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Aims: Despite receiving guideline-directed medical heart failure (HF) therapy, patients with pulmonary hypertension associated with left heart disease (PH-LHD) experience higher mortality and hospitalization rates than the general HF population. AZD3427 is a functionally selective, long-acting mimetic of relaxin, a hormone that has the potential to induce vasodilation and prevent fibrosis. In a phase 1b study conducted in patients with HF, AZD3427 demonstrated a favourable safety and pharmacokinetic profile. To address the unmet medical need in patients with PH-LHD in the context of HF, AZD3427 is currently under development as a potential treatment option., Methods and Results: The Re-PHIRE study is a phase 2b, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study to evaluate the effect of AZD3427 on a broad range of PH-LHD phenotypes. In total, 220 patients will be randomized to four treatment groups to receive a subcutaneous injection of AZD3427 or placebo every 2 weeks for 24 weeks. The primary endpoint of the study is the change in pulmonary vascular resistance in patients treated with AZD3427 versus placebo after 24 weeks of treatment. Key secondary endpoints include changes in mean pulmonary arterial pressure, pulmonary artery wedge pressure, systemic vascular resistance, 6-min walking distance, N-terminal pro B-type natriuretic peptide levels, echocardiographic parameters, and health-related quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire)., Conclusions: Re-PHIRE is the first study of a relaxin mimetic in patients with PH-LHD. The insights gained from the Re-PHIRE study are expected to inform the further development of AZD3427 in the PH-LHD population, including identifying the most suitable pulmonary hypertension and HF phenotypes for treatment., (© 2025 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Risk stratification is an essential part of evaluating disease severity in patients with pulmonary arterial hypertension (PAH). This study applied the 4-strata COMPERA 2.0 risk model to the Phase 3 PATENT-1/2 studies of riociguat., Methods: This was a post hoc analysis of PATENT-1 and PATENT-2. Log-rank tests of Kaplan-Meier curves were performed to compare the risk strata at PATENT-1 baseline and Week 12 regarding time to clinical worsening and survival at 2 years in the PATENT-2 population., Results: Data on COMPERA 2.0 status at baseline were available for 214 patients with riociguat and 100 with placebo; overall, 120 patients were identified as intermediate-low risk and 96 as intermediate-high risk. At PATENT-1 Week 12, improvements in COMPERA 2.0 risk strata and median 6-min walk distance were seen with riociguat vs placebo in patients assessed as intermediate-low risk and intermediate-high risk at baseline by COMPERA 2.0. More patients improved their COMPERA 2.0 risk status with riociguat vs placebo in the intermediate-low (38 % vs 22 %) and intermediate-high risk groups (42 % vs 31 %). COMPERA 2.0 assessed at PATENT-1 baseline and Week 12 discriminated between risk strata for survival and clinical worsening in PATENT-2 at 2 years (p ≤ .001 for all analyses)., Conclusions: In conclusion, this analysis supports the risk-reduction benefits of riociguat in patients with PAH at intermediate-low risk and intermediate-high risk, and externally validated the utility of COMPERA 2.0 in the long-term risk assessment of patients from a clinical trial population., Competing Interests: Declaration of competing interest Marius M. Hoeper: reports fees for consultations and/or lectures from Acceleron, Actelion, Altavant, AOP Orphan, Bayer AG, Ferrer, Gossamer Bio, Janssen, Keros, and MSD. Stephan Rosenkranz: reports remunerations for lectures and/or consultancy from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP Orphan, AstraZeneca, Bayer AG, Boehringer Ingelheim, Edwards, Bristol-Myers Squibb, Ferrer, Gossamer Bio, Inari, Janssen, Lilly, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, AstraZeneca, Bayer AG, and Janssen. David B. Badesch: consultant and steering committee member for Acceleron/Merck, and previously served as a consultant for Bayer AG; has received research grants from Acceleron/Merck, Actelion/Janssen/Johnson & Johnson, Altavant, Arena, Bayer AG, Belleraphon, Liquidia, and United Therapeutics; and his wife is a long-term holder of common stock for Johnson & Johnson in a family trust. Marc Humbert: consultant and an advisory committee member for Acceleron, Aerovate, Altavant, AOP Orphan, Bayer AG, Ferrer, Janssen, Merck & Co., Inc., Morphogen-IX, and United Therapeutics; and has received research grants from Acceleron, Janssen, and Merck & Co., Inc. David Langleben: reports receiving speaker and/or consulting fees from, has served on advisory boards for, and/or has been an investigator in clinical trials for Acceleron/Merck, Aerovate, Altavant, Arena, Bayer AG, Enzyvant, Gossamer Bio, Janssen, and PhaseBio. John W. McConnell: has no conflicts of interest to declare. Sara Hegab: employee of Bayer US LLC. Claudia Rahner: employee of Chrestos Concept GmbH & Co. KG, contracted by Bayer AG. Jean-François Richard: employee of Merck & Co., Inc., Rahway, NJ, USA. Hossein-Ardeschir Ghofrani: reports receiving grants from Actelion, Bayer AG, Ergonex, and Pfizer; personal fees from Actelion, Bayer AG, Ergonex, Gilead, GSK, Merck & Co., Inc., Novartis, and Pfizer; and is currently on the independent data monitoring committee for 2 studies funded by Actelion., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)