ralinepag (APD811) / United Therapeutics Corporation, Pfizer, Everest Medicines - LARVOL DELTA

Late Breaking Abstract - Clinical improvement with ralinepag in a contemporary pulmonary arterial hypertension population: Insights from the ADVANCE Outcomes study (ERS 2026) - "Conclusions Ralinepag resulted in a significant 55% reduction in the risk of clinical worsening and 47% greater odds of achieving clinical improvement. The results underscore the durable efficacy of ralinepag in a lower risk, pretreated, and contemporary PAH population."

Clinical • Late-breaking abstract • Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases

Sotatercept Versus Other Add-on Therapies in Pulmonary Arterial Hypertension: a Bayesian Network Meta-Analysis (ERS 2026) - "Oral Treprostinil (MD 17m), Inhaled Iloprost (MD 26.0m), Selexipag (MD 8.3m), Ralinepag (MD 7.3m), and MK-5475 (MD -5.7m) showed non-significant effects (Figure 1). Sotatercept demonstrated the highest probability of being the most effective add-on therapy for improving 6MWD in PAH, supporting its positioning as preferred add-on for patients not achieving treatment goals."

Retrospective data • Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases

Treatment with Ralinepag Improves Outcomes in Patients with Connective Tissue Disease Associated with Pulmonary Arterial Hypertension: Results from the Phase 3 ADVANCE Outcomes Study (ESC 2026) - No abstract available

Clinical • Late-breaking abstract • P3 data • Cardiovascular

United Therapeutics Corporation...announced that the FDA has accepted the New Drug Application (NDA) for ralinepag to treat PAH. (United Therapeutics Press Release) - "The FDA has set a Prescription Drug User Fee Act target action date of June 24, 2027....The filing was based on results from the phase 3 ADVANCE OUTCOMES study evaluating the safety and efficacy of ralinepag in patients with PAH."

FDA filing • PDUFA • Pulmonary Arterial Hypertension

Ralinepag in pulmonary arterial hypertension: a step forward. (PubMed, Lancet) - No abstract available

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Ralinepag for the treatment of pulmonary arterial hypertension (ADVANCE OUTCOMES): a randomised, double-blind, placebo-controlled phase 3 study. (PubMed, Lancet) - P3 | "In patients with PAH receiving contemporary background therapy, ralinepag significantly reduced the risk of first clinical worsening compared with placebo, but was associated with more adverse-event-related treatment discontinuations. These results support the use of ralinepag as an oral, once-daily prostacyclin-pathway treatment option for PAH."

Journal • P3 data • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Food Effects on the Pharmacokinetics of Single Dose and Steady-State Ralinepag, a Novel Oral Prostacyclin Agonist, in Healthy Volunteers. (PubMed, Am J Cardiovasc Drugs) - "Food status did not significantly affect the PK or safety of ralinepag XR."

Journal • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pain • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Ralinepag dry powder inhalation (DPI) program to be pursued for pulmonary arterial hypertension by United Therapeutics (GlobeNewswire) - "United Therapeutics has made a payment of $5 million to support the accelerated development of MNKD-1501; MannKind is eligible to receive up to $35 million in development milestone payments and 10% royalties on net sales."

Licensing / partnership • Pulmonary Arterial Hypertension

New Targets, New Trials in PAH: A New Hope? (ISHLT 2026) - "This talk will explore emerging therapeutic targets in pulmonary arterial hypertension (PAH), such as drugs targeting the BMPR2 and activin signaling pathways. It will highlight novel agents such as Sotatercept, Seralutinib, and Ralinepag, emphasizing how these therapies may redefine and reshape the future treatment landscape of PAH."

Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases

ADVANCE Outcomes: A Phase 3, Randomized Clinical Trial Evaluating Ralinepag for Pulmonary Arterial Hypertension (ATS 2026) - No abstract available

Clinical • Late-breaking abstract • P3 data • Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases

A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients (clinicaltrials.gov) - P3 | N=728 | Completed | Sponsor: United Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Rheumatology

Risk Improvements in Ralinepag Open-Label Extension (ERS 2025) - "CONCLUSIONS Ralinepag treatment in the OLE resulted in early and sustained improvement or maintenance in risk. Sponsored by United Therapeutics"

Clinical • Cardiovascular • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

United Therapeutics Corporation Reports Record Second Quarter 2025 Financial Results (Businesswire) - "Tyvaso DPI record total revenue of $315 million, reflecting 22 percent growth over the second quarter of 2024....Double-digit, year-over-year revenue growth for Nebulized Tyvaso, Orenitram, and Unituxin with record quarterly revenue for Orenitram; Phase 3 TETON 2 study of Nebulized Tyvaso in idiopathic pulmonary fibrosis is complete; data expected in September 2025; phase 3 TETON 1 data expected in the first half of 2026; Enrollment for the phase 3 ADVANCE OUTCOMES study of ralinepag in pulmonary arterial hypertension is complete; data expected in the first half of 2026."

Enrollment closed • P3 data • Sales • Idiopathic Pulmonary Fibrosis • Neuroblastoma • Neuroendocrine Tumor • Pulmonary Arterial Hypertension

A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients (clinicaltrials.gov) - P3 | N=1000 | Active, not recruiting | Sponsor: United Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Rheumatology

Safety and pharmacokinetics of ralinepag, a novel oral prostacyclin receptor agonist. (PubMed, JHLT Open) - "One received a single dose of ralinepag IR (30 µg) followed by single ascending doses of XR (60, 120, and 180 µg), and the other received single ascending doses of selexipag (200, 400, and 600 µg). Ralinepag XR has a half-life suitable for once-daily dosing. The reduced Cmax and delayed Tmax contributes to lower peak-to-trough fluctuations and may provide favorable effects for sustained efficacy and improved tolerability."

Journal • PK/PD data • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Ralinepag Treatment to Achieve and Maintain REVEAL Lite 2 Low Risk Status: Interim Results of ADVANCE EXTENSION (ATS 2025) - "CONCLUSIONS Treatment with ralinepag in the OLE produced early and sustained REVEAL Lite 2 risk improvements after experiencing a CWE, with a substantial proportion of participants maintaining or achieving low risk status. Sponsored by United Therapeutics"

Cardiovascular • Pain • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Developing Models for New Drugs in PAH: A Pharmacokinetic Simulation of Ralinepag (ISHLT 2025) - P3 | "The model also accurately predicted blood plasma concentrations consistent with those observed in the phase 2 study with patients with PAH.Conclusion The accuracy of this model across multiple doses and formulations suggests that it will be applicable in analyzing results from the ongoing phase 3 ADVANCE OUTCOMES study. Beyond simulating PK, we plan to extend the model to link with variables such as hemodynamics and exercise capacity, with potential utility to calculate dosing equivalencies for transition from other PAH therapies to ralinepag."

PK/PD data • Cardiovascular • Pulmonary Arterial Hypertension • Respiratory Diseases

A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension (clinicaltrials.gov) - P3 | N=1000 | Enrolling by invitation | Sponsor: United Therapeutics | Trial completion date: Sep 2024 ➔ Dec 2026 | Trial primary completion date: Sep 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Rheumatology

United Therapeutics Corporation Reports Fourth Quarter and Full Year 2024 Financial Results (Businesswire) - "'both TETON studies in idiopathic pulmonary fibrosis are enrolled, facilitating data starting the second half of this year; ralinepag, our potentially best-in-class once-daily oral prostacyclin agonist, will generate data next year'...Total Tyvaso revenues grew by 19 percent to $415.9 million in the fourth quarter of 2024, compared to $350.6 million in the fourth quarter of 2023...Total Tyvaso revenues grew by 31 percent to $1,620.4 million in 2024, compared to $1,233.7 million in 2023...The growth in Remodulin revenues resulted from an increase in U.S. Remodulin revenues, driven by an increase in quantities sold. The growth in Orenitram revenues resulted from an increase in quantities sold and, to a lesser extent, a price increase."

Clinical data • Commercial • P3 data • Idiopathic Pulmonary Fibrosis • Interstitial Lung Disease • Pulmonary Arterial Hypertension • Respiratory Diseases

A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients (clinicaltrials.gov) - P3 | N=1000 | Recruiting | Sponsor: United Therapeutics | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Rheumatology

New and Emerging Therapeutic Drugs for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review. (PubMed, Cureus) - "Several FDA-approved therapeutic options are available, including prostacyclin analogs (epoprostenol, iloprost, and treprostinil), the non-prostanoid IP receptor agonist selexipag, selective endothelin receptor antagonists (ERA) (ambrisentan, bosentan, and macitentan), phosphodiesterase 5 inhibitors (sildenafil and tadalafil), and the soluble guanylate cyclase (sGC) stimulator riociguat...The review found that while udenafil, imatinib, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were evaluated, imatinib was notably associated with adverse side effects. Conversely, udenafil, racecadotril, sotatercept, anastrozole, riociguat, tacrolimus, and ralinepag were found to be safe, well-tolerated, and effective in improving hemodynamic measures and 6-MWDs. This study aims to summarize the developing treatment options currently under clinical trials, highlighting the need for further trials before their application in clinical practice."

Journal • Review • Cardiovascular • Fibrosis • Hypertension • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Initial Long-term Data From a Phase 3 Open-label Extension Study (ROR-PH-303) Evaluating Ralinepag for the Treatment of Pulmonary Arterial Hypertension (Advance Extension) (ATS 2024) - P3 | "Ralinepag has produced sustained, durable improvements in 6MWD and WHO FC, and reduced risk scores. The safety profile of ralinepag is similar to that reported in previous studies. Data from this Phase 3 OLE study demonstrate the benefit-risk ratio of ralinepag remains unchanged and positive."

Clinical • P3 data • Cardiovascular • Hypertension • Pain • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

"Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial." F. Torres, H. Farber, A. Ristic, et al. Eur Respir J 2019; 54: 1901030. (PubMed, Eur Respir J) - No abstract available

Journal • P2 data

A Study of Ralinepag in Healthy Chinese Adult Subjects (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Everstar Medicines (Shanghai) Limited | Recruiting ➔ Completed

Trial completion

Ralinepag Phase II Open-Label Extension Study in Patients with Pulmonary Arterial Hypertension. (PubMed, Adv Ther) - "Ralinepag produced sustained, durable improvements in 6MWD along with durable reductions in PVR and a manageable AE profile. Most participants continuing treatment with ralinepag maintained functional measures throughout the OLE and those switching from placebo to ralinepag often experienced functional improvements."

Clinical • Journal • P2 data • Cardiovascular • Hypertension • Pain • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases