Translational pharmacokinetic/pharmacodynamic model for mRNA‐0184, an investigational therapeutic for the treatment of heart failure

Abstract

Abstract Heart failure (HF) is a complex, progressive disorder that is associated with substantial morbidity and mortality on a global scale. Relaxin‐2 is a naturally occurring hormone that may have potential therapeutic benefit for patients with HF. To investigate the therapeutic potential of relaxin in the treatment of patients with HF, mRNA‐0184, a novel, investigational, lipid nanoparticle (LNP)–encapsulated mRNA therapy that encodes for human relaxin‐2 fused to variable light chain kappa (Rel2‐vlk) was developed. A translational semi‐mechanistic population pharmacokinetic (PK)/pharmacodynamic (PD) model was developed using data from non‐human primates at dose levels ranging from 0.15 to 1 mg/kg. The PK/PD model was able to describe the PK of Rel2‐vlk mRNA and translated Rel2‐vlk protein in non‐human primates adequately with relatively precise estimates. The preclinical PK/PD model was then scaled allometrically to determine the human mRNA‐0184 dose that would achieve therapeutic levels of Rel2‐vlk protein expression in patients with stable HF with reduced ejection fraction. Model‐based simulations derived from the scaled PK/PD model support the selection of 0.025 mg/kg as an appropriate starting human dose of mRNA‐0184 to achieve average trough relaxin levels between 1 and 2.5 ng/mL, which is the potential exposure for cardioprotective action of relaxin.