OR10-06 Somatrogon Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Pediatric Phase 3 Clinical Trial

Abstract

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.

Weekly Lonapegsomatropin in Treatment–Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial

“…In a Phase 2 study, mean AHV for the somapacitan 0.16 mg/kg/week group was 12.9 cm/year compared to 11.4 cm/year with daily somatropin 0.034 mg/kg/day at week 26 (not significantly different), with comparable safety ( 24 ). Somatrogon demonstrated noninferior AHV compared to daily somatropin (10.10 cm/year vs 9.78 cm/year) with a similar safety profile in a Phase 3 study ( 25 ). In comparison, AHV for lonapegsomatropin diverged early and was numerically greater at week 5, achieving significance and superiority at and beyond 26 weeks, confirming observations of the Phase 2 trial ( 8 ).…”

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs

“…In June 2020, the data from a Phase 3 trial of Somatrogon hGH-CTP (MOD-4023, Pfizer/OPKO Biologics), a long-acting derivative of rhGH modified by the addition of three C-terminal peptide segments from human chorionic gonadotropin to allow for once-weekly delivery, in children with GHD (NCT02968004) were presented at ENDO 2020 ( 79 ). Previously untreated prepubertal children with GHD received either weekly Somatrogon hGH-CTP (0.66 mg/kg/wk) or once daily Genotropin (0.24 mg/kg/wk) for 12 months.…”

Spotlight on Lonapegsomatropin Once-Weekly Injection and Its Potential in the Treatment of Growth Hormone Deficiency in Pediatric Patients

“…Similar growth responses to LAGH were demonstrated in the phase 2 REAL3 trial of somapacitan in PGHD with a statistically superior response to the dose (0.16 mg/kg/wk) that was chosen for the phase 3 trial and a numerically superior response to somatrogon (0.66 mg/kg/wk) in PGHD in the phase 3 trial (Table 2). 15,16,29 During the heiGHt™ trial, IGF-I levels were measured at peak (2-3 days after lonapegsomatropin injection) and trough (day 6-7 after lonapegsomatropin injection). Average IGF-I levels were >+2 SDS in 2 children receiving daily Genotropin ® and did not exceed +3 SDS.…”

“…The Phase III trial of somatrogon in AGHD (ClinicalTrials.gov Identifier: NCT01909479) was completed in 2016 and failed to meet the primary endpoint, 14 whereas the other phase III trial of somatrogon in PGHD (ClinicalTrials.gov Identifier: NCT02968004) that was completed in 2019 demonstrated non-inferiority of somatrogon to DGH. 15 , 16 Based upon these results, somatrogon received market authorization for treatment of PGHD in the European Union by the European Medicines Agency in February 2022. 17 A Biologics License Application for somatrogon for the treatment of PGHD was submitted to the US Food and Drug Administration (FDA) in 2021 and received a Complete Response Letter in January 2022, but is currently not approved yet in the US.…”