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. 2025 Jun;12(3):1956-1964.
doi: 10.1002/ehf2.15203. Epub 2025 Jan 20.

Relaxin mimetic in pulmonary hypertension associated with left heart disease: Design and rationale of Re-PHIRE

Marcin Ufnal  1 , Kathleen Connolly  2 , Marcus Millegard  3 , Elena Surkova  2 , Marco Guazzi  4 , Diana Bonderman  5 , Justin Ezekowitz  6 , Finn Gustafsson  7 , Michał Ciurzyński  8 , Raquel López Vilella  9 , Tariq Ahmad  10 , Roy Gardner  11 , Pavel Jansa  12 , Sandra van Wijk  13 , Koichiro Kinugawa  14 , Erik Björklund  15 , Zhi-Cheng Jing  16 , Stephan Rosenkranz  17
Affiliations

Relaxin mimetic in pulmonary hypertension associated with left heart disease: Design and rationale of Re-PHIRE

Marcin Ufnal et al. ESC Heart Fail. 2025 Jun.

Abstract

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.

Keywords: Heart failure; Left heart disease; Pulmonary hypertension; Pulmonary vascular resistance; Relaxin.

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Conflict of interest statement

MG, DB, JE, FG, MC, RLV, TA, RG, PJ, SW, KK, EB, ZCJ and SR serve as the national investigator lead and/or primary investigators and receive reimbursement for their work in the Re‐PHIRE study.MU, KC, MM, and ES are employees and stockholders of AstraZeneca. DB reports speakers fees, research support and travel grants from Alnylam, Astra Zeneca, Boehringer Ingelheim, Novartis, Zoll, Bayer, BMS, Abbott, MSD. JE reports research support for trial leadership or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck & Co, Novo Nordisk, Otsuka; honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Otsuka; serves as an advisor to US2.ai. FG serves as an advisor for Astra‐Zeneca, Abbott, Pfizer, Bayer, Ionis, Alnylam, Pharmacosmos, AdjuCor, FineHeart and receives speaker’s fee from Novartis. TA reports consulting fees from BI and AZ and research grants from AZ, BI, Amgen. RG reports speaker or consultant fees from Abbott, Anacardio, Astra Zeneca, Boehringer Ingelheim, Boston Scientific, Novartis, Pfizer, Pharmacosmos, Roche Diagnostics, and research grants to his institution from Abbott, Boston Scientific, and Roche Diagnostics. PJ reports fees and grants from Janssen Pharmaceutical Companies of Johnson and Johnson, AOP Orphan, Bayer HealthCare, and MSD, outside of the article. SW reports research grant from AstraZeneca to research foundation ‘stichting Perfusie’, speaker and consulting fees from Astrazeneca, and reimbursement of expenses as national lead (NL) for REPHIRE. SR reports speaker or consultant fees from Abbott, Accelleron, Actelion, Aerovate Therapeutics, Altavant Sciences, AOP Health, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly and Company, Ferrer, Gossamer Bio, Inari Medical, Janssen, MSD, and United Therapeutics, and research grants to his institution from AstraZeneca, Bayer, Janssen, and MSD.

Figures

Figure 1
Figure 1
Pathophysiology of the development of PH‐LHD. CpcPH, combined post‐ and pre‐capillary pulmonary hypertension; IpcPH, isolated post‐capillary pulmonary hypertension; LV, left ventricle; PH‐LHD, pulmonary hypertension associated with left heart disease; PVR, pulmonary vascular resistance; RV, right ventricle.
Figure 2
Figure 2
Study schematic: treatment groups, study procedures, and time points of the Re‐PHIRE study. 6MWT, 6‐min walk test; ECHO, echocardiogram; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; NYHA, New York Heart Association; Q2W, every 2 weeks; R, randomization; RHC, right heart catheterization; SC, subcutaneous.
Figure 3
Figure 3
Screening period: stepwise approach to minimize screening failure based on haemodynamic criteria derived from RHC. ECHO, echocardiogram; ERS, European Respiratory Society; ESC, European Society of Cardiology; FC, functional classification; HF, heart failure; mPAP, mean pulmonary artery pressure; NYHA, New York Heart Association; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; PH‐LHD, pulmonary hypertension associated with left heart disease; RHC, right heart catheterization.
See this image and copyright information in PMC

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