ESPE Abstracts

Objectives: Vosoritide is a C-type natriuretic peptide analog which binds its receptor on chondrocytes, leading to increased chondrocyte proliferation and differentiation via its inhibition of the ERK1/2-MAPK pathway. It was recently approved for increasing linear growth in children with achondroplasia. This is the first study to examine the safety and efficacy of vosoritide in children with hypochondroplasia.

Methods: This is a prospective, Phase II study of children with selected genetic causes of short stature including hypochondroplasia. Subjects must be prepubertal between the ages of 3 and 11 for boys and 3 and 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, 26 subjects with hypochondroplasia have enrolled in the trial (23 with the Asn540Lys mutation). Median age at screening was 5.7 years (IQR 4.3, 8.1). Median baseline height is -3.3 SD (IQR -3.8, -2.8). 12 subjects have initiated on vosoritide and 7 have completed 6 months of therapy. Median AGV during the observation period is 5 cm/yr (IQR 4.5, 5.8). At 6 months, median AGV was 7.4 cm/yr (IQR 6.8, 8) with a median increase in AGV of 2.1 cm/yr. The 6-month change in height standard deviation ranged from -0.09 to +0.49 SD with a median of +0.27 SD. There were no serious adverse events related to vosoritide treatment. One subject had a brief episode of syncope with her first injection which self-resolved, and she continued on therapy with no further incidents. PK parameters were similar to previously published parameters for vosoritide in children with achondroplasia. Analysis of cGMP levels as well as patient reported quality of life outcomes are ongoing.

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