Ralinepag for Pulmonary Arterial Hypertension

Enrolling by invitation at 260 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: United Therapeutics

Disqualifiers: Pregnancy, Breastfeeding, Transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 6 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how well the medication ralinepag works for individuals with pulmonary arterial hypertension (PAH), a condition characterized by high blood pressure in the lungs. The trial seeks to determine if continued treatment benefits those who participated in a previous ralinepag study. Participants will take ralinepag tablets, with doses adjusted to the highest tolerable amount. This trial suits those who completed a previous ralinepag study, did not experience serious drug-related side effects, and are willing to meet the study requirements. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to the potential availability of a new treatment for PAH.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that ralinepag is likely to be safe for humans?

Research has shown that ralinepag is generally safe for people with pulmonary arterial hypertension (PAH). Earlier studies found ralinepag to be safe, with common side effects such as headache and nausea, similar to other PAH treatments. One important study found that ralinepag significantly lowered pressure in the lung blood vessels, indicating its effectiveness and safety. The medication is taken as a once-daily tablet, with the dose adjustable to the highest level a person can comfortably handle. Overall, the evidence supports ralinepag's safety for people with PAH. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Ralinepag is unique because it targets pulmonary arterial hypertension (PAH) with an extended-release formulation that promises a smoother dosing experience compared to current treatments like endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. Most treatments for PAH require multiple doses throughout the day, but Ralinepag offers a once-daily oral tablet that could improve adherence and patient convenience. Researchers are excited because Ralinepag acts as a prostacyclin receptor agonist, potentially providing a more effective and sustained response in dilating blood vessels and reducing blood pressure in the lungs.

What evidence suggests that ralinepag might be an effective treatment for pulmonary arterial hypertension?

Studies have shown that ralinepag can help treat pulmonary arterial hypertension (PAH). In one study, ralinepag reduced blood vessel resistance by 29.8%, an important measure of heart and lung function. This reduction was significant, indicating it likely did not occur by chance. Another study confirmed ralinepag's safety and effectiveness for long-term use in people with PAH. Ralinepag targets a specific receptor to relax blood vessels and improve blood flow, aiding the heart in pumping blood through the lungs. Participants in this trial will receive ralinepag as an experimental treatment, with doses adjusted to the highest tolerated level. ^{1 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for individuals with WHO Group 1 Pulmonary Arterial Hypertension (PAH) who completed a prior ralinepag study. Participants must agree to use contraception if conception is possible and not attempt pregnancy during the study. Those who had drug-related issues or didn't complete previous ralinepag studies, are pregnant or breastfeeding, or had certain medical procedures are excluded.

Inclusion Criteria

Evidence of a personally signed and dated informed consent form indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures

I am willing and able to follow the study's schedule and procedures.

I agree to use birth control during the study and for 30 days after.

Exclusion Criteria

Subjects who withdrew consent during participation in another ralinepag study

Subjects who prematurely discontinued investigational medicinal product (IMP) due to a drug-related AE/SAE or tolerability issue in the preceding ralinepag study in which they were enrolled, or subjects who did not complete all protocol defined study procedures at a Study Drug Termination Visit or End of Study Visit in the preceding ralinepag study

I have had a lung or heart/lung transplant or started long-term therapy with a prostacyclin since my last ralinepag study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Titration

A 16-week blinded Dose Titration Period for subjects from a double-blind study

16 weeks

Treatment

Participants receive ralinepag in an open-label extension until discontinuation or marketing approval

Up to 6 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ralinepag

Trial Overview The trial tests the long-term effects of Ralinepag on PAH in an open-label extension format. This means everyone gets Ralinepag and knows what they're taking. It's for those who've already been part of earlier Phase 2 or Phase 3 trials involving this medication.

How Is the Trial Designed?

Group I: Ralinepag Experimental Treatment 1 Intervention

Ralinepag once daily extended-release tablets (oral) 50, 250, and 400 mcg titrated to the highest tolerated dose.

Who Is Running the Clinical Trial?

United Therapeutics

Lead Sponsor

Trials

112

Recruited

14,500+

Dr. Martine Rothblatt

United Therapeutics

Chief Executive Officer since 1996

PhD in Medical Ethics from the Royal London College of Medicine and Dentistry, JD and MBA from UCLA

Dr. Michael Benkowitz

United Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Published Research Related to This Trial

Ralinepag, a selective prostacyclin receptor agonist, was found to be generally safe and well-tolerated in a Phase 1 study involving 82 healthy subjects, with only one serious adverse event (atrial fibrillation) reported.

The pharmacokinetic profile of ralinepag showed favorable properties, with a mean terminal elimination half-life of 20.5-26.4 hours and effective dosing strategies indicating potential for further clinical development, including an extended-release formulation for once-daily dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers. Grundy, JS., King, CD., Adams, JW., et al.[2020]

Selexipag significantly reduced the risk of disease progression in patients with pulmonary arterial hypertension (PAH) compared to placebo, as shown in the GRIPHON trial, and has a long-term safety profile consistent with earlier findings.

In the ongoing GRIPHON OL study, 953 patients treated with selexipag showed promising survival rates over a median exposure of 31.7 months, with 1-year survival at 92% and 5-year survival at 71.2%, indicating its potential effectiveness in long-term management of PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension. Galiè, N., Gaine, S., Channick, R., et al.[2022]

Selexipag is an effective treatment for pulmonary arterial hypertension (PAH) and works as a prostacyclin receptor agonist, which helps improve blood flow in the lungs.

In clinical trials, particularly the GRIPHON study, selexipag demonstrated significant efficacy and tolerability, making it a suitable option for patients who do not respond adequately to existing oral therapies, but it should not replace parenteral prostacyclin for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. Genecand, L., Wacker, J., Beghetti, M., et al.[2022]

Inhaled MK-5475, a new treatment for pulmonary arterial hypertension (PAH), was well tolerated and did not cause systemic side effects, such as changes in blood pressure or heart rate, in participants aged 18-70.

The treatment led to significant reductions in pulmonary vascular resistance, ranging from 21% to 30%, indicating its potential effectiveness in improving blood flow in the lungs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). Bajwa, EK., Cislak, D., Palcza, J., et al.[2023]

In a phase 2 study involving 61 patients with pulmonary arterial hypertension (PAH), ralinepag significantly reduced pulmonary vascular resistance (PVR) by 163.9 dyn·s·cm-5 compared to placebo, indicating its efficacy in improving this condition.

Ralinepag was well-tolerated, with serious adverse events occurring in only 10% of patients compared to 29% in the placebo group, suggesting a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Torres, F., Farber, H., Ristic, A., et al.[2020]

Selexipag is an effective treatment for pulmonary arterial hypertension (PAH), showing significant improvements in pulmonary artery obstruction and right ventricular function in both animal models and clinical trials, including a large study with 1156 patients.

In clinical trials, selexipag demonstrated good tolerability and a significant reduction in the risk of death or complications related to PAH, indicating its potential to prevent disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological characteristics and clinical study results of Selexipag (Uptravi® tablets), a selective prostacyclin receptor agonist]. Kuwano, K., Kosugi, K., Fuchikami, C., et al.[2021]

Newly-approved drugs for Pulmonary Arterial Hypertension (PAH), such as macitentan, riociguat, and selexipag, show promise in improving treatment outcomes, despite the condition's historically poor prognosis.

The review highlights innovative therapeutic approaches, including initial combination therapies and potential new signaling pathways, which could lead to more effective treatments for PAH in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Drugs, Therapeutic Strategies, and Future Direction for the Treatment of Pulmonary Arterial Hypertension. Mercurio, V., Bianco, A., Campi, G., et al.[2019]

Selexipag, a new oral medication for pulmonary arterial hypertension (PAH), significantly improves outcomes related to PAH, including reducing complications and enhancing exercise capacity, as shown in the GRIPHON trial with a hazard ratio of 0.6 for death or complications.

While selexipag does not significantly reduce all-cause mortality, it is well tolerated and can be effectively used in combination with other PAH treatments, improving the quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Special Focus on Selexipag - Treatment of Pulmonary Arterial Hypertension. Sorensen, LM., Wehland, M., Kruger, M., et al.[2019]

In a 24-week study involving 83 Chinese patients with pulmonary arterial hypertension (PAH), treatment with ambrisentan significantly improved exercise capacity, as measured by the 6-minute walk distance, with increases of 42.2 meters at week 12 and 53.4 meters at week 24 (P < 0.0001).

The study also found that 64.6% of patients experienced risk improvement within 24 weeks, and the median time to clinical improvement (TTCI) was 131 days, indicating that TTCI is a valuable endpoint for assessing treatment efficacy in PAH, as it is not influenced by baseline risk status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials. Wang, A., Chen, M., Zhuang, Q., et al.[2023]

Initiating oral selexipag within 12 months of a pulmonary arterial hypertension (PAH) diagnosis significantly reduced the rate of all-cause hospitalizations by 24% compared to patients who did not start any prostacyclin pathway agent during the same period.

Patients who started selexipag also experienced lower overall medical costs, saving an average of $23,623, although there was no significant difference in PAH-related hospitalizations or disease progression between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of selexipag use within 12 months of pulmonary arterial hypertension diagnosis on hospitalizations and medical costs: A retrospective cohort study. Tsang, Y., Stokes, M., Kim, YJ., et al.[2023]

In a study of 113 Korean patients with pulmonary arterial hypertension (PAH) treated with selexipag over 24 weeks, adverse events (AEs) were more common during the dose-titration phase than during the maintenance phase, indicating careful monitoring is crucial during initial treatment.

The most frequent AEs included diarrhea, headache, nausea/vomiting, and myalgia, but importantly, the incidence and severity of these AEs did not increase with higher doses of selexipag, suggesting that higher doses can be safely managed without a corresponding rise in adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world practice patterns and characteristics of adverse events with selexipag in Korean patients with pulmonary arterial hypertension. Chang, SA., Lee, SH., Choi, JH., et al.[2022]

Citations

1. ir.unither.com ir.unither.com/press-releases/2025/06-23-2025-120029259

United Therapeutics Corporation Concludes Enrollment of ... A previous phase 2 study of ralinepag in 61 PAH participants met its primary endpoint, showing a 29.8% reduction (p=0.03) in median pulmonary ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38198043/

Ralinepag Phase II Open-Label Extension Study in ... This clinical study of 45 patients investigated whether ralinepag was safe and effective for long-term use to treat people with pulmonary arterial hypertension.

3. sciencedirect.com sciencedirect.com/science/article/pii/S2950133425000655

Safety and pharmacokinetics of ralinepag, a novel oral ... Ralinepag is an oral, potent, highly selective prostacyclin receptor agonist and is in development for pulmonary arterial hypertension.

4. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT03626688

Ralinepag to Improve Treatment Outcomes in PAH Patients Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of ralinepag when added to pulmonary arterial hypertension ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03626688

NCT03626688 | A Study Evaluating the Efficacy and Safety ... Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of ralinepag when added to pulmonary arterial hypertension (PAH) standard ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7238799/

Safety, tolerability, and pharmacokinetics of the selective ... Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02279745

Long-term Safety and Efficacy of Ralinepag in Pulmonary ... This study was an open-label extension study to determine the long-term safety and tolerability of ralinepag in subjects with WHO Group 1 PAH who completed ...

8. publications.ersnet.org publications.ersnet.org/content/erj/54/4/1901030

Efficacy and safety of ralinepag, a novel oral IP agonist, in ... Ralinepag reduced PVR compared with placebo in PAH patients on mono (41%) or dual combination (59%) background therapy.