ESPE Abstracts (2022) 95 P1-507

Children's National Hospital, Washington, DC, USA

Objectives: Vosoritide is a C-type natriuretic peptide (CNP) analog which binds its receptor on chondrocytes, leading to increased chondrocyte proliferation and differentiation via its inhibition of the ERK1/2-MAPK pathway. Rasopathies, including Noonan Syndrome, lead to increased signaling through this pathway. NPR2 encodes the receptor for CNP and heterozygous mutations in NPR2 account for ~2% of cases of idiopathic short stature.

Methods: This is a prospective, Phase II study of patients with selected genetic causes of short stature including Rasopathies and NPR2 mutations. Subjects must be prepubertal between the ages of 3-11 for boys and 3-10 for girls and have a height </= -2.25 SD. Subjects are followed for a 6-month observation period to establish a baseline annualized growth velocity (AGV) and then receive daily subcutaneous vosoritide (15 mg/kg/day) for 12 months. The primary outcomes are rate of AEs and change in AGV from baseline. Pharmacokinetic studies and pharmacodynamic studies, using cGMP production as a pharmacodynamic marker, are completed at Day 1 and Months 6 and 12.

Results: To date, 3 subjects with Noonan Syndrome due to PTPN11 mutations and 3 subjects with heterozygous NPR2 mutations are enrolled in the study. Demographics and 6-month treatment response are listed in the Table. One subject with Noonan syndrome for whom growth response is available (VOS03) had previously been treated with growth hormone (GH) for 2 years. His AGV was 6.7 cm/yr while on GH, 4.1 cm/yr during the 6-month observation period, and 11.6 cm/year during the first 6 months of vosoritide treatment. There were no serious adverse events related to vosoritide treatment. cGMP levels were markedly lower in subjects with NPR2 mutations as compared to Noonan Syndrome.

Subject ID Sex Age at screening Diagnosis Height SDS at screening 6 Month Rx ∆Height SDS Observation AGV 6 Month AGV 6 Month ∆AGV
VOS05 M 10y3m NPR2 -2.65 0.24 2.8 7.2 4.4
VOS07 M 10y11m NPR2 -3.34 0.41 0.5 9.7 9.2
VOS30 M 6y8m NPR2 -2.25 Pending Pending Pending Pending
VOS03 M 4y2m Noonan -3.75 0.74 4.1 11.6 7.5
VOS10 M 5y2m Noonan -2.25 0.36 5.9 9.2 3.3
VOS15 M 3y10m Noonan -2.31 Pending 2.7 Pending Pending

Conclusions: This is the first clinical trial of vosoritide for children with genetic short stature due to NPR2 mutations or Noonan Syndrome. Vosoritide treatment may work as a precision therapy to improve growth in multiple genetic conditions which interact with the ERK1/2-MAPK pathway.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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