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Pediatric and Adolescent Endocrinology

ORF47-07 - Vosoritide Improves Growth in RASopathies, Aggrecan and NPR2 Deficiency: A Phase 2 Trial

Monday, June 15, 2026
2:45 PM - 3:00 PM CT
Location: Room W187
Disclosure(s):
Andrew Dauber, MD, MMSc: Ascendis: Clinical Trial Investigator (), Consultant (); BioMarin: Advisory Board (), Clinical Trial Investigator (), Consultant (), Contracted Research (Principal Investigators must provide information, even if received by the institution) (), Grant Recipient (); Eton Pharmaceutical: Consultant (); Lumos: Clinical Trial Investigator (); Neurocrine: Clinical Trial Investigator (); Novo Nordisk: Clinical Trial Investigator (), Consultant (); Pfizer Inc: Advisory Board (), Clinical Trial Investigator (), Consultant (), Grant Recipient (); QED Pharmaceutical: Advisory Board (), Clinical Trial Investigator (), Consultant (); Sandoz: Consultant ()
Nadia Merchant, MD, FAAP, FACMG: Alexion Pharmaceutical: Advisory Board (), Honorarium Recipient (); Ascendis Pharma: Advisory Board (), Clinical Trial Investigator (); BioMarin: Advisory Board (), Clinical Trial Investigator (), Honorarium Recipient (); BridgeBio: Advisory Board (), Clinical Trial Investigator (), Honorarium Recipient (); Catalyst: Advisory Board (), Honorarium Recipient (); Kyowa Kirin: Advisory Board (), Honorarium Recipient (); Tyra: Clinical Trial Investigator (); UltraGenyx: Advisory Board (), Honorarium Recipient ()



Background: Short stature can be caused by a number of genetic etiologies including disorders leading to activation of the MAPK pathway. Vosoritide is a c-type natriuretic peptide (CNP) analog that promotes growth by inhibiting the MAPK pathway. We performed a Phase 2 trial of vosoritide in children with short stature due to RASopathies, Aggrecan and NPR2 deficiency, all rare genetic disorders leading to overactivity of the MAPK pathway.

Methods: Subjects were pre-pubertal children between the ages of 3-11 years with heights <-2.25 SD with a confirmed genetic diagnosis. 12 subjects had ACAN mutations, 7 had NPR2 mutations, and 11 subjects had RASopathies (8 Noonan syndrome, 2 NF1, 1 Costello syndrome). Subjects were observed for 6 months without treatment to obtain a baseline growth velocity and then treated with daily subcutaneous vosoritide (15 mcg/kg/day) for 12 months. The co-primary outcomes were changes in annualized growth velocity (AGV), height standard deviation scores (SDS), and safety.

Results: 30 subjects enrolled in the trial. Mean age at screening was 7.2 + 2.2 years. 2 subjects in the RASopathy cohort discontinued therapy due to unrelated reasons. 28 subjects were included in the efficacy analysis. The absolute AGV increased from 4.03 + 2.19 cm/yr during observation to 8.79 + 1.34 cm/yr in the NPR2 cohort (p=0.004), 4.72 + 1.35 cm/yr to 8.05 + 1.10 cm/yr in the RASopathy cohort (p < 0.0001), and 4.68 + 1.48 cm/yr to 7.71 + 1.96 cm/yr in the ACAN cohort (p=0.001). Compared to the observation period, there was a mean (95% CI) increase in height SDS of 0.74 (0.46-1.02), 0.64 (0.51-0.78), and 0.59 (0.33-0.85) in the NPR2, RASopathy, and ACAN cohorts respectively (p < 0.001 in all groups). There was no significant change in bone age/chronological age during the 12 months of treatment.
Vosoritide was well tolerated during the 1st year of treatment with the most common side effect being injection site reactions present in 40% of subjects. There were no grade 3 or higher treatment-related adverse events. However, 5 subjects in the long-term extension phase discontinued treatment due to adverse events (4 ACAN and 1 Noonan). 4 of the subjects developed significant genu valgum with 3 of the subjects developing a slipped capital femoral epiphysis (SCFE) requiring surgical intervention. Patients with genetic overactivity of the CNP pathway have been reported to develop SCFE raising a concern that this is a treatment specific adverse event.

Conclusions: Vosoritide treatment showed robust efficacy in increasing growth velocity in children with RASopathies, NPR2 and ACAN deficiency. Vosoritide has the potential to be a precision medicine for growth promotion for disorders affecting the MAPK pathway. Longer term data raises a concern for the risk of genu valgum and SCFE in a subset of patients, particularly those with ACAN deficiency.