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Aim: Relaxin-2, a well-known human hormone primarily associated with pregnancy, has shown promising cardiovascular benefits in both preclinical models and clinical trials. However, its therapeutic potential has been limited due to the short half-life and the short duration of treatment. To address this, we developed AZD3427, a novel long-acting relaxin-2 analogue and assessed its efficacy during prolonged treatment in a large animal model with cardiac dysfunction., Methods and Results: Extensive protein engineering resulted in AZD3427, a novel fusion protein, which closely mimics the natural hormone's structure and consists of a single relaxin-2 and the Fc fragment of human IgG1 to extend its half-life. AZD3427 exhibits an improved pharmacokinetic profile, allowing for weekly or less frequent, subcutaneous dosing, and maintains the pharmacology profile of relaxin-2 with signalling via RXFP1 in cell systems. The effects of chronic RXFP1 agonism with AZD3427 were investigated in a non-human primate (NHP) model with systolic dysfunction and metabolic syndrome. Administration of AZD3427 over a twenty-one-week period led to significant improvements in cardiac function, as evidenced by increased ejection fraction (EF), cardiac output (CO) and stroke volume (SV), as well as reduced systemic vascular resistance (SVR). Importantly, no adverse events related to treatments were observed and there were no concomitant changes in heart rate (HR) or blood pressure (BP). During the eighteen-week washout period, the observed effects gradually disappeared., Conclusions: Prolonged administration of AZD3427, a long-acting relaxin receptor RXFP1 agonist, resulted in remarkable improvement in cardiac function in a NHP model. Findings of this study are an important translational step to developing future therapies and support further clinical development of AZD3427 as a novel treatment for patients with heart failure (HF)., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.) more...