A Once-Weekly C-Type Natriuretic Peptide for Treatment of Heart Failure with Preserved Ejection Fraction

C-type natriuretic peptide (CNP) has therapeutic potential in heart failure with preserved ejection fraction (HFpEF) due to its broad range of beneficial effects on cardiovascular structure and function. This study presents the design of a CNP analogue (65) for once-weekly subcutaneous administration. The design of 65 incorporated five strategic substitutions and an engineered fatty acid protractor to enhance the chemical stability, improve the pharmacokinetics, and lower the isoelectric point (pI). Low pI was found to be essential for minimizing injection site reactions and improving subcutaneous bioavailability. 65 demonstrated a promising pharmacokinetic profile for once-weekly treatment and an improved bioavailability compared to high pI CNP analogs. Furthermore, 65 was engineered for solubility at pH 6.5 to enable stability in liquid formulation. In vivo assessments supported the therapeutic potential in HFpEF of fatty acid-derivatized low pI CNP analogues. 65 is currently under clinical investigation in Phase 1.