Ralinepag for Pulmonary Arterial Hypertension

Recruiting in Palo Alto (17 mi)

+185 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: United Therapeutics

Must be taking: Endothelin antagonists, PDE5 inhibitors

Must not be taking: IV prostacyclins, Oral prostacyclins

Disqualifiers: Severe liver disease, Renal insufficiency, Malignancy, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing ralinepag, a medication being developed for the treatment of pulmonary arterial hypertension (PAH). It aims to see if adding ralinepag to their usual treatments can improve their condition. The medication works by relaxing and opening up the blood vessels in the lungs, which can lower the pressure and improve blood flow.

Will I have to stop taking my current medications?

The trial does not specify that you need to stop taking your current medications. However, if you are on certain medications for pulmonary arterial hypertension (PAH) or other conditions, you must be on a stable dose for at least 30 days before starting the trial and maintain that dose throughout the study.

What data supports the effectiveness of the drug Ralinepag for Pulmonary Arterial Hypertension?

The phase 2 study showed that Ralinepag, a drug similar to selexipag, was effective in treating pulmonary arterial hypertension (PAH) by acting on the prostacyclin receptor, which helps relax blood vessels and improve blood flow. ^{1 2 3 4 5}

Is ralinepag safe for humans?

Ralinepag has been tested in healthy volunteers and was generally safe, but some people experienced nausea and vomiting at higher doses. One person had a moderate heart rhythm issue (atrial fibrillation), but no other major safety problems were found. ^{1 6 7 8 9}

How is the drug Ralinepag different from other treatments for pulmonary arterial hypertension?

Ralinepag is unique because it is an oral medication that acts as a selective prostacyclin receptor agonist, which helps relax blood vessels in the lungs and reduce blood pressure. Unlike some other treatments, it has a long half-life, allowing for less frequent dosing and potentially more stable blood levels. ^{1 6 8 10 11}

Research Team

Eligibility Criteria

Adults with symptomatic Pulmonary Arterial Hypertension (PAH) who can walk at least 150 meters unaided, are on stable PAH or other related medications for 30 days (10 days for diuretics), and have had a right heart catheterization within the last 3 years. Participants must not be pregnant, breastfeeding, have severe liver disease, recent malignancy except certain skin cancers, life expectancy less than a year, significant heart conduction issues or recent drug abuse.

Inclusion Criteria

Has WHO/ NYHA functional class II to IV symptoms.

If taking concomitant medications that may affect the clinical manifestations of PAH (eg, calcium channel blockers, diuretics, digoxin, or L arginine supplementation, beta blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers), must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics must be stable for at least the 10 days prior to Baseline.

You are at least 18 years of age.

Exclusion Criteria

You are allergic to ralinepag or any ingredients in it.

The doctor believes that you have less than 1 year to live.

Has evidence of thromboembolic disease as determined by a V/Q lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ralinepag or placebo in addition to their standard of care or PAH-specific background therapy

28 weeks

Visits at Baseline, Week 4, 8, 12, 16, and every 12 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Treatment Details

Interventions

• Placebo (Drug)
• Ralinepag (Prostacyclin Receptor Agonist)

Trial Overview The trial is testing Ralinepag's effectiveness and safety in improving outcomes for PAH patients when added to their current treatment regimen. It compares Ralinepag against a placebo while all participants continue their standard care. The goal is to see if Ralinepag can better manage symptoms and progression of PAH.

Participant Groups

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.

Group II: Placebo Placebo Group 1 Intervention

Matching placebo tablets (oral)

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

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

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]

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&#174; tablets), a selective prostacyclin receptor agonist]. Kuwano, K., Kosugi, K., Fuchikami, C., et al.[2021]

References

1. England 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. [2020]

2. England 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. [2023]

3. United States 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. [2022]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

New Drugs, Therapeutic Strategies, and Future Direction for the Treatment of Pulmonary Arterial Hypertension. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials. [2023]

6. United Arab Emirates pubmed.ncbi.nlm.nih.gov

A Special Focus on Selexipag - Treatment of Pulmonary Arterial Hypertension. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Real-world practice patterns and characteristics of adverse events with selexipag in Korean patients with pulmonary arterial hypertension. [2022]

8. United States 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. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). [2023]

10. England pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. [2022]

11. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological characteristics and clinical study results of Selexipag (Uptravi&#174; tablets), a selective prostacyclin receptor agonist]. [2021]