart rate recovery following completion of the six-minute walk test, and health-related quality of life.
Participants can enroll in long-term extension study after Phase 3 trial
Participants who completed the placebo-controlled portion of the Phase 3 trial will have the option to continue into ADVANCE EXTENSION (NCT03683186), a long-term study where all will be treated with ralinepag.
PAH is marked by abnormally high pressure in the blood vessels of the lungs. Ralinepag is designed to mimic the activity of prostacyclin, a signaling molecule that reduces blood pressure by prompting blood vessels to relax and widen. Prostacyclin-mimicking therapies are a cornerstone of standard PAH treatment, alongside endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors (PDE-5) — medications that reduce blood pressure through other biological mechanisms.
Although other prostacyclin-mimicking therapies are approved for PAH, ralinepag’s formulation as a once-daily oral therapy make it unique, according to United.
“We are excited for the potential of ralinepag to be the first once-a-day oral prostacyclin agonist [activator], which, if successful, could fundamentally change the PAH treatment paradigm, potentially leading over time to upfront use of oral prostacyclins as a first-line therapy alongside traditional ERA and PDE-5 oral products,” Solum said.
An earlier Phase 2 clinical trial (NCT02279160) tested ralinepag against a placebo in 61 people with PAH. Results showed that, after 22 weeks of treatment, median pulmonary vascular resistance (PVR) was reduced by 29.8% with ralinepag compared with the placebo. PVR is essentially a measure of how difficult it is for blood to flow through the lungs’ vessels; PAH is generally characterized by abnormally elevated PVR.
After completing the placebo-controlled Phase 2 study, 45 participants entered into an extension study (NCT02279745) where all were treated with ralinepag and evaluated for long-term outcomes. Data from the extension study indicated that, after up to two years on ralinepag, median PVR decreased and so did mean pulmonary arterial pressure, a measure of how much pressure is in the lungs’ blood vessels. More than 85% of participants in the extension study showed no worsening in functional classification over the course of the trial, according to United.
The data also indicated patients taking long-term ralinepag experienced significant improvements in six-minute walk distance, by a mean of 36.3 meters (about 119 feet).
Data from the Phase 2 trial and extension study also indicated ralinepag was generally well tolerated, with a manageable side effect profile similar to other prostacyclin-mimicking therapies. Side effects reported included headache and nausea.
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