Oral ralinepag cuts clinical worsening in pulmonary arterial hypertension

Pulmonary arterial hypertension is a rare, progressive disease in which the small vessels of the lungs stiffen and narrow, forcing the right side of the heart to pump against mounting resistance until, in the worst cases, it fails [s1]. One of the three main drug pathways targets prostacyclin, a signalling molecule that relaxes those vessels — but the most effective prostacyclin drugs are delivered by continuous infusion or inhalation, a heavy burden for patients to carry. Ralinepag is an oral, once-daily pill designed to hit the same target more conveniently. In a large phase 3 trial, it more than halved the risk of the disease worsening — a genuine benefit that arrives with a clear tolerability cost, and from a study its maker paid for [s1].

What they did

ADVANCE OUTCOMES was a randomised, double-blind, placebo-controlled, event-driven phase 3 trial [s1]. Eligible patients were aged 18 or older with pulmonary arterial hypertension diagnosed under the 2022 European guidelines — a mean pulmonary artery pressure above 20 mm Hg, a wedge pressure of 15 mm Hg or lower, and pulmonary vascular resistance above 2 Wood units [s1]. Participants were randomly assigned 1:1 to ralinepag or placebo, started at 50 micrograms once daily and titrated weekly to the highest individually tolerated dose [s1]. Crucially, this was an add-on trial: at baseline, 548 of 687 patients (80%) were already taking two background PAH therapies [s1], so ralinepag was tested on top of contemporary treatment rather than against nothing.

The primary outcome was time to a first clinical worsening event — a composite of death from any cause, hospital admission for worsening PAH or right heart failure, starting parenteral or inhaled prostacyclin-pathway therapy, disease progression, or an unsatisfactory long-term clinical response [s1]. "Event-driven" means the trial ran until enough of these events had accrued to answer the question, rather than for a fixed time. It is registered as NCT03626688 [s2].

What it showed

Patients were enrolled between 24 January 2019 and 20 June 2025 [s1]. Of 1,037 people screened, 728 were randomly assigned and received at least one dose; the primary analysis covered 687 after 41 randomly assigned and treated patients from sites in China were excluded, which the investigators attribute to regulatory challenges and data-integrity concerns [s1]. Of those 687, 350 received ralinepag and 337 placebo, with a mean baseline six-minute walk distance of 438.9 metres [s1]. Median follow-up was 85.0 weeks in the ralinepag group and 78.4 weeks in the placebo group [s1].

The efficacy result was large. A first clinical worsening event occurred in 64 of 350 patients (18%) on ralinepag versus 121 of 337 (36%) on placebo — a hazard ratio of 0.45 (95% confidence interval 0.33 to 0.62; p<0.0001) [s1]. In plain terms, the drug cut the risk of the composite endpoint by more than half in a population already on standard therapy. The investigators report that the largest numerical differences within the composite came from disease progression, the need to start infused or inhaled prostacyclin drugs, and unsatisfactory long-term response [s1] — components that lean toward function and disease trajectory rather than death alone.

The cost side

Benefit came with a tolerability penalty that the numbers make plain. An adverse event was the primary reason for stopping treatment in 65 of 350 patients (19%) on ralinepag, compared with just 10 of 337 (3%) on placebo [s1] — a more than sixfold difference in discontinuations driven by side-effects, consistent with the flushing, headache, jaw pain, and gut symptoms that dog prostacyclin-pathway drugs as they are titrated up. Against that, the more serious safety tallies were balanced between the groups: serious adverse events occurred in 98 patients (28%) on ralinepag and 104 (31%) on placebo, and adverse events leading to death in 15 (4%) and 14 (4%) respectively [s1]. So the drug did not appear to raise the rate of the gravest outcomes, but a meaningful minority could not stay on it.

The funding, stated plainly

ADVANCE OUTCOMES was funded by United Therapeutics Corporation, which develops ralinepag [s1], and the company is the trial's sponsor [s2]. That does not invalidate a double-blind, placebo-controlled, event-driven result — this is a rigorous design — but it is the context in which the finding should be read, and it is why independent replication and regulatory scrutiny of the full dataset matter. The exclusion of the Chinese sites, while explained, also removed 41 randomised patients from the analysis, a decision worth watching as the complete results are examined.

What to watch

The investigators conclude that ralinepag significantly reduced the risk of first clinical worsening in patients on contemporary background therapy, while causing more adverse-event-related discontinuations [s1]. For a disease with few oral options that alter its course, a once-daily pill that delays deterioration is a real addition — if regulators clear it and if patients can tolerate the titration. The open questions are how ralinepag performs against, or alongside, existing oral prostacyclin-pathway agents, and whether the worsening benefit eventually shows up as longer survival rather than fewer composite events.

Sources

• [s1] Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study. The Lancet. 28 July 2026. doi:10.1016/S0140-6736(26)01011-1. PMID 42520828.
• [s2] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in Patients With PAH (ADVANCE OUTCOMES), NCT03626688. U.S. National Library of Medicine.