Endocrine Abstracts

JOINT1218

Turner syndrome, Noonan syndrome, and short stature homeobox-containing gene deficiency disorders (SHOX-Ds) are associated with excess extracellular-signal-regulated kinase (ERK) signalling, similar to achondroplasia. All 3 are characterized by short stature, among other phenotypes. Treatment with human growth hormone (hGH) is standard of care, but response generally declines over time. Vosoritide, an analogue of the master growth regulator C-type natriuretic peptide, is an approved targeted therapy for achondroplasia that stimulates endochondral bone growth by reducing ERK activity. Phase 2 proof-of-concept studies in children with short-stature disorders including Noonan syndrome (NCT04219007) and Turner syndrome (NCT05849389) are ongoing. Study 111-211 (NCT06668805) is a phase 2, randomized, active-controlled, multicentre basket study to generate efficacy and safety data across a range of vosoritide doses vs hGH in children with genetically confirmed Turner syndrome, Noonan syndrome, or SHOX-D with inadequate response to hGH. Participants will be aged ≥3 years and <11 years (females) or <12 years (males) and prepubertal with height Z-scores ≤−2.00 from US Centers for Disease Control and Prevention (CDC) average-stature references. Participants must have been receiving ≥0.35 mg/kg/week hGH for ≥1 year or an optimized dose according to the local standard of care without dose changes in the previous 6 months. They must have an inadequate hGH response that is less than age- and sex-matched average-stature annualized growth velocity (AGV) determined using median heights from CDC growth charts. Baseline AGV will be prospectively established during a 6-month growth assessment phase while participants continue their hGH regimen. Randomization will be 1:1:1:1 to 7.5, 15.0, or 22.5 µg/kg/day vosoritide or daily hGH at a dose equivalent to participants’ previous regimen. Study-site personnel and participants will be blinded to vosoritide doses; hGH will be open-label. Transition to the selected therapeutic vosoritide dose will occur after the 6-month dose-finding phase for vosoritide participants and after 24 months for hGH participants, if desired. Treatment will continue until participants are near final adult height (FAH), and follow-up will continue until FAH. The primary objective is to evaluate the efficacy of 3 doses of vosoritide vs hGH as measured by change from baseline (CFB) AGV after 6 months of treatment. Secondary endpoints include CFB height and height Z-score at 6 months; CFB height, height Z-score, and AGV over 24 months (therapeutic dose vs hGH); and adverse event incidence. This study may support vosoritide as a second-line treatment for these conditions if hGH treatment becomes inadequate.