Faculty Bibliography

Recombinant human growth hormone (rhGH) has been in clinical use for more than 30 years. With the expiration of patent exclusivity for the first wave of rhGH products and other biopharmaceuticals, the opportunity emerged for the development of biosimilar medicines. A biosimilar is defined by the European Medicines Agency (EMA) as a biological medicine that is similar to another biological medicine that has already been authorized for use. The EMA led the way (well ahead of the Food and Drug Administration in the US) in developing the biosimilar concept, and the type of science-based regulatory framework required to ensure high-quality, safe, and effective biosimilar medicines; the provisions for approval of biosimilars have been in place in Europe since 2005. Under these provisions, Omnitrope^® was approved by the EMA in 2006 as the world's first biosimilar medicine; 2016 therefore marks the 10th anniversary of its approval in Europe. A substantial data set, based on clinical development studies and 10 years of postapproval use, has now accumulated for biosimilar rhGH; this data set shows that the product is an effective treatment option for children who require rhGH treatment, and has a safety profile that is consistent with the rhGH class. The decade since the EMA approved biosimilar rhGH has seen the successful approval and clinical use of 20 biosimilar medicines, confirming the integrity of the scientific basis for the biosimilar concept, as well as the quality of regulatory decision-making.

OBJECTIVE:The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). PARTICIPANTS/METHODS:A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. EVIDENCE/METHODS:Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. CONSENSUS PROCESS/METHODS:Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. CONCLUSIONS:LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.

After the introduction of recombinant human growth hormone (rhGH) in 1985, a myriad of children and adults have benefited from its growth-promoting and metabolic effects. Nowadays, current therapeutic regimens rely on daily subcutaneous GH injections that could be burdensome and inconvenient to pediatric patients. As expected with any long-term parenteral pharmacological treatment, these daily regimens may promote nonadherence, poor compliance, treatment abandonment and/or suboptimal clinical outcomes. In order to improve patient and caregiver acceptance of proposed regimens, simplified dosing schedules could potentially aid in reducing poor compliance and maximize the therapeutic end results. Long-acting GH formulations have been designed and perfected over the last two decades, and currently there are several formulations in advanced stages of research as a reasonable attempt to improve patient's adherence to GH treatment. A long-acting GH preparation allowing for reduced injection frequency is likely to improve treatment adherence and to decrease the distress and inconvenience associated with daily injections. This review presents an update about the status of current and recent efforts that have enabled the formulation of sustained-release, long-acting rhGH as it has been longed for many years in the pediatric endocrinology field.

CONTEXT/BACKGROUND:Iodide (I(-)), an essential constituent of the thyroid hormones, is actively accumulated in the thyroid by the Na(+)/I(-) symporter (NIS), a key plasma membrane protein encoded by the slc5a5 gene. Mutations in slc5a5 cause I(-) transport defects (ITDs), autosomal-recessive disorders in which I(-) accumulation is totally or partially impaired, leading to congenital hypothyroidism. The characterization of NIS mutants has yielded significant insights into the molecular mechanism of NIS. OBJECTIVE:This study aimed to determine the basis of a patient's ITD clinical phenotype, by sequencing her slc5a5 gene. DESIGN/METHODS:Genomic DNA was purified and the slc5a5 gene sequence determined. Functional in vitro studies were performed to characterize the V270E NIS mutant. PATIENT/METHODS:The index patient was diagnosed with hypothyroidism with minimal radioiodide uptake in a normally located, although enlarged, thyroid gland. RESULTS:We identified a new NIS mutation: V270E. The patient had the compound heterozygous NIS mutation R124H/V270E. R124H NIS has been characterized previously. We show that V270E markedly reduces I(-) uptake via a pronounced (but not total) impairment of the protein's plasma membrane targeting. Remarkably, V270E is intrinsically active. Therefore, a negative charge at position 270 interferes with NIS cell surface trafficking. The patient's minimal I(-) uptake enabled sufficient thyroid hormone biosynthesis to prevent cognitive impairment. CONCLUSIONS:A nonpolar residue at position 270, which all members of the SLC5A family have, is required for NIS plasma membrane targeting.

INTRODUCTION/BACKGROUND:This study was conducted using an integrated retrospective database to evaluate the effectiveness of Omnitrope(®) (Sandoz) on children with growth hormone deficiency (GHD), idiopathic short stature (ISS), and Turner Syndrome (TS) who switched from a non-Omnitrope recombinant human growth hormone (rhGH) preparation during routine clinical care. METHODS:This was a retrospective study which identified patients with GHD, ISS, and TS during the study time period of January 1, 2006 and July 31, 2011. Patients were included if they switched to Omnitrope from another non-Omnitrope rhGH therapy during the study time period, were <18 years of age at time of switch, and on a prior rhGH therapy for at least 15 months pre-switch and on Omnitrope for 15 months post-switch. Auxological parameters (height, height standard deviation score [HSDS], height velocity [HV], and height velocity standard deviation score [HVSDS]) were evaluated during post-switch. RESULTS:One hundred and three patients were identified: GHD (n = 57), ISS (n = 26), and TS (n = 20). There was continuous growth in height for all 103 patients with an average rate of 6.52 cm over the 15-month post-switch period. Patients with GHD grew an average rate of 6.30 cm, patients with ISS grew an average rate of 6.58 cm, and patients with TS grew an average rate of 6.52 cm over the 15-month post-switch period. The average rate of HSDS was increased by 0.04 for all patients. The HV and HVSDS demonstrated the expected decline with advancing age and prolonged duration of treatment. CONCLUSIONS:The growth trajectories of rhGH-treated patients were not negatively impacted by switching to Omnitrope and growth rates remained as expected prior to the switch.

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.