Sponsor decision

Study ROR-PH-302, ADVANCE CAPACITY, was designed to evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment.

ROR-PH-302 was a 28-week multicenter, randomized, double-blind, placebo-controlled study. Subjects who met entry criteria were randomly allocated 2:1 to receive ralinepag or placebo, in addition to their PAH-specific background therapy, as applicable. The primary endpoint was change from Baseline in peak VO2 (assessed by CPET) at Week 28. All subjects who completed the study on study drug through Week 28 had the option to receive ralinepag in an open-label extension (OLE) study. Subjects who discontinued study drug prior to Week 28, as well as those who completed Week 28 on study drug but chose not to participate in the OLE study, were contacted every 6 months and at the end of the study to determine their survival status. Subjects who prematurely discontinued study drug or withdrew from the study for any reason were not eligible to enter the OLE study.

Inclusion Criteria:

1. Signed informed consent form.
2. At least 18 years of age.
3. Primary diagnosis of PAH.
4. Has had a diagnostic RHC performed at or within 3 years before Screening (or at Screening if one is not available) that is consistent with the diagnosis of PAH.
5. Has World Health Organization (WHO)/New York Heart Association (NYHA) Functional Class (FC) II to III symptoms
6. Must be on a stable dose of PAH-specific oral therapy, defined as no change in dose or regimen for at least 90 days prior to randomization. Allowable PAH-specific therapy is an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator. Subjects may be on a stable dose of either a PDE5-I or a sGC stimulator, not both.
7. Has a 6-minute walk distance (6MWD) of ≥150 meters at Screening.
8. Has a peak VO2 of ≥9 to <18 mL/min/kg during the Screening CPET, as assessed by the CPET core laboratory.
9. If the subject is taking concomitant medications that may affect the clinical manifestations of PAH, the subject must be on a stable dose for at least 30 days prior to randomization. The exception is that the dose of diuretics must be stable for at least the 10 days prior to randomization.
10. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the Week 28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process during the study and for 30 days after the final dose of study drug. Eligible male subjects must agree not to participate in sperm donation for 90 days after the final dose of study drug. Women who are surgically sterile or postmenopausal are not considered to be of childbearing potential. If of childbearing potential, female partners of male study participants should agree to utilize medically acceptable methods of contraception for the duration of study participation.

Exclusion Criteria:

1. For subjects with known human immunodeficiency virus-associated PAH, a cluster of differentiation 4 T-cell count <200/mm3 at Screening.
2. Has 3 or more left ventricular disease/dysfunction risk factors.
3. Symptomatic coronary artery disease and/or myocardial infarction within past 6 months.
4. Current symptomatic aortic or mitral valve disease.
5. Has evidence of more than mild lung disease on pulmonary function tests performed within 1 year prior to, or during, Screening.
6. Has evidence of thromboembolic disease as determined by ventilation-perfusion lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.
7. Current diagnosis of ongoing and clinically significant sleep apnea as defined by the Investigator.
8. Requires use of supplemental oxygen during CPET.
9. Respiratory exchange ratio <1.0 at Screening CPET as determined by the CPET core laboratory.
10. Acute non-cardiac disorder that may affect exercise performance or be aggravated by exercise (eg, infection, renal failure, thyrotoxicosis).
11. Male subjects with a QTcF >450 msec and female subjects with a QTcF >470 msec on electrocardiogram (ECG) recorded at Screening and analyzed by the central ECG laboratory. Subjects with evidence of intraventricular conduction delay, defined as a QRS interval >110 msec, will be excluded if QTcF is >500 msec for both males and females.
12. Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension, cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy).
13. Confirmed active infection with hepatitis B virus or hepatitis C virus.
14. Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the upper limit of normal or total bilirubin ≥2 times the upper limit of normal at Screening.
15. Chronic renal insufficiency as defined by an estimated glomerular filtration rate using the Modification of Diet in Renal Disease Study equation of <30 mL/min/1.73 m2 or requiring dialysis at Screening.
16. Hemoglobin concentration <9 g/dL at Screening.
17. Subjects treated with an intravenous, subcutaneous, inhaled, or oral prostacyclin pathway agent (eg, epoprostenol, treprostinil, iloprost, beraprost, or selexipag) for PAH within 90 days of randomization (use in vasoreactive testing is permitted). Subject is not eligible if previous prostacyclin therapy was stopped for a safety or tolerability issue related to systemic prostacyclin adverse effects.
18. Subject has pulmonary veno-occlusive disease.
19. Malignancy diagnosed and/or treated within 3 years of Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent.
20. Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine, or phencyclidine in urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. Subjects will not be excluded due to a positive drug screen caused by prescribed medications.
21. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
22. Prior participation in any study of ralinepag or another interventional clinical study with medicinal products within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, if the subject can fulfill all other entry criteria and comply with all study procedures.
23. Any reason that, in the opinion of the Investigator, precludes the subject from participating in the study (eg, any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis (eg, right-to-left shunt detected during CPET) or impair study participation or cooperation.
24. Known hypersensitivity to ralinepag or any of the excipients.
25. Life expectancy <12 months based on the Investigator's opinion.
26. Women who are pregnant, lactating, or breast-feeding.