Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long‐acting C‐type natriuretic peptide prodrug, TransCon CNP

AIM: TransCon CNP is a novel prodrug designed to provide sustained release of C‐type natriuretic peptide (CNP) for once‐weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP. METHODS: This randomized, placebo‐controlled, single‐ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single‐ascending dose cohorts [3, 10, 25, 75 or 150 μg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine‐monophosphate (cGMP) and amino‐terminal propeptide of CNP (NTproCNP). RESULTS: TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post‐dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75‐150 μg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor‐B (NPR‐B) for at least 1 week post‐dose. TransCon CNP was well‐tolerated, with no serious treatment‐emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals. CONCLUSIONS: Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once‐weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia.