Long-term Safety and Efficacy Evaluation of Ralinepag in Pulmonary Arterial Hypertension: An Open-label Extension Study

The primary objective of this study is to evaluate the long-term **safety** and tolerability of ralinepag in subjects with pulmonary arterial hypertension (PAH) who have previously participated in a Phase 2 or Phase 3 study of ralinepag. This is clinically relevant as it aims to ensure that the prolonged use of ralinepag does not result in adverse effects, thereby supporting its potential as a sustainable treatment option for PAH.

The secondary objectives of the study are to assess the long-term effects of ralinepag on several parameters, including:

• N-terminal pro-brain natriuretic peptide (NT-proBNP)
• 6-Minute Walk Distance (6MWD)
• WHO/New York Heart Association (NYHA) Functional Class (FC)
• Health-related quality of life (HRQoL) measures
• Time to all-cause hospitalization
• Time to all-cause mortality

These secondary objectives are important for understanding the broader impact of ralinepag on disease progression, functional capacity, and overall patient well-being.

The clinical trial involves a total of **451 participants** who have previously participated in a Phase 2 or Phase 3 study of ralinepag. The study population includes both **male and female subjects** within the age range of 18 to 65 years. Participants are individuals diagnosed with **pulmonary arterial hypertension (PAH)**. The trial population was selected based on their completion of the protocol-defined Study Drug Termination Visit or End of Study Visit procedures in the preceding ralinepag study. Participants are required to have signed an informed consent form and must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Both male and female subjects are required to use a highly effective method of birth control throughout the study period and for 30 days after the last dose of ralinepag, if the possibility of conception exists. The study includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of all participants.

The clinical trial is designed to evaluate the long-term safety and tolerability of **ralinepag** in subjects with **pulmonary arterial hypertension** (PAH) who have previously participated in a Phase 2 or Phase 3 study of the drug. This study follows a randomized, open-label extension design, allowing for the continued assessment of the drug's effects over an extended period. The trial is expected to conclude by December 29, 2025, with recruitment having commenced on February 13, 2020.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed through criteria such as the completion of prior study procedures and the signing of an informed consent form. Follow-up visits will be scheduled to monitor the efficacy and safety of the treatment, with assessments including NT-proBNP levels, 6-minute walk distance (6MWD), and WHO/NYHA functional class. The primary endpoints focus on these efficacy measures, as well as health-related quality of life (HRQoL) and time to all-cause hospitalization and mortality.

The expected duration of participant involvement in the study is contingent upon the maximum treatment period, which varies between 48 to 72 weeks depending on the specific formulation of **ralinepag** administered. Participants are required to adhere to the study protocol, including the use of effective birth control methods throughout the study and for 30 days following the last dose. Conditions that may lead to early termination from the study include non-compliance with study procedures or withdrawal of consent.

The clinical trial involves the administration of **Ralinepag**, a **prolonged-release tablet** formulated for **oral use**. Ralinepag is chemically synthesized and is identified by the sponsor product code APD811. The active substance, Ralinepag, is also known by its chemical name, 2-((trans-4-((((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetic acid. The maximum daily dose of Ralinepag is 9000 micrograms, with a total maximum dose of 12960 milligrams over a treatment period of 48 weeks for certain formulations, and 19440 milligrams over 72 weeks for others. The trial aims to evaluate the long-term safety and tolerability of Ralinepag in subjects with pulmonary arterial hypertension (PAH) who have participated in preceding Phase 2 or Phase 3 studies.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of Ralinepag. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted under the authorization of United Therapeutics Corporation, with Ralinepag designated as an orphan drug under the designation number EU/3/18/2130. The pharmaceutical form of the medication is consistent across all formulations, ensuring uniformity in administration and evaluation of outcomes.

The efficacy of **Ralinepag** in the clinical trial will be assessed through several primary endpoints. These include the evaluation of NT-proBNP levels, the 6-minute walk distance (6MWD), and the World Health Organization/New York Heart Association Functional Class (WHO/NYHA FC). Additionally, the proportion of subjects achieving all three of the following criteria at specified time points will be measured: NT-proBNP level less than 300 pg/mL, 6MWD greater than 440 meters, and WHO/NYHA FC II status or better. Health-related quality of life (HRQoL) measures will also be assessed where validated. Furthermore, the time to all-cause hospitalization and time to all-cause mortality during the study period will be evaluated.