ESPE Yearbook of Paediatric Endocrinology

In Brief: This phase 1 study in healthy adults assessed the safety and feasibility of transcon-CNP, a novel prodrug that releases native C-type natriuretic peptide (CNP). The novel drug was well tolerated and CNP remained in systemic circulation for >7 days following a single dose.

Commentary: Achondroplasia is caused by autosomal activating mutation in the fibroblast growth factor receptor 3 gene (FGFR3) resulting in constitutive receptor activation and signalling through the mitogen-activated protein kinase (MAPK) pathway in chondrocytes, resulting in inhibited longitudinal bone growth. C-type natriuretic peptide, encoded by NPPC, and its receptor, natriuretic peptide receptor 2 (NPR2), are potent stimulators of endochondral ossification at the growth plate. Transcon-CNP is a long-acting prodrug that releases native CNP and has demonstrated positive effects on bone growth in both murine and non-human primate models.

This study was funded and performed by Ascendis pharmaceutical and is the first in-human trial with transcon-CNP. The study drug was administered SC in single doses to ascending-dose cohorts (3, 10, 25, 75 and 150 μg CNP/kg). A total of 49 healthy men were randomized to the study drug in a 4:1 ratio (active:placebo). The average half-life was ~120 hours, which is substantially longer than the half-life of endogenous CNP¹ (only 2–3 minutes) and vosoritide² (19–46 minutes).

Transcon CNP administration caused sustained increases of cGMP levels in both plasma and urine indicating that the CNP released from the PEG carrier is active and that the level of released CNP affords a sustained activation of NPR2 for at least 7 days post-administration. Interestingly, there was no change in endogenous levels of NTproCNP, indicating that CNP released from transcon-CNP does not interfere with endogenous CNP biosynthesis. Transient, symptomatic vasodilatory adverse events were reported at higher doses and symptoms included mild postural dizziness, feeling lightheaded on standing, and palpitations. However, no major safety or tolerability concerns were observed.

Ongoing and future phase 2 and phase 3 trials with subsequent extensions will determine if transcon-CNP is an efficacious and safe treatment to improve growth and possibly also mitigate other complications of achondrondroplasia. If so, it would represent a once-a-week alternative to vosorotide for growing children with achondroplasia.

References: 1. Bioactivity and metabolism of C-type natriuretic peptide in normal man. Hunt PJ, Richards AM, Espiner EA, Nicholls MG, Yandle TG. J Clin Endocrinol Metab. 1994;78(6):1428–1435. doi:10.1210/jcem.78.6.8200946. 2. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020 Oct 10;396(10257):1070]. Savarirayan R, Tofts L, Irving M, et al. Lancet. 2020;396(10252):684–692. doi:10.1016/S0140-6736 (20)31541-5IF: 202.731 Q1).