ESPE Abstracts

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.

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.