Ralinepag

In PAH, the small arteries in the lungs narrow, which raises the pressure in the artery that carries blood from the heart to the lungs and makes the right side of the heart work harder^[14]. Over time this extra strain can damage the right ventricle, the heart chamber that pumps blood to the lungs^[14].

Prostacyclin is a natural signal that helps keep these vessels relaxed, and it acts through a receptor called the IP receptor^[12]. Medicines on the prostacyclin pathway include Uptravi (selexipag), a pill that activates the IP receptor, and treprostinil, sold as the Orenitram pill and in other forms^[12][13]. Ralinepag is a selective IP receptor agonist, meaning it switches on that receptor^[1].

Ralinepag is a non-prostanoid, which means its chemical structure differs from prostacyclin's, according to the Phase 2 investigators^[5]. United Therapeutics says it binds the IP receptor about 6 times more strongly than MRE-269, the active form of selexipag^[2]. A laboratory binding figure does not show whether a drug works better in people, and no trial has compared ralinepag with selexipag.

Ralinepag was first made as an immediate-release capsule taken twice a day and later reformulated as an extended-release tablet for once-daily dosing^[7]. In a study in healthy volunteers, the tablet had a half-life of 19 to 23 hours, the time it takes for the blood level to fall by half^[7].

ADVANCE OUTCOMES (NCT03626688) was a Phase 3, randomized, double-blind, placebo-controlled, event-driven trial in adults with PAH, with ralinepag or placebo added to their existing PAH treatment^[1][8]. It enrolled from January 24, 2019 to June 20, 2025 and is listed as completed, with 209 sites, 68 of them in the US^[1][8]. Of 728 people randomized and treated, 687 were analyzed: 350 on ralinepag and 337 on placebo^[1].

The investigators excluded 41 people from sites in China because of regulatory challenges and data integrity concerns^[1]. At the start, 80% of people were already taking 2 PAH medicines, and the average 6-minute walk distance was 438.9 meters^[1].

The largest differences between groups were in disease progression, starting an IV, under-the-skin or inhaled prostacyclin-pathway drug, and unsatisfactory long-term response^[1]. The results were presented at the 2026 American Thoracic Society meeting and published in The Lancet in July 2026^[2][1].

ADVANCE CAPACITY (NCT04084678), a Phase 3 study measuring exercise capacity on a cardiopulmonary exercise test, was ended by sponsor decision after enrolling 10 people^[9]. An open-label extension (NCT03683186) for people who took part in an earlier Phase 2 or Phase 3 ralinepag study is listed as enrolling by invitation^[10][3].

In the earlier Phase 2 trial (NCT02279160) of 61 people, the immediate-release form taken twice daily lowered pulmonary vascular resistance, the resistance blood meets in the lung arteries, by 163.9 dyn·s·cm⁻⁵ at week 22, against a rise of 0.7 on placebo^[5][11].

Ralinepag has no FDA label, so its official side effects and warnings are not set. United Therapeutics reported that the most common side effects on ralinepag in ADVANCE OUTCOMES were headache, diarrhea, nausea and myalgia (muscle pain), and that no new safety signals were seen^[3]. The company describes the safety profile as consistent with the known side effects of prostacyclin-pathway drugs^[2].

In the Lancet paper, side effects were the main reason for stopping treatment in 65 of 350 people on ralinepag (19%) and 10 of 337 on placebo (3%)^[1]. Serious adverse events happened in 98 people on ralinepag (28%) and 104 on placebo (31%), and adverse events leading to death in 15 (4%) and 14 (4%)^[1]. In the Phase 2 open-label extension, the most commonly reported side effects included headache (64.4%), diarrhea (37.8%) and jaw pain (33.3%), and side effects became less common once people reached and stayed on a stable dose^[6].

Arena Pharmaceuticals developed ralinepag under the code APD811 and ran its Phase 2 PAH trial from 2014 to 2017^[11][5]. United Therapeutics announced on January 24, 2019 that it had closed a license giving it exclusive worldwide rights, and that the 2019 terms included $800 million upfront and up to $400 million in milestones^[4]. ADVANCE OUTCOMES began the same day and finished enrolling in June 2025^[8][1].

The Lancet published the results online on July 28, 2026^[1]. United Therapeutics submitted the New Drug Application in June 2026, and on August 24, 2026 said the FDA had accepted it with a target action date of June 24, 2027^[3][2]. The FDA had not announced a decision as of November 8, 2026.