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.

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TransCon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Phase 3 heiGHt Trial Background TransCon Growth Hormone is a sustained-release recombinant human growth hormone (hGH; somatropin) prodrug in development as a long-acting GH (LAGH) for children with growth hormone deficiency (GHD). In its prodrug form, TransCon hGH is inactive with hGH transiently bound to a TransCon carrier via a TransCon linker. Upon injection and triggered by physiological pH and temperature, unmodified recombinant hGH is sustainably released and thus designed to maintain the same mode-of-action and distribution as daily hGH replacement therapy but with once-weekly dosing. In a 6-month phase 2 trial of TransCon hGH vs. a daily hGH in children with GHD, mean annualized height velocity (AHV) for TransCon hGH was 12.9 cm/y compared to 11.6 cm/y for a daily hGH at an equivalent hGH dose (0.21 mg/kg/wk). The subsequent pivotal phase 3 global heiGHt Trial (ClinicalTrials.gov: NCT02781727) was designed to investigate the safety, tolerability, and efficacy of weekly TransCon hGH versus daily hGH over 52 weeks in treatment-naive prepubertal children with GHD. Methods Subjects were randomized in a 2:1 ratio and received either once-weekly TransCon hGH 0.24 mg hGH/kg/wk or dose-equivalent once-daily Genotropin over 52 weeks. Key baseline demographics variables included age, gender, height standard deviation score (SDS), IGF-1 SDS, peak stimulated GH, and bone age delay. Study endpoints included AHV, IGF-1 response, immunogenicity, and safety. Results At baseline, the mean age of study participants, of whom 82% were male, was 8.5 years. Mean height SDS was -2.93, and mean IGF-1 SDS was -2.04. Mean peak stimulated GH was 5.77 µg/L, and mean bone delay was 2.63 years. The final sample size (n=161) was larger than planned (n=150) which strengthens the study power for noninferiority. Top-line results, including AHV, change in height SDS, serum IGF-1 levels, change in bone age, and adverse events, will be available for presentation at ENDO 2019. Conclusion Only LAGHs based on unmodified hGH have obtained approval in Europe or the United States. By February 2019, all subjects will have completed their participation in this pivotal trial of a LAGH designed to release unmodified hGH, with top-line analyses available in March. The heiGHt Trial was well-powered to demonstrate noninferiority between TransCon hGH and a daily hGH, with baseline demographic variables in the range of recent GH trials.

Purpose The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone (LAGH) lonapegsomatropin in children with growth hormone deficiency (GHD). Methods Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the US switched to the TransCon hGH Auto-Injector when available.​ Endpoints were long-term safety, annualized height velocity (AHV), pharmacodynamics (insulin-like growth factor-1 standard deviation score [IGF-1 SDS] values), and patient- and caregiver-reported assessments of convenience and tolerability. Results Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through Week 104 in treatment-naïve subjects from the heiGHt trial (−2.89 to −1.37 for- the lonapegsomatropin group; −3.0 to −1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (−1.42 at fliGHt baseline to −0.69 at Week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. Conclusions Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the 2nd year of therapy without excess advancement of bone age.

Background: Once-weekly TransCon hGH (lonapegsomatropin) is an investigational long-acting prodrug of somatropin in development for GHD. In the pivotal 52-week phase 3 heiGHt trial, lonapegsomatropin demonstrated superior annualized height velocity (AHV) compared to the same weekly dose of daily somatropin in treatment-naïve children with GHD. In the 26-week fliGHt trial, switch from daily somatropin to lonapegsomatropin provided continued growth and maintained a good safety profile. Methods: Results are reported from heiGHt and fliGHt subjects who continued into the open-label long-term extension enliGHten trial (data cut: June 1st 2020). Subjects received either lonapegsomatropin (Group A; vial/syringe) or daily somatropin (Group B; pen device) in heiGHt, or lonapegsomatropin in fliGHt (Group C; vial/syringe). Upon entry into enliGHten, all subjects received lonapegsomatropin via vial/syringe, with subsequent switch to TransCon hGH Auto-Injector when available. Average IGF-1 was obtained on post-dose Day 5 (±1) in enliGHten. A by-visit ANCOVA model was used for numeric efficacy endpoints. Results: A total of 298 (98%) subjects continued into enliGHten. (A: n=103; B: n=55; C: n=140). The treatment difference in LS mean ∆ height SDS (A vs B) at the end of heiGHt (Week 52, 1.10 vs 0.96, P=0.015) was sustained through Week 104 (1.61 vs 1.49, P=0.158). For Group C, height SDS improved from −1.42 at fliGHt baseline to −0.69 at Week 78. AHV was within the expected range for 2nd year therapy. Among children who switched (B), an attenuation in the expected 2nd year decline of AHV suggested that lonapegsomatropin had an improved treatment effect relative to the previous daily somatropin. Mean (SD) average IGF-1 SDS remained stable and generally within the expected range for all groups (Week 104, A: 0.95 [1.22], B: 1.04 [1.25]; Week 78, C:1.81 [1.08]). An improvement in injection site tolerability was observed after switching to the TransCon hGH Auto-Injector; subjects and parents also indicated overall ease-of-use of the device (assessed by the Device Usability Questionnaire). With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals. Throughout enliGHten and the parent trials, non-neutralizing low-titer anti-hGH binding antibodies were detected post-dose in a total of 15 subjects (5.0%). Lab parameters were stable and generally remained within the normal range throughout the trials. As of the data cut, 2 subjects have achieved near adult height (AHV <2 cm/year over the last 9 months or bone age >14 [females] or >16 [males]) and thus have completed the trial. Conclusions: Children treated with lonapegsomatropin showed continued improvement of height SDS through their 2nd year of therapy. Lonapegsomatropin continued to demonstrate a safety profile comparable to that of daily somatropin therapy.

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Differences between groups may reflect differences in diet. In all groups, household and processed food salt constituted a significant part of total iodine intake, highlighting the success and importance of USI in ensuring iodine sufficiency. There appears to be leeway to reduce salt intake without adversely affecting the iodine status of the population in Armenia.