Abstract Context Genetic defects in many biological pathways, including activation of the Ras-MAPK pathway, cause short stature. Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia. Objective To determine whether vosoritide improves growth in children with disorders of the Ras-MAPK pathway including RASopathies, ACAN and NPR2 deficiency. Design Prospective phase 2 basket trial Setting Academic medical center Participants Thirty pre-pubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height -2.25 SD Intervention 6-month observation period followed by 12-month treatment with vosoritide subcutaneously 15 micrograms/kg/day. Main Outcome Measures Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV) and height standard deviation scores. Results The AGV increased from 4.53+1.61 cm/yr to 8.09+1.58 cm/yr with treatment (p0.0001). This corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (p0.0001). The increase in AGV was seen in all genetic subgroups. There was a height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment versus observation period (p0.0001). Short-term safety was reassuring with mild injection site reactions being the most common adverse events. However, with longer use, five subjects discontinued medication due to adverse events including three slipped capital femoral epiphyses and four cases of genu valgum. Conclusions Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN and NPR2 deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway.
Dauber et al. (Thu,) studied this question.