Bone Abstracts

Objectives: Achondroplasia (ACH), the most common form of human dwarfism, is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, a key negative regulator of endochondral ossification. C-type natriuretic peptide (CNP) inhibits the FGFR3 pathway and thereby promotes proliferation and differentiation of chondrocytes to promote bone growth. TransCon CNP is a prodrug designed to provide continuous exposure to CNP to optimize efficacy with a well-tolerated and convenient once-weekly dose. The objective of the TransCon CNP phase 1 trial was to evaluate the safety, tolerability, and pharmacokinetics of subcutaneous single ascending doses of TransCon CNP.

Methods: To initiate the clinical development of TransCon CNP, a phase 1 trial in healthy adult male subjects was completed; 45 subjects participated in a double-blind, placebo-controlled, dose escalation trial.

Results: The trial confirmed that one dose of TransCon CNP (administered at 3–150 μg CNP/kg) provided continuous systemic exposure over 7 days to active free CNP released from the prodrug by a predictable non-enzymatic process depending on physiologic temperature and pH. A dose-related increase in CNP exposure was observed with a mean Cmax obtained with a single dose of 10 μg CNP/kg of 2.6 picomolar (pM) that increased to 42 pM with a single dose of 150 μg CNP/kg. Maximum plasma concentrations were reached 2–3 days post-dose and, after 7 days post-dose, the levels were reduced by approximately 2-fold. Plasma concentration of free CNP is dictated by the kinetics of the prodrug and the long linker release half-life, resulting in an effective half-life of CNP of ~90 hours (in contrast, native CNP has a half-life of ~2 minutes), which supports a once-weekly dosing regimen. No serious adverse events were reported and TransCon CNP was generally well-tolerated. Mean resting blood pressure and heart rate were unchanged from pre-dose baseline. In addition, mean orthostatic changes in vital signs were consistent between placebo and TransCon CNP cohorts.

Conclusion: This phase 1 TransCon CNP trial in heathy subjects suggests the potential of a safe and efficacious once-weekly therapy in children with achondroplasia. Further studies should be evaluated to confirm and extend these findings.

Disclosure: All authors are employees of Ascendis Pharma.