ESPE Yearbook of Paediatric Endocrinology

In brief: This multinational, randomised, double-blind, placebo-controlled, dose-escalation Phase 2 study evaluated the safety and efficacy of TransCon CNP (navepegritide), a C-type natriuretic peptide (CNP) analogue designed to allow continuous CNP exposure with once-weekly dosing, in 42 children with achondroplasia aged 2-10 years. The study was sponsored by Ascendis Pharma.

Commentary: Achondroplasia is one of the most common constitutional bone disorders (> 300,000 affected individuals worldwide). It is associated with skeletal defects (disproportionate short stature, abnormal curvature of the spine, genu varum) but also with extra-skeletal manifestations (reduction of the upper airway with otitis and apnoea, stenosis of the foramen magnum and lumbar canal with spinal cord compression, hypotonia and muscle weakness) with the potential for functional limitations and psychosocial challenges. Achondroplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which leads to increased activation of the RAS/mitogen-activated protein kinase (MAPK) pathway in chondrocytes, resulting in impaired endochondral ossification.

Transcon-CNP is a long-acting prodrug that releases native CNP and has demonstrated beneficial effects on bone growth in both mouse and non-human primate models. Results from a Phase 1 study showed that TransCon CNP was well tolerated in healthy adult volunteers. In this Phase 2 study in children with achondroplasia aged 2-10 years, TransCon CNP was well tolerated with no serious treatment-related adverse events and demonstrated a dose-dependent improvement in annualised growth velocity compared to placebo.

This study provides the first evidence that TransCon CNP increases annualised growth velocity in children with achondroplasia with a favourable safety profile, supporting further investigation of its safety and efficacy, as well as its impact on achondroplasia-related health complications.

Various therapeutic trials are currently being evaluated in achondroplasia (vosoritide, TransCon CNP, infigratinib). It will be important to determine the relative efficacy of these different treatments in the future, and also to evaluate therapies combining these compounds.