This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile. This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023.

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.

ObjectiveResults of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients’ inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants.Design243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study.MethodsA custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsIn total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in ‘thyroid dysgenesis’ (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in ‘dyshormonogenesis’ (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic.ConclusionsIn contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.

Context Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). Objective Compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. Design 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study. Intervention Subjects were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. Patients or Other Participants 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). Main Outcome Measures The primary endpoint was annualized HV at month 12. Results HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: –0.24, 0.89). The lower bound of the two-sided 95% confidence interval was higher than the prespecified non-inferiority margin (–1.8 cm/year), demonstrating non-inferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height SDS at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon:78.9%, somatropin:79.1%). Conclusions The efficacy of once-weekly somatrogon was non-inferior to once-daily somatropin, with similar safety and tolerability profiles.

To compare efficacy and safety of insulin glargine 300 units/mL (Gla-300) and 100 units/mL (Gla-100) in children and adolescents (6-17 years old) with type 1 diabetes. RESEARCH DESIGN AND METHODSEDITION JUNIOR was a noninferiority, international, open-label, two-arm, parallelgroup, phase 3b trial. Participants were randomized 1:1 to Gla-300 or Gla-100, titrated to achieve fasting self-monitored plasma glucose levels of 90-130 mg/dL (5.0-7.2 mmol/L), with continuation of prior prandial insulin. The primary end point was change in HbA 1c from baseline to week 26. Other assessments included change in fasting plasma glucose (FPG), hypoglycemia, hyperglycemia with ketosis, and adverse events. RESULTSIn 463 randomized participants (Gla-300, n 5 233; Gla-100, n 5 230), comparable least squares (LS) mean (SE) reductions in HbA 1c were observed from baseline to week 26 (20.40% [0.06%] for both groups), with LS mean between-group difference of 0.004% (95% CI 20.17 to 0.18), confirming noninferiority at the prespecified 0.3% (3.3 mmol/mol) margin. Mean FPG change from baseline to week 26 was also similar between groups. During the 6-month treatment period, incidence and event rates of severe or documented (£70 mg/dL [£3.9 mmol/L]) hypoglycemia were similar between groups. Incidence of severe hypoglycemia was 6.0% with Gla-300 and 8.8% with Gla-100 (relative risk 0.68 [95% CI 0.35-1.30]). Incidence of any hyperglycemia with ketosis was 6.4% with Gla-300 and 11.8% with Gla-100. CONCLUSIONSGla-300 provided similar glycemic control and safety profiles to Gla-100 in children and adolescents with type 1 diabetes, indicating that Gla-300 is a suitable therapeutic option in this population.