Faculty Bibliography

As the first wave of biopharmaceuticals is set to expire, biosimilars or follow-on protein products (FOPPs) have emerged. The regulatory foundation for these products is more advanced and better codified in Europe than in the US. Recent approval of biosimilar Somatropin (growth hormone) in Europe and the US prompted this paper. The scientific viability of biosimilar growth hormone is reviewed. Efficacy and safety data (growth rates, IGF-1 generation) for up to 7 years for pediatric indications measure up favorably to previously approved growth hormones as reference comparators. While the approval in the US is currently only for treatment of growth hormone deficiency (GHD) in children and adults, the commercial use of approved biosimilar growth hormones will allow in the future for in-depth estimation of their efficacy and safety in non-GH deficient states as well.

Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 +/- 1.5 years received a second implant. Eighteen were naïve to GnRHa therapy at first implantation. Peak LH declined from 0.92 +/- 0.58 mIU/mL at 12 months to 0.51 +/- 0.33 mIU/mL at 24 months (P < .0001) in naïve subjects, and from 0.74 +/- 0.50 mIU/mL at 12 months to 0.45 +/- 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.

OBJECTIVE:Our objective was to summarize important advances in the management of children with idiopathic short stature (ISS). PARTICIPANTS/METHODS:Participants were 32 invited leaders in the field. EVIDENCE/METHODS:Evidence was obtained by extensive literature review and from clinical experience. CONSENSUS/METHODS:Participants reviewed discussion summaries, voted, and reached a majority decision on each document section. CONCLUSIONS:ISS is defined auxologically by a height below -2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 microg/kg.d) for children shorter than -2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3-0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4-7 yr) is 3.5-7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.

PURPOSE OF REVIEW/OBJECTIVE:Approximately 100,000 infants are born small for gestational age (birth weight <2 standard deviation) annually in the US alone. Because of catch-up growth, 10-20% of all children born small for gestational age will be eligible for growth hormone therapy. Growth hormone has been approved by the Food and Drug Administration in 2003 and by the European Agency for the Evaluation of Medical Products though at different enrollment and treatment criteria. Benefits and risks of growth hormone therapy for small for gestational age children are the purpose of the present review. RECENT FINDINGS/RESULTS:Mean height increased by as much as two standard deviation over 3 years of treatment in infants born small for gestational age. Rapid catch-up growth is desirable and will only be achieved with higher growth hormone doses (0.48 mg/kg/week) Treatment should be continuous and not interrupted. The safety profile of growth hormone treatment is excellent. Transient elevation of insulin levels returned to near normal after growth hormone treatment was discontinued. SUMMARY/CONCLUSIONS:Growth hormone treatment in small for gestational age children has been found to be well tolerated and is an important advance in the treatment of short stature in pediatrics. Treatment of short prematurely born infants with growth hormone may offer similar efficacy and safety as growth hormone treatment in small for gestational age infants.

BACKGROUND: Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM: To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS: 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS: Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION: GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment

CONTEXT/BACKGROUND:GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin. OBJECTIVE:The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children. DESIGN/METHODS:This was a phase III, open-label, prospective study of 1-yr duration. SETTING/METHODS:The study was conducted at nine U.S. medical centers. PATIENTS/METHODS:Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible. INTERVENTION/METHODS:A 50-mg histrelin implant was inserted sc in the inner upper arm. MAIN OUTCOME MEASURES/METHODS:Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures. RESULTS:Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P < 0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred. CONCLUSIONS:The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.