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.

2nd Department of Internal Medicine University of Toyama Toyama Japan

2nd Department of Medicine Charles University and General University Hospital Prague Czechia

Canadian VIGOUR Centre University of Alberta Edmonton Canada

Department of Cardiology Guangdong Cardiovascular Institute Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Southern Medical University Guangzhou China

Department of Cardiology Pulmonology and Intensive Care Medicine Center for Molecular Medicine Cologne Medical Faculty University of Cologne Cologne Germany

Department of Cardiology Zuyderland Medical Center Heerlen The Netherlands

Department of Internal Medicine 2 Division of Cardiology Medical University of Vienna Vienna Austria

Department of Internal Medicine and Cardiology with the Centre for Management of Venous Thromboembolic Disease Medical University of Warsaw Warsaw Poland

Department of Medical Sciences Uppsala University Hospital Uppsala Sweden

Early Clinical Development Cardiovascular Renal and Metabolism BioPharmaceuticals R and D AstraZeneca Cambridge UK

Early Clinical Development Cardiovascular Renal and Metabolism BioPharmaceuticals R and D AstraZeneca Gothenburg Sweden

Early Clinical Development Cardiovascular Renal and Metabolism BioPharmaceuticals R and D AstraZeneca Warsaw Poland

Heart Failure and Transplantation Unit La Fe University and Polytechnic Hospital Valencia Spain

Heart Failure Program Yale School of Medicine New Haven Connecticut USA

Scottish National Advanced Heart Failure Service Golden Jubilee National Hospital Clydebank UK

The Heart Center Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

University of Milan School of Medicine San Paolo University Hospital Milan Italy

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