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Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Background In 2007, Omnitrope® was the first biosimilar recombinant human growth hormone (rhGH) to be approved in Sweden for treatment in adults and children. Over 10 years’ safety and effectiveness data for biosimilar rhGH can now be presented. Methods PATRO Children and PATRO Adults are multicenter, longitudinal, observational, post-marketing surveillance studies. Eligible patients include children 0–18 years and adults receiving biosimilar rhGH treatment. Adverse events (AEs) are monitored for safety evaluation. Growth variables in children and metabolic data in adults are recorded for effectiveness evaluation. Results As of January 2019, data from 136 children (48% male) were reported from Swedish centers. Mean age in rhGH treatment-naïve patients at study entry (n = 114) was 7.5 years, with mean 3.6 years treatment duration. No severe AEs of diabetes, impaired glucose tolerance, or malignancy were reported. The most frequently reported AE was nasopharyngitis (n = 16 patients). No clinically relevant anti-hGH or neutralizing antibodies were observed. The mean change from baseline in height standard deviation score (SDS) in naïve prepubertal GH deficiency patients was + 0.79 at 1 year, + 1.27 at 2 years, and + 1.55 at 3 years. Data from 293 adults (44% rhGH-naïve, 51% male) were included. Fatigue was the most frequently reported AE (n = 26 patients). The incidence of new neoplasms or existing neoplasm progression was 23.8 patients per 1000 patient-years. Type 2 diabetes mellitus was reported in four patients. At baseline in rhGH-naïve adults, mean (SD) body mass index (BMI) was 29.1 (5.6) kg/m2 and mean (SD) insulin-like growth factor (IGF)-I SDS was − 3.0 (1.4). Mean daily dose increased from 0.1 mg at baseline to 0.3 mg after 4 years. IGF-I SDS normalized during the first year of treatment. Mean BMI and glucose were unchanged over 4 years, while low−/high-density lipoprotein cholesterol ratio decreased. Conclusions For the first time, Swedish data from the PATRO Children and Adults studies are presented. The 10-year data suggest that biosimilar rhGH is well tolerated across pediatric and adult indications. Safety and effectiveness were similar to previous reports for other rhGH preparations. These results need to be confirmed in larger cohorts, highlighting the importance of long-term post-marketing studies.

BACKGROUND: In addition to stimulating linear growth in children, growth hormone (GH) influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. Hypothesis: There are different dose-dependent thresholds for metabolic effects in response to GH treatment. METHOD: A randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a) individualized GH dose including six different dose groups ranging from 17--100 mug/kg/day (n=87) and (b) fixed GH dose of 43 mug/kg/day (n=41). The individualized GH dose group was used for finding dose--response effects, where the effective GH dose (ED 50%) required to achieve 50% Delta effect was calculated with piecewise linear regressions. RESULTS: Different thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval) was calculated as 33(+/-24.4) mug/kg/day for [increment] left ventricular diastolic diameter (cm), 39(+/-24.5) mug/kg/day for [increment] alkaline phosphatase (mukat/L), 47(+/-43.5) mug/kg/day for [increment] lean soft tissue (SDS), 48(+/-35.7) mug/kg/day for [increment] insulin (mU/L), 51(+/-47.6) mug/kg/day for [increment] height (SDS), and 57(+/-52.7) mug/kg/day for [increment] insulin-like growth factor I (IGF-I) SDS. Even though lipolysis was seen in all subjects, there was no dose--response effect for Delta fat mass (SDS) or Delta leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial. CONCLUSIONS: Dose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.