ESPEYB18 5. Bone, Growth Plate and Mineral Metabolism Novel treatments for rare skeletal disorders (2 abstracts)
5.1. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial
Savarirayan R , Tofts L , Irving M , Wilcox W , Bacino CA , Hoover-Fong J , Ullot Font R , Harmatz P , Rutsch F , Bober MB , Polgreen LE , Ginebreda I , Mohnike K , Charrow J , Hoernschemeyer D , Ozono K , Alanay Y , Arundel P , Kagami S , Yasui N , White KK , Saal HM , Leiva-Gea A , Luna-González F , Mochizuki H , Basel D , Porco DM , Jayaram K , Fisheleva E , Huntsman-Labed A & Day J
Murdoch Children’s Research Institute, Royal Children’s Hospital, and University of Melbourne, Parkville, VIC, Australia.
Lancet. 2020 Sep 5;396(10252):684–692. Abstract: https://pubmed.ncbi.nlm.nih.gov/32891212/
In brief: Activating mutations in FGFR3 inhibit endochondral ossification in achondroplasia resulting in disproportionate extreme short stature. In this randomised, double-blind, phase 3, placebo-controlled trial, once-daily subcutaneous treatment with vosoritide, a C-type natriuretic peptide-analogue, was found to increase the rate of linear growth in children with achondroplasia.
Comment: Achondroplasia is characterised by extreme, disproportionate short stature with macrocephaly and several complications including foramen magnum stenosis with cervico-medullary compression, hydrocephalus, obstructive sleep apnea. There is an increased risk of sudden death in infancy. Mortality is increased from birth to 4 years of age as well as in the fourth and fifth decades of life.
The condition is caused by an autosomal dominant mutation in the fibroblast growth factor receptor 3 gene (FGFR3) that constitutively activates the mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase pathway in chondrocytes. C-type natriuretic peptide (CNP) acts on the natriuretic peptide receptor 2 (NPR2) and is a potent stimulator of endochondral ossification at the level of the growth plate. CNP stimulates growth, at least in part, by inhibiting FGFR3-mediated MAPK signalling. Vosoritide is a recombinant C-type natriuretic peptide analogue with an extended half-life.
A previous phase 2 and dose-finding study of daily subcutaneous vosoritide treatment in children (5 to 14 years of age) with achondroplasia demonstrated that the dose-dependent increase in growth rate appeared to level off at a positive effect of approximately 1.5 cm/year that was maintained up to 42 months of treatment.
In this phase 3, randomized, double-blind, placebo-controlled, 52-week trial (NCT03197766), the efficacy and safety of daily subcutaneous injections of vosoritide (15.0 μg/kg) was compared to placebo in 121 children (age range, 5 to <18 years) with achondroplasia. Two patients in the vosoritide group discontinued their participation after 2 and 6 days due to pain from injection and fear of needles, respectively. The remaining 119 participants completed the study and enrolled in the extension study. All 121 randomized patients were included in the efficacy analyses.
After 52 weeks of treatment, the annualized growth velocity was 1.57 cm/year higher in the vosoritide compared to the placebo group (95% CI 1.22–1.93; P<0.0001) and slightly better at 1.71 cm/year (95% CI 1.40–2.01) if adjusted for baseline growth velocity. In addition, all subgroup analyses (sex, age, tanner stage, height z-score, baseline growth velocity) indicated a positive effect of vosoritide. This study demonstrates that vosoritide is efficacious in increasing the growth velocity in children with achondroplasia and supports previous studies indicating that is safe. Further studies with earlier start and longer duration of treatment are needed to determine the total amount of height gain that can be accomplished with this treatment and possible effects on other important complications of the condition.
Volume 18
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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