Context For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections (hGH) is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD. Objective The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin. Design The heiGHt Trial was a randomized, open-label, active-controlled, 52-week phase 3 trial (NCT02781727). Setting This trial took place at 73 sites across 15 countries. Patients This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD. Interventions Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/wk or an equivalent weekly dose of somatropin, delivered daily. Main Outcome Measure The primary end point was annualized height velocity (AHV) at Week 52. Secondary efficacy end points included change from baseline in height standard deviation scores (SDS). Results Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs. 10.3 (0.3) cm/year for daily somatropin (P=0.009), with lonapegsomatropin demonstrating both non-inferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to Week 52 by 1.10 (0.04) vs. 0.96 (0.05) in the weekly lonapegsomatropin vs. daily somatropin groups (P=0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups. Conclusions The trial met its primary objective of non-inferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

Context: TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD).Objective: To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD. Design:Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer).Setting: Thirty-eight centers in 14 European countries and Egypt.Patients: Prepubertal male and female treatment-naïve children with GHD (n = 53).Interventions: Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks.Main Outcome Measures: GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity.Results: Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH. Conclusions:The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.

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