PMID- 38198043 OWN - NLM STAT- MEDLINE DCOM- 20240222 LR - 20240306 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 41 IP - 3 DP - 2024 Mar TI - Ralinepag Phase II Open-Label Extension Study in Patients with Pulmonary Arterial Hypertension. PG - 1062-1074 LID - 10.1007/s12325-023-02769-7 [doi] AB - INTRODUCTION: Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag. METHODS: Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures. RESULTS: In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4%; diarrhea, 37.8%; jaw pain, 33.3%). There was a notable decline in AEs after reaching and maintaining a stable dose. At month 24 after entering the OLE, 6MWD significantly increased by a mean of 36.3 m (P = 0.004) from OLE baseline, and most participants remained stable in their functional class (84.8%). Post-baseline PVR in 1 or 2 years decreased by a median of 52.2 dyn.s/cm(5) and mean pulmonary arterial pressure decreased by a median of 2.0 mmHg (P = 0.05). CONCLUSION: 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. CI - (c) 2024. The Author(s). FAU - Barbera, Joan AU - Barbera J AUID- ORCID: 0000-0003-1469-4990 AD - Department of Pulmonary Medicine, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain. jbarbera@clinic.cat. AD - Biomedical Research Networking Center on Respiratory Diseases, Madrid, Spain. jbarbera@clinic.cat. FAU - Jansa, Pavel AU - Jansa P AD - 2nd Department of Medicine-Clinical Department of Cardiology and Angiology, General University Hospital, Prague, Czech Republic. FAU - Klings, Elizabeth AU - Klings E AD - The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA. FAU - Ristic, Arsen AU - Ristic A AD - Department of Cardiology of the Clinical Center of Serbia, Belgrade, Serbia. AD - University School of Medicine, Belgrade, Serbia. FAU - Keogh, Anne AU - Keogh A AD - Head PAH Clinical Trials Unit, St Vincent's Hospital, Sydney, Australia. AD - University of NSW, Sydney, Australia. FAU - Solum, Derek AU - Solum D AD - United Therapeutics Corporation, Research Triangle Park, NC, USA. FAU - Rao, Youlan AU - Rao Y AD - United Therapeutics Corporation, Research Triangle Park, NC, USA. FAU - Grover, Rob AU - Grover R AD - United Therapeutics Corporation, Research Triangle Park, NC, USA. FAU - Saib, Isil AU - Saib I AD - United Therapeutics Corporation, Research Triangle Park, NC, USA. FAU - Sood, Namita AU - Sood N AD - University of California-Davis, Sacramento, CA, USA. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial DEP - 20240110 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 0 (Acetates) RN - 0 (Carbamates) RN - 0 (Prostaglandins I) RN - 0 (ralinepag) MH - Humans MH - *Acetates/adverse effects MH - *Carbamates MH - Double-Blind Method MH - Prostaglandins I/adverse effects MH - *Pulmonary Arterial Hypertension/drug therapy MH - Treatment Outcome PMC - PMC10879237 OAB - Pulmonary arterial hypertension is a rare disease caused by elevated pressure in the blood vessels connecting the heart to the lungs. A previous phase 2 study found that ralinepag significanlty reduced pulmonary vascular resistance (the force or resistance that blood encounters as it flows through the blood vessels in the lungs) compared with placebo. This clinical study of 45 patients investigated whether ralinepag was safe and effective for long-term use to treat people with pulmonary arterial hypertension. All participants received ralinepag twice daily until a new once daily pill was available later in the study. The primary endpoints were long-term safety and tolerability, and secondary endpoints included exercise capacity, impact on daily life (functional class), clinical worsening, and hemodynamic measures (metrics to measure how well the heart is working). The study found that ralinepag had a manageable side effect profile, with a decrease in side effects for patients who continued taking ralinepag over time. Moreover, the study showed that ralinepag improved the ability to exercise, maintained functional measures, and helped to reduce pressure in the blood vessels connecting the heart to the lungs over a 24-month period for participants with pulmonary arterial hypertension. OABL- eng OTO - NOTNLM OT - ADVANCE OT - Combination therapy OT - Long-term outcomes OT - Open-label extension OT - PAH OT - Ralinepag OT - Safety OT - Tolerability COIS- Joan Barbera is a consultant and speaker for Janssen-Cilag, Merck Sharp & Dome and Ferrer, consultant for Acceleron Pharma, and has received grants from Janssen-Cilag, Merck Sharp & Dome and Ferrer. Pavel Jansa has received fees and grants from Janssen Pharmaceutical Companies of Johnson and Johnson, AOP Orphan, United Therapeutics, and Merck Sharp & Dohme. He has served as advisory boards member for Janssen Pharmaceutical Companies of Johnson and Johnson, AOP Orphan, and Merck Sharp & Dohme. Elizabeth Klings receives research support from United Therapeutics, Novartis, Bayer, Novo Nordisk/FORMA. She was an advisory board member for Vertex and Global Blood Therapeutics/Pfizer. She is the member of the safety review committee for a phase 1 trial for CSL Behring. Arsen Ristic and Anne Keogh have nothing to disclose. Namita Sood is a member of a speaker bureau for Bayer Pharmaceuticals and was a site PI for ADVANCE. Derek Solum, Youlan Rao, Rob Grover, and Isil Saib are employees of United Therapeutics. EDAT- 2024/01/10 12:42 MHDA- 2024/02/22 06:42 PMCR- 2024/01/10 CRDT- 2024/01/10 11:23 PHST- 2023/11/07 00:00 [received] PHST- 2023/12/12 00:00 [accepted] PHST- 2024/02/22 06:42 [medline] PHST- 2024/01/10 12:42 [pubmed] PHST- 2024/01/10 11:23 [entrez] PHST- 2024/01/10 00:00 [pmc-release] AID - 10.1007/s12325-023-02769-7 [pii] AID - 2769 [pii] AID - 10.1007/s12325-023-02769-7 [doi] PST - ppublish SO - Adv Ther. 2024 Mar;41(3):1062-1074. doi: 10.1007/s12325-023-02769-7. Epub 2024 Jan 10.