Faculty Bibliography

BACKGROUND:Silver-Russell syndrome (SRS) is an imprinting defect disease. This is the first study of Chinese children with SRS caused by chromosome 11p15 imprinting defects. METHODS:Twenty-five SRS cases, diagnosed in Beijing Children's Hospital from 2006 to 2012, were studied retrospectively to detect chromosome 11p15 imprinting defects. RESULTS:Over 80% of the children had (i) small for gestational age and postnatal growth retardation (mean height standard deviation score [HT SDS] was -3.56), (ii) mean body mass index (BMI) SDS was -2.10, and (iii) skeletal malformation. Chromosome 11p15 imprinting defects were examined in 16 of the 25 patients. Six had hypomethylation in chromosome 11p15 imprinting control region 1 (ICR1) of the paternal allele; one had hypomethylation in chromosome 11p15 ICR1 and hypermethylation in imprinting control region 2 (ICR2). Another patient had a duplicated maternal chromosome 11p15 fragment. Six patients had been treated with for 3-24 months. Growth rates ranged from 4 to 10.8 cm/year. CONCLUSIONS:This study demonstrated that Chinese children with SRS had more growth retardation than bone retardation, severely low levels of BMI, triangular faces, and limb asymmetry. Chromosome 11p15 imprinting defects contributed to 50% of these cases, and ICR1 hypomethylation was associated with asymmetry.

BACKGROUND:Sustained-release GH formulations may provide a strategy for improving treatment compliance and persistence in GH-deficient patients. OBJECTIVE:The aim of the study was to examine efficacy and safety of LB03002, a sustained-release GH formulation for once-weekly administration. DESIGN/METHODS:We conducted a phase III, 12-month, multinational, randomized, open-label, comparator-controlled trial with a 12-month uncontrolled extension. PATIENTS/METHODS:Prepubertal GH treatment-naive GH-deficient children (mean age, 7.8 y) participated in the study. INTERVENTION/METHODS:We administered once-weekly LB03002 (n=91) or daily GH (n=87) for 1 year, followed by once-weekly LB03002 for all patients for another year (LB03002 throughout, n=87; switched to LB03002, n=80). OUTCOME MEASURES/METHODS:Height, height velocity (HV), IGF-1, GH antibodies, and adverse events were determined throughout. Primary analysis was noninferiority of LB03002 vs daily GH at 1 year by analysis of covariance. RESULTS:Mean±SD HV during year 1 was 11.63±2.60 cm/y with LB03002, and 11.97±3.09 cm/y with daily GH, with increases from baseline of 8.94±2.91 and 9.04±3.19 cm/y, respectively. The least square mean HV difference for LB03002 - daily GH was -0.43 cm/y (99% confidence interval, -1.45 to 0.60 cm/y). Mean HV also remained above baseline in year 2 (8.33±1.92 cm/y in the LB03002 throughout group, and 7.28±2.34 cm/y in the switched to LB03002 group). Injection site reactions occurred more frequently in LB03002-treated patients but were considered mild to moderate in >90% of cases. CONCLUSIONS:Growth response with once-weekly LB03002 in GH-deficient children is comparable to that with daily GH, achieving expected growth rates for 24 months. Once-weekly LB03002 is a strong candidate for long-term GH replacement in GH-deficient children.

Close adherence to the recommended treatment regimen is important for the success of recombinant human growth hormone therapy, although nonadherence can be common. Ease of use and safety during use/storage are among several important factors in the design of a growth hormone injection device intended for long-term use. This study was performed to validate the usability and assess the ease of use of a new pen device (SurePal™) that has been developed to support daily administration of the recombinant human growth hormone product, Omnitrope® (somatropin). The primary objectives of the study were to assess if study participants, representing intended users of the pen in clinical practice, were able to perform an injection procedure into an injection pad effectively and safely and disassemble the pen without receiving a needlestick injury. A total of 106 participants (61 adults and 45 children/adolescents) were enrolled at two study centers (one in the US, one in Germany). Results for both primary usability tasks met the predefined acceptance criteria, with >85% of participants successfully performing each task. All of the other tasks/handling steps assessed were also successfully performed by most participants, with high success rates reflected in the high proportion of participants who classified each task as "very easy" or "easy". After a second use of the device, 87%-97% of participants rated it as "very easy" or "easy" to use. In summary, the new pen device is safe and easy to use for both adults and children, and will help to support effective, long-term daily administration of the recombinant human growth hormone product, Omnitrope®.

OBJECTIVES/OBJECTIVE:To study the incidence trend of type 1 diabetes mellitus (T1DM) in children in Beijing from 1995 to 2010, to compare it with incidences reported worldwide and to predict the requirement of medical resources in the future. METHODS:This study involved newly diagnosed T1DM cases younger than 15 years of age in the Beijing Children's Hospital from January 1995 to December 2010. We calculated the incidence of T1DM children in Beijing according to hospitalization data and Beijing's population. We defined it as the underestimated incidence rate (UE-IR). RESULTS:The UE-IRs of T1DM ranged from around 0.88/100,000 to 2.37/100,000 for children in Beijing younger than 15 years of age from 1995 to 2010. The UE-IR increased faster in boys (1.47 times) and in the age group of 0-4 years (1.89 times) after 2003. The UE-IR was greatest in children aged 5-9 years (1.81/100,000) followed by the age of puberty (10-14 years, 1.76/100,000). The predicted number of new T1DM cases in Beijing will increase 1.97 times over the next 10 years. CONCLUSIONS:The incidence trend of T1DM was increasing gradually in those younger than 15 years of age in Beijing. The incidence of younger children and boys grew faster. The 5- to 14-year-old children represented a high-risk population of T1DM. The number of predicted new T1DM cases will grow rapidly. This means that we should train more health care providers for pediatric diabetes patients, in order to achieve high-quality medical care and to be able to prevent or postpone chronic complications.

The term small for gestational age (SGA) refers to infants whose birth weights and/or lengths are at least two standard deviation (SD) units less than the mean for gestational age. This condition affects approximately 3%-10% of newborns. Causes for SGA birth include environmental factors, placental factors such as abnormal uteroplacental blood flow, and inherited genetic mutations. In the past two decades, an enhanced understanding of genetics has identified several potential causes for SGA. These include mutations that affect the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, including mutations in the IGF-1 gene and acid-labile subunit (ALS) deficiency. In addition, select polymorphisms observed in patients with SGA include those involved in genes associated with obesity, type 2 diabetes, hypertension, ischemic heart disease and deletion of exon 3 growth hormone receptor (d3-GHR) polymorphism. Uniparental disomy (UPD) and imprinting effects may also underlie some of the phenotypes observed in SGA individuals. The variety of genetic mutations associated with SGA births helps explain the diversity of phenotype characteristics, such as impaired motor or mental development, present in individuals with this disorder. Predicting the effectiveness of recombinant human GH (hGH) therapy for each type of mutation remains challenging. Factors affecting response to hGH therapy include the dose and method of hGH administration as well as the age of initiation of hGH therapy. This article reviews the results of these studies and summarizes the success of hGH therapy in treating this difficult and genetically heterogenous disorder.

BACKGROUND:GH treatment currently requires daily sc injections, resulting in suboptimal compliance. A GH regimen with fewer injections may offer patients and caregivers a less arduous option. LB03002 is a novel sustained-release GH formulation for once-weekly dosing. PATIENTS AND METHODS/METHODS:GH-deficient, GH-naive prepubertal children were randomized to four groups who received 0.2 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); 0.5 mg/kg/wk LB03002 for 36 months (n=13); 0.7 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); or daily GH 0.03 mg/kg/d for 24 months, switched to 0.5 mg/kg/wk LB03002 for 12 months (n = 12). RESULTS:Height velocity increased in all groups; the increase was less for the 0.2 mg/kg/wk LB03002 group at 12 (P = 0.008) and 24 months (P = 0.030), with no statistically significant differences at any time for the 0.5 mg/kg/wk and 0.7 mg/kg/wk LB03002 groups, vs. daily GH. Height sd score gain at 12 months was significantly (P = 0.023) less for the 0.2 mg/kg/wk group (1.05 ± 0.38) than daily GH (1.47 ± 0.29), but with no statistically significant difference for the 0.5 mg/kg/wk (1.37 ± 0.39) and 0.7 mg/kg/wk (1.50 ± 0.44) LB03002 groups vs. daily GH. There were no significant differences in height sd score gain between any groups at 24 and 36 months. Bone maturation did not differ for any LB03002 dose compared with daily GH. Serum IGF-I concentrations increased as expected, with no long-term differences between groups. Mean fasting glucose and glycosylated hemoglobin concentrations did not exceed normal ranges for any treatment group at any time. CONCLUSION/CONCLUSIONS:LB03002 at doses of 0.5 mg/kg/wk and 0.7 mg/kg/wk was shown to be effective and safe with once-weekly dosing in GH-deficient children, and 0.5 mg/kg/wk LB03002 was chosen as the optimal dose for long-term assessment.

As the first wave of biopharmaceuticals is expiring, biosimilars or follow-on -protein products (FOPP's) have emerged. Biosimilar drugs are cheaper than the originator/comparator drug. The regulatory foundation for these products is more advanced and better codified in Europe than in the US. Biosimilar soamtropin has been approved in both the US and Europe. The scientific viability of biosimilar drugs and especially growth hormone has been proven by several rigorously conducted clinical trials. Efficacy and safety data (growth rates, IGF-1 generation) for up to 7 y for pediatric indications measure up favorably to previously approved growth hormones which served as reference comparators. The Obama Administration appears to be committed to establish innovative pathways for the approval of biologics and biosimilars in the US. The cost savings in health care expenditures will be substantial as the global sales of biologics have reached $ 93 billion in 2009.

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.