Endocrine Abstracts

JOINT1217

Idiopathic short stature (ISS) is diagnosed in individuals with height 2 to 2. 25 standard deviations below age- and sex-matched populations with no other defined aetiology. Evidence suggests that C-type natriuretic peptide is a master regulator of growth. Its analogue vosoritide is an approved targeted therapy for achondroplasia, a condition in which fibroblast growth factor receptor 3 (FGFR3) overactivity causes impaired endochondral ossification and growth. Preliminary experience from an ongoing phase 1/2 proof-of-concept study (NCT04219007) supports that vosoritide may offer benefits in a broad spectrum of short-stature conditions beyond achondroplasia, including children with short stature attributed to variants in natriuretic peptide receptor 2 (NPR2) and aggrecan (ACAN). Study 111-210 (NCT06382155) is a phase 2, randomized, controlled, multicentre study designed to compare efficacy and safety over a range of vosoritide doses vs placebo (short-term) and human growth hormone (hGH; long-term) in children with ISS. Study 111-210 aims to recruit approximately 100 prepubertal children with ISS aged ≥3 to <10 years (females) or <11 years (males) with a height Z-score less than or equal to −2. 25 from US Centers for Disease Control and Prevention average-stature references. Participants must also be naïve to growth-promoting agents. Baseline annualized growth velocity (AGV) will be established prospectively during a 6-month pretreatment growth-assessment phase. Participants will then be randomized 1:1:1:1:1 to 7. 5, 15. 0, or 22. 5 µg/kg/day vosoritide, 0. 24 mg/kg/week (starting dose) of daily hGH (US only), or placebo in the dose-finding phase of the study. Participants and investigator/study-site personnel will be blinded to vosoritide and placebo. Participants will complete a minimum of 6 months of blinded treatment (maximum 6 months of placebo), followed by open-label treatment with the selected therapeutic dose of vosoritide until they reach near-final adult height in the long-term phase. Participants randomized to hGH will receive open-label hGH for a minimum of 4 years, after which they may transition to open-label vosoritide at the therapeutic dose, if desired. The objectives of the dose-finding phase are to evaluate the safety and efficacy of 3 doses of vosoritide compared with placebo as measured by change from baseline in AGV after 6 months of treatment. The objectives of the long-term phase are to evaluate the safety and efficacy of the therapeutic dose of vosoritide vs hGH on height and height Z-score after long-term treatment.