Faculty Bibliography

OBJECTIVE:Two strengths of a novel ready-to-use liquid preparation of the recombinant human GH (rhGH) Omnitrope were developed to increase the convenience for the patients. DESIGN/METHODS:Omnitrope 3.3 mg/ml solution or Omnitrope 6.7 mg/ml solution was compared to Omnitrope 5 mg/ml powder and Genotropin 5 mg/ml powder in terms of pharmacokinetics, pharmacodynamics, safety, and local tolerance after a single s.c. dose of 5 mg. METHODS:Two randomized, double-blind, single-dose, three-way crossover studies were carried out in 36 young healthy volunteers each. Endogenous GH secretion was suppressed with a 25-h continuous i.v. infusion of octreotide (40 microg/h) starting 1 h before rhGH administration. RESULTS:Pharmacokinetic parameters were similar for the three treatments in both studies respectively. Bioequivalence criteria were met for area under the concentration-time curve (AUC) and C(max). Likewise, the pharmacodynamic parameters for IGF1, IGF-binding protein 3, and non-esterified fatty acid were similar for all preparations. No differences in adverse events were observed between groups. CONCLUSIONS:Omnitrope 3.3 mg/ml solution, 6.7 mg/ml solution, and 5 mg/ml powder, and Genotropin 5 mg/ml powder are bioequivalent, have similar pharmacokinetic and pharmacodynamic profiles, and are equally safe. Overall, the products can be considered to be therapeutically interchangeable.

OBJECTIVE:LB03002 is a novel, sustained-release recombinant human GH, developed for once-a-week s.c. injection. To evaluate the suitability for long-term GH replacement therapy in children with GH deficiency (GHD), the present study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of LB03002 at three doses. STUDY DESIGN AND PATIENTS/METHODS:The randomised, comparator-controlled, assessor-blinded, phase II study assessed 37 (24 boys, 13 girls) pre-pubertal, GH-naïve children with GHD, in 11 European centres, for PK and PD analyses. GH, IGF1 and IGFBP3 concentrations were measured following the last daily GH dose and the first and 13th once-a-week administration of LB03002 at doses of 0.2, 0.5 or 0.7 mg/kg. RESULTS:GH C(max) values after the three doses of LB03002 were increased up to fourfold, with a clear dose proportionality. For each LB03002 dose, GH area under the concentration versus time curve did not increase from the first to 13th (month 3) administration, indicating no accumulation of circulating GH. IGF1 C(max) showed a progressive increase during LB03002 administration. Conversely, IGFBP3 showed a rapid increase in C(max). IGF1 SDS were fully normalised after 3 months of treatment, whereas IGFBP3 SDS were already in the normal range for all the three LB03002 dosages after 1 week. CONCLUSIONS:At the doses used, LB03002 has a suitable profile for long-term treatment to promote growth in children with GHD. The quantitative changes in IGF1 and IGFBP3 indicate adequate stimulation of the IGF system by LB03002 and the pattern of increase is comparable with that seen in GHD children in a standard IGF1 generation test using daily GH.

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.

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.

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.