Research in context
Evidence before this study
We searched PubMed on April 6, 2020, for original research and review articles published in English since January, 2000, with the following search terms: “achondroplasia”, “C-natriuretic peptide”, “growth hormone”, “FGFR3”, “management”, AND “treatment”. The literature indicates that treatment of achondroplasia, to date, has been solely focused on management of symptoms. Research is focusing on the therapeutic manipulation of fibroblast growth factor receptor 3 (FGFR3) activity with C-type natriuretic peptide, as this might be associated with increased skeletal growth. Human growth hormone has been administered to children with achondroplasia but does not have a significant or durable effect on growth or on final height and has unknown effects on body proportionality. A precision therapy to address the pathogenesis of this condition has been lacking. C-type natriuretic peptide is a potent stimulator of endochondral ossification through downregulation of the intracellular signalling pathway of the FGFR3 receptor. Achondroplasia is caused by a gain-of-function mutation in the FGFR3 gene, which results in constitutive overactivity of the receptor and impaired endochondral ossification. The first clinical trial to assess the safety of administration of the C-type natriuretic peptide analogue, vosoritide, was done in 35 children with achondroplasia, and reported in 2019. This phase 2, dose-finding study showed a generally mild side-effect profile and dose-related increases in annualised growth velocity. Limitations of this study were that participants acted as their own controls with regard to growth velocity comparisons, and that the design was open-label, with no placebo group enrolled.
Added value of this study
To our knowledge, this study is the first phase 3, randomised, double blind, placebo-controlled study done to assess the effect of vosoritide on growth in children with achondroplasia. Children administered vosoritide had a highly significant and potentially clinically important increase in annualised growth velocity over baseline after 1 year of treatment as compared with those who received placebo with similar adverse effect profiles. We believe that this study provides the first (level 1) randomised controlled trial evidence that vosoritide effectively enhances growth of children aged from 5 to less than 18 years with achondroplasia.
Implications of all the available evidence
This randomised controlled study provides strong evidence that daily subcutaneous administration of vosoritide (at a dose of 15·0 μg/kg of bodyweight) has a significant effect on growth velocity in children with achondroplasia aged 5 to less than 18 years. The balance of benefits and harms reported here are consistent with the previously published phase 2, open-label dose-finding studies. The children enrolled in these studies will be followed until they achieve final adult height to assess durability of response and whether a pubertal growth velocity increase is restored (as it is normally absent in children with achondroplasia). Studies are also under way to assess the use of vosoritide in children aged 0 to <5 years to evaluate whether earlier treatment will lead to better outcomes in terms of final height, body segment proportionality, and other comorbidities observed such as symptomatic foramen magnum stenosis, sleep disordered breathing, and spinal canal stenosis. We believe that this study provides the first, robust evidence for an effective, precision therapy for achondroplasia, underpinning a fundamental change in the clinical management policies, natural growth history, and treatment recommendations for children affected by this condition. It will serve as a benchmark against which other, emerging precision therapies for achondroplasia (including tyrosine kinase inhibitors, long acting forms of C-type natriuretic peptide, and fibroblast growth factor receptor ligand traps) can be measured.