ESPE Yearbook of Paediatric Endocrinology

In brief: This multinational, randomised, double-blind, placebo-controlled, Phase 2 study examined the safety and efficacy of vosoritide, a recombinant C-type natriuretic peptide (CNP) analogue, in 75 children with achondroplasia under age 5 years. Mean gain in height Z-score after 52-weeks was 0•25 (95% CI -0•02 to 0•53). The study was sponsored by BioMarin Pharmaceutical.

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) as well as extra-skeletal manifestations (reduction of the upper airway with otitis and sleep apnoea, stenosis of the foramen magnum and lumbar canal with spinal cord compression, hypotonia and muscle weakness, overweight and obesity) 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. C-type natriuretic peptide (CNP) upon binding its receptor on chondrocytes has the property to inhibit the RAS/MAPK pathway. Vosoritide, a recombinant CNP analogue, has been reported to increase annualised growth velocity in children with achondroplasia aged 5-18 years.

In this Phase 2 study in infants and children under 5 years of age, vosoritide showed with no serious treatment-related adverse events and resulted in improved height Z-scores. Interestingly, in addition to the effects on growth, treatment with vosoritide was also associated with changes in facial volume, sinus volume and foramen magnum area. These data, which need to be validated in a future phase 3 trial, are very promising as one of the challenges of early treatment of these children, in addition to improving growth, would be to mitigate other complications of achondroplasia (in particular sleep apnoea, stenosis of the foramen magnum, hypotonia and muscle weakness).

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.