United Therapeutics' Ralinepag Achieves 55% Risk Reduction in Pivotal PAH Trial, Paving Way for FDA Submission
核心洞察
United Therapeutics (搜索) announced that ralinepag met its primary endpoint in the phase 3 ADVANCE OUTCOMES study, reducing the risk of clinical worsening events by 55% compared to placebo in patients with pulmonary arterial hypertension (搜索).
The once-daily oral prostacyclin receptor (搜索) agonist demonstrated statistically significant improvements in secondary endpoints, including a 47% increase in odds of clinical improvement and improvements in six-minute walk distance and NT-proBNP levels.
The company plans to submit a New Drug Application to the FDA by the second half of 2026, positioning ralinepag as potentially the first and only once-daily oral prostacyclin therapy for PAH (搜索) treatment.
United Therapeutics Corporation announced that its investigational drug ralinepag achieved a 55% reduction in the risk of clinical worsening events compared to placebo in patients with pulmonary arterial hypertension (搜索) (PAH (搜索)), meeting the primary endpoint of its pivotal phase 3 ADVANCE OUTCOMES study. The results position ralinepag as a potential breakthrough therapy for PAH, with the company planning to submit a New Drug Application (NDA) to the FDA by the second half of 2026.
Robust Clinical Efficacy Across Multiple Endpoints
The ADVANCE OUTCOMES study, which enrolled 687 patients with PAH (搜索), demonstrated ralinepag's efficacy with a hazard ratio of 0.45 (95% CI [0.33-0.62]; p<0.0001) for the primary endpoint of time to first adjudicated clinical worsening event. The study population was predominantly pre-treated, with 80% of patients on dual background therapy and 70% classified as World Health Organization (WHO)/New York Heart Association (NYHA) Functional Class II at baseline.
Ralinepag also achieved statistically significant improvements in several important secondary endpoints. The drug increased the odds of achieving clinical improvement by 47% from baseline to Week 28 (p=0.015), while demonstrating improvements in six-minute walk distance (6MWD) and reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared to placebo.
"PAH (搜索) is a progressive, life-threatening disease that has a devastating impact on patients' lives. In the ADVANCE OUTCOMES study, ralinepag delayed disease progression in patients with PAH facing significant disease burden at baseline. Ralinepag's potency and once-daily oral dosing make these outcomes highly relevant in real-world settings," said Vallerie V. McLaughlin, M.D., Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine and Director, Pulmonary Hypertension Program at University of Michigan and Chair of the ADVANCE OUTCOMES Steering Committee.
Consistent Benefits Across Patient Subgroups
The treatment benefits were consistent across all patient subgroups analyzed, including time since diagnosis, disease etiology, baseline 6MWD, and use of background therapies. This consistency reinforces the robustness of the treatment effect and suggests broad therapeutic relevance for ralinepag in the PAH (搜索) patient population.
Treatment with ralinepag was well-tolerated, with a safety profile consistent with known prostacyclin-related adverse events. No new safety signals were observed during the study.
Potential to Transform PAH Treatment Landscape
Ralinepag is designed as a highly selective and potent prostacyclin (IP) receptor agonist with multiple pathway effects, including vasodilatory, anti-proliferative, and anti-inflammatory properties. The drug demonstrates six-fold higher binding affinity for the IP receptor (搜索) than MRE-269 (selexipag's active metabolite) and achieves sustained IP receptor occupancy similar to parenteral therapy.
"These results mark a significant advancement for PAH (搜索) patients. With its extended-release profile and pharmacokinetic characteristics that mimic the steady-state exposure of parenteral therapy, ralinepag provides disease-mitigating capabilities that target underlying PAH pathology and achieve impressive clinical benefits," said Derek Solum, Ph.D., Senior Director, Product Development at United Therapeutics (搜索) and the lead for the global ADVANCE OUTCOMES program.
The drug is six- to eight-fold more potent at increasing in vitro cAMP levels compared with the active metabolite of selexipag. In a previous phase 2 study, ralinepag significantly reduced pulmonary vascular resistance compared with placebo in PAH (搜索) patients on mono (41%) or dual combination (59%) background therapy.
Addressing Critical Unmet Medical Need
PAH (搜索) affects approximately 500,000 individuals worldwide, with around 50,000 people affected in the United States. The disease is characterized by increased pressure in the pulmonary arteries, leading to right heart strain and ultimately right heart failure (搜索) and death. Despite increases in the number of people diagnosed with the disease, only a small fraction of patients with PAH are currently treated due to the rarity and complexity of diagnosing the condition.
"United Therapeutics (搜索) was founded on the idea that we could bring transformative therapies to people living with PAH (搜索). Our achievement in this pivotal trial is among the most important in our history and strengthens our decades-long commitment to advancing prostacyclin-based science," said Martine Rothblatt, Ph.D., Chairperson and Chief Executive Officer of United Therapeutics.
Next Steps and Regulatory Timeline
United Therapeutics (搜索) intends to present full results from the ADVANCE OUTCOMES study at an upcoming international conference. The company plans to submit an NDA for ralinepag to the FDA by the second half of 2026, potentially positioning it as the first and only once-daily oral prostacyclin therapy for PAH (搜索) treatment.
The ADVANCE OUTCOMES study was designed as a pivotal phase 3 multicenter, global, randomized, double-blind, placebo-controlled, event-driven study. Patients were randomly assigned (1:1) to receive ralinepag or placebo in addition to their standard of care PAH (搜索)-specific background therapy, with once-daily dosing individualized and titrated based on tolerability and clinical response.