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ENDO 2020

Innovations in Treatments: Device- and Drug-Based Approaches for Management of T1D

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ENDO is the place where leading experts, researchers, and the most respected clinicians in the field come together to share the latest findings in hormone science and discuss breakthroughs in clinical care.

technical paper

Background: The Phase 3 fliGHt Trial evaluated children with growth hormone deficiency (GHD) of a broad range of baseline demographics and treatment durations who switched from daily growth hormone (hGH; somatropin) therapy to once-weekly TransCon hGH. TransCon hGH is an investigational long-acting prodrug consisting of 3 components: hGH, an inert carrier that protects it, and a linker that temporarily binds the two. When injected into the body, at physiologic pH and temperature, unmodified hGH is gradually released in a predictable manner.Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. The primary objective was to assess safety and tolerability over this 26-week trial. Efficacy measures included annualized height velocity (AHV), height standard deviation score (SDS), and insulin-like growth factor 1 (IGF-1) SDS.Results: Of the 146 enrolled subjects, 98.6% completed the trial. Mean age at baseline was 10.6 years (range: 1, 17). The majority (97.9%) were treatment-experienced with a prior daily hGH mean dose of 0.29 mg/kg/week (range: 0.13, 0.49); 3 subjects were treatment-naïve and <3 years old. Just over half the subjects (56.8%) experienced a treatment-emergent adverse event (TEAE), with only 4.1% of subjects experiencing a TEAE considered related to study drug. No TEAE led to discontinuation of study drug. The type and frequency of TEAEs reported were similar to the published adverse event profile of daily hGH therapies. Mean hemoglobin A1c remained 5.2% at baseline and Week 26. No neutralizing antibodies were detected; low-titer anti-hGH binding antibodies were detected in 2.8% of subjects. Growth outcomes were as expected for this treatment-experienced heterogenous population, with a least-squares mean (LSM) AHV of 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). In the age-defined subgroups, mean observed AHV at Week 26 ranged from 8.2 to 16.2 cm/year and mean observed height SDS change from baseline to Week 26 ranged from +0.23 to +0.96. Of note, the linear relationship between average IGF-1 SDS and TransCon hGH doses demonstrated in previous treatment-naïve trials was preserved in this population of treatment-experienced children who had dose titrations.Conclusions: TransCon hGH treatment outcomes, including AHV and height SDS, were as expected across a diversity of ages, disease characteristics, and treatment experiences, reflective of a real-world setting. Dose titrations of TransCon hGH demonstrated a predictable IGF-1 response. Switching to TransCon hGH resulted in a similar adverse event profile to daily hGH therapy.

Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

Background: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone (rhGH; somatropin) in development for once weekly treatment of children with growth hormone deficiency (GHD). Somatrogon contains the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) derived from human chorionic gonadotropin. A 12 month phase 2 trial of once weekly Somatrogon vs daily Genotropin in children with GHD demonstrated that 0.66 mg/kg/wk of Somatrogon had a similar benefit - risk profile as 0.24 mg/kg/wk of Genotropin. The open label extension of this phase 2 study has generated an additional 5 years of longitudinal efficacy and safety data with this dose. This report summarizes top line results from a pivotal phase 3 global trial (ClinicalTrials.gov: NCT02968004) designed to investigate the non-inferiority of once weekly Somatrogon hGH-CTP compared to daily hGH after 12 months in treatment-naive prepubertal children with GHD. Methods: The Phase 3 trial enrolled 224 subjects who were randomized in a 1:1 ratio to receive either once weekly Somatrogon hGH-CTP (0.66 mg/kg) or once daily Genotropin (0.24 mg/kg/wk) for 12 months. Randomization was stratified by geographic region, peak GH level and age. The primary endpoint of the study was height velocity (HV) at month 12; secondary endpoints included HV at month 6, change in height SDS at month 6 and 12, IGF-1 and IGF-I SDS, immunogenicity, and safety. Results: At baseline, the mean (SD) age and height SDS of the somatrogon (N=109, 75.2% male) and Genotropin (N=115, 68.7% male) groups were 7.83 (2.66) and -2.94 (1.29) and 7.61 (2.37) and -2.78 (1.27), respectively. One subject in each group discontinued during the 12 month study, and 95% of the completers continued into an open-label extension study. At month 12, mean HV was 10.12 cm/yr in the Somatrogon group and 9.78 cm/yr in the Genotropin group, with the treatment difference of 0.33 cm/year favoring Somatrogon. The lower bound of the two-sided 95% confidence interval of the treatment difference was -0.39, which was higher than the pre-established non-inferiority margin and demonstrated non-inferiority of once weekly somatrogon vs daily Genotropin therapy. Height velocity at month 6 (10.60 cm/yr vs 10.04 cm/yr), change in height SDS at months 6 (0.54 vs 0.48) and 12 (0.92 vs 0.87) were likewise numerically higher in the Somatrogon-treated cohort. The majority of adverse events were mild to moderate in severity (somatrogon: 78.9%, Genotropin: 79.1%) and, overall, weekly somatrogon was generally well-tolerated and comparable to daily Genotropin. Conclusion: Top-line results from the pivotal phase 3 trial demonstrate that Somatrogon (hGH-CTP) given once weekly by sc injection is non-inferior to Genotropin (hGH) given once daily and that once weekly somatrogon administration was generally well-tolerated in patients with pGHD.

Somatrogon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Pediatric Phase 3 Clinical Trial

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Innovations in Treatments: Device- and Drug-Based Approaches for Management of T1D

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Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

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