Barbara Lippe

Long-Term Safety of Recombinant Human Growth Hormone in Children

BACKGROUND Between 1985 and 2006, the National Cooperative Growth Study (NCGS) monitored the safety and efficacy of recombinant human growth hormone (rhGH) in 54,996 children. METHODS Enrolled patients were followed until rhGH discontinuation. Investigators submitted adverse event reports for targeted events or those potentially rhGH-related. RESULTS Early concerns about de novo leukemia in patients without risk factors have not been substantiated--three observed vs. 5.6 expected in age-matched general population based on years at risk [standard incidence ratio (SIR), 0.54; 95% confidence interval (CI), 0.11-1.58]. De novo malignancies (intracranial and extracranial) were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected; SIR, 1.12; 95% CI, 0.75-1.61). Second neoplasms occurred in 49 patients, of whom 37 had irradiation for their initial tumors (including five of 16 retinoblastoma patients, three of whom had bilateral retinoblastoma) consistent with an increased risk with rhGH. Thirty-three patients developed type 1 diabetes mellitus (DM) (37 expected; SIR, 0.90; 95% CI, 0.62-1.26). Type 2 DM and nonspecified DM were reported in 20 and eight patients, respectively. Two deaths were reported in patients with Prader-Willi syndrome and five deaths from aortic dissection in patients with Turner syndrome. In patients with organic GH deficiency and idiopathic panhypopituitarism, 11 events of acute adrenal insufficiency occurred, including four deaths, consistent with a reported increased risk for adrenal insufficiency in hypopituitary patients with or without rhGH treatment. CONCLUSION After more than 20 yr, leukemia, a major safety issue initially believed associated with GH, has not been confirmed, but other signals, including risk of second malignancies in patients previously treated with irradiation, have been detected or confirmed through the NCGS. These data further clarify the events associated with rhGH and, although confirming a favorable overall safety profile, they also highlight specific populations at potential risk.

Growth Response, Near-Adult Height, and Patterns of Growth and Puberty in Patients with Noonan Syndrome Treated with Growth Hormone

CONTEXT Noonan syndrome (NS) is a heterogeneous genetic disorder characterized by short stature. SETTING The National Cooperative Growth Study (NCGS), a postmarketing observational study of recombinant human GH (rhGH)-treated children, includes a large cohort of children with NS. PATIENTS We studied NCGS-enrolled prepubertal and pubertal children with NS. MAIN OUTCOMES Baseline characteristics and growth responses in NS patients with reported near-adult height (NAH) (n = 65) were compared to patients with idiopathic GH deficiency (n = 3007) and Turner syndrome (TS; n = 1378) with reported NAH to identify factors contributing to NAH optimization in NS. RESULTS NS patients (mean enrollment age, 11.6 yr) received rhGH (mean, 0.33 mg/kg . wk) for a mean of 5.6 yr. No significant difference was observed in Delta height sd score (SDS) between NS (+1.4 +/- 0.7) and TS (+1.2 +/- 0.9). However, Delta height SDS for NS and TS differed significantly from idiopathic GH deficiency (+1.7 +/- 1.0) (P < 0.0001). Mean gain in NAH above projected was 10.9 +/- 4.9 cm (males) and 9.2 +/- 4.0 cm (females). Duration of prepubertal rhGH was an important contributor to prepubertal change in height SDS (r(2) = 0.97). Height SDS at pubertal onset highly correlated with NAH SDS (rho = 0.783; P < 0.0001). Duration of puberty highly correlated with pubertal height gain in centimeters for males (rho = 0.941) and females (rho = 0.882) (P < 0.01). No new adverse events were observed. CONCLUSIONS rhGH significantly improved height SDS for children with NS at NAH. Duration of prepubertal rhGH and height SDS at puberty were important contributors to NAH. Because starting age of the patients in this report was 11.6 yr, these data suggest that greater growth optimization is possible with earlier initiation of therapy.

Sudden Death in Prader-Willi Syndrome: Brief Review of Five Additional Cases

Eiholzer review or otherwise published. We also summarize 3 other cases that are now reported but not included in the Eiholzer paper, which brings the reported total to 18. The first is a patient who was followed in the NCGS (National Cooperative Growth Study – Genentech’s GH Phase IV Post Marketing Surveillance Study). The patient was a male with PWS who died at home at the age of 6 years and 10 months after 6 months of GHT. His height at onset of GHT was 100.6 cm, weight 24 kg and BMI 24. He received 0.8 mg Nutropin AQ (1 mg/m 2 ) daily or 0.23 mg/kg/week. His medical history included preexisting cardiomegaly and additional medical problems that were not specified. A chest X-ray and echocardiogram showed cardiomegaly and he was found to have an elevated pCO 2 prior to GHT. In addition to GH, his medication included carbamezipine and the use of nasal oxygen. It was reported that he died suddenly secondary to pulmonary hypertension and a presumed cardiac event. No height or weight data were available at the time of death and no autopsy was performed. The reporting investigator assessed the patient’s death as being unrelated to GH. Dear Sir, Growth hormone (GH) has been used for the treatment of children with PraderWilli syndrome (PWS) for at least 20 years [1] . The referral of PWS children to pediatric endocrinologists has resulted, in many regions and countries, in a consolidation of the care of PWS patients by a small group of physicians. This includes enrollment into GH safety databases, and together, these sources may provide a new window into the natural history of this condition both with and without GH treatment. Over the last few years there have been a number of reports of sudden death in PWS patients without GH treatment [2– 4] . Sudden death was first reported in association with GH in 2002 with reports of 2 patients [5, 6] . In the January 2005 issue of Hormone Research , Eiholzer reported, in the form of a Mini Review, 13 children (age ! 18 years), who died while undergoing GH therapy (GHT), including the 2 cases reported in 2002 cited above [7] . One of the patients in the Eiholzer report, patient 7, table 2, was a patient receiving a Genentech GH product in Canada, and is cited as having been published. In this letter we report on 2 additional cases from the USA that were reported to Genentech but are not mentioned in the Published online: December 12, 2006 HORMONE RESEARCH

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis.

We evaluated safety and efficacy of recombinant human growth hormone (rhGH) for improving growth, lean body mass (LBM), pulmonary function, and exercise tolerance in children with cystic fibrosis (CF) and growth restriction.

First-year response to rhGH therapy in children with CKD: a National Cooperative Growth Study Report

A clear definition of the appropriate growth response during recombinant human growth hormone (rhGH) treatment has never been established in the pediatric chronic kidney disease (CKD) population. We present here data from Genentech’s National Cooperative Growth Study (NCGS) on the first-year growth response in prepubertal children with CKD. Using NCGS data, we constructed response curves for the first year of rhGH therapy in 270 (186 males, 84 females) naïve-to-treatment, prepubertal children with CKD prior to transplant or dialysis. Data from both genders were combined because gender was not significantly related to height velocity (p = 0.51). Response to rhGH was expressed as height velocity (HV) in cm/year. Mean, mean ± 1SD, and mean − 2SD for HV during the first year of rhGH treatment as well as pretreatment HV were plotted versus age. Age-specific HV plots for rhGH-treated children with CKD are presented. At all ages, the first-year mean HV was greater than the mean pretreatment HV. The mean − 2SD for HV in children on rhGH treatment was similar to the mean pretreatment HV. These growth plots will be useful to clinicians for assessing a patient’s first-year growth response. We propose that a HV below the mean − 1SD is an inadequate response. These curves may help identify patients with a suboptimal growth response due to confounding medical factors and/or non-compliance.

Is there “seasonal” variation in height velocity in children treated with growth hormone? Data from the National Cooperative Growth Study

BackgroundGrowth rate In children is reported to have seasonal variability. There are fewer published data regarding seasonal variability while on growth hormone (GH) therapy, and none analyzing growth rate with respect to number of daylight hours.MethodsWe analyzed 11,587 3-month intervals in 2277 prepubertal children (boys ages 3–14 years, girls ages 3–12 years) with idiopathic GH deficiency from the National Cooperative Growth Study (NCGS) database. All were naive to recombinant human GH (rhGH) therapy. Data were submitted from 31 US study centers. Seasonal variation in height velocity (HV) was assumed to be associated with the average number of daylight hours during the interval of time over which HV was computed. Number of daylight hours was determined from the date of the measurement and the latitude of the study center. Other independent variables evaluated included: height standard deviation score (SDS) at the beginning of the interval, chronologic age at the beginning of the interval, time from the start of rhGH treatment to the middle of the interval, month of the year, body mass index SDS at the beginning of the interval, rhGH dose/kg, mother’s height SDS, father’s height SDS, and log base 10 of the maximum stimulated GH concentration.ResultsAll variables examined, except month of the year, correlated significantly with interval HV. There was significant “seasonal” variability at all latitudes, with summer annualized HV being greater than winter HV. This difference was greatest in the first year of therapy (0.146 cm/yr/daylight hour; P < 0.0001) but persisted in subsequent years (0.121 cm/yr/daylight hr; P < 0.0001). The difference increased with distance from the equator. Growth rate over the year was not different among the latitudes reflected in this North American study.ConclusionsThere is “seasonal” variation in growth of children on rhGH therapy that correlates with number of daylight hours. The effect is modest and is greatest in the first year of therapy. Annual growth rate appears to be equal in children among latitudes covered by the US consistent with exposure to an equal number of daylight hours over the year. The physiologic mechanism behind this seasonal variation is not yet understood.

Stimulant Medication Use and Response to Growth Hormone Therapy: An NCGS Database Analysis

Background/Aims: Determine (1) frequency of attention-deficit hyperactivity disorder (ADHD) treatment and (2) growth responses in growth hormone (GH)-treated children who are receiving ADHD medication versus GH alone. Methods: Prepubertal children with idiopathic short stature (ISS) or GH deficiency (IGHD) enrolled in Genentech’s National Cooperative Growth Study. ADHD treatment was determined by documentation of psycho-stimulant medication use at enrollment. Results: ADHD medication use increased from 0.8% (7/850) in 1985 to 5.8% (752/12,113) in 2005. First-year GH treatment response for ADHD + IGHD versus IGHD: 8.5 ± 2.0 vs. 9.4 ± 2.6 cm/year, but when adjusted for age, sex, and enrollment body mass index, the difference is clinically insignificant (–0.4 cm/year). First-year growth was similar in all ISS: 8.1 ± 1.9 versus 8.6 ± 2.1 cm/year (ADHD + ISS vs. ISS, an adjusted –0.2-cm/year difference). Conclusion: Increasing numbers of GH-treated children are taking ADHD medications and their growth responses during the first year of GH therapy are similar to those not taking ADHD medications.

Treatment of growth hormone-deficient infants with recombinant human growth hormone to near-adult height: patterns of growth.

Background/Aims: To determine adult statures and linear growth patterns of children with growth hormone deficiency (GHD) who began treatment with recombinant human growth hormone (rhGH) in infancy. Methods: Forty-seven patients with GHD in whom administration of rhGH was initiated at or before 2 years of age and who had achieved near-adult heights (NAH) were identified in the database of the Genentech National Cooperative Growth Study. Results: After beginning treatment at a mean age of 0.9 years and height of –2.3 SD, these subjects achieved mean statures of –0.6, –0.3, and –0.4 SD at 5 and 10 years of age and at NAH, respectively. In 23 patients whose parental heights were known, mean NAH was comparable to the target height. Patients with uncomplicated courses whose heights were normal or tall when spontaneous puberty occurred or was induced realized the tallest NAHs. Patients with severe prenatal or perinatal, congenital and acquired neurologic insults, sexual precocity, or associated illnesses achieved less optimal NAHs. Conclusion: A normal pattern of linear growth during childhood and adolescence and satisfactory NAHs can be achieved in the majority of patients when treatment of the GHD subject is begun during infancy.

Bioequivalence studies for three formulations of a recombinant human growth hormone: Challenges and lessons learned☆

Two bioequivalence (BE) studies in healthy volunteers comparing new formulations of the recombinant human growth hormone (rhGH) Nutropin AQ (somatropin [rDNA origin] injection; Genentech, Inc., South San Francisco, CA) with the currently marketed formulation (5 mg/mL) were conducted to extend available dosing options. All formulations were administered by subcutaneous (SC) injection ranging in volume from 0.25 to 1.0 mL depending on the formulation concentration. Study A was a 2-period crossover design to assess the BE of 5 and 10 mg/mL. The estimate for relative bioavailability (AUC(0-24 h)) was within the prespecified BE interval (0.80-1.25). However, while the C(max) estimate (1.17) was contained within the range for BE, the 90% CI (0.986-1.38) extended beyond the prespecified BE interval. As a result, Study A failed to show BE between the 5 and 10mg/mL formulations. Review of the data showed unexpected increased variability in the observed C(max). Further review of individual data suggested that in 4 subjects, the GH concentration profile of 1 of the 2 injections closely resembled the absorption kinetics of an intramuscular injection rather than an SC injection. Because study conduct may have contributed to these results, we performed a second study, Study B. This study incorporated injection technique training, a defined injection site, and a larger sample size to accommodate variability. It also included a third formulation, creating a 3-period crossover design to assess the BE of 2.5, 5, and 10 mg/mL. Study B results demonstrated BE of the new 2.5- and 10-mg/mL formulations to the reference 5-mg/mL formulation, and BE to each other, with all 90% CIs within the BE range of 0.80 to 1.25. Thus the challenge of recognizing that design issues could affect outcomes gave us the tools to perform a second study, and the positive results taught us that demonstrating BE is an issue not only of pharmacology, but also of study methodology and execution.

Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS)

BackgroundModels assessing characteristics contributing to response to recombinant human growth hormone (rhGH) response rarely address growth extremes in both years 1 and 2 or examine how children track from year to year. Using National Cooperative Growth Study (NCGS) data, we determined characteristics contributing to responsiveness to rhGH and the pattern of change from years 1 to 2.Patients and methodsHeight velocity standard deviation score (HV SDS) for 2 years for prepubertal children with idiopathic GH deficiency (IGHD) (n = 1899) and idiopathic short stature (ISS) (n = 1186) treated with similar doses for two years were computed. Group 1 = HV SDS < −1; 2 = HV SDS −1 to +1; 3 = HV SDS > +1.ResultsFor IGHD, mean age was 7.5 years and similar in all groups. Year 1 HV SDS was associated with greater body mass index (BMI) SDS, lower pre-treatment HV, baseline height SDS, greater target height SDS minus height SDS, and lower maximum stimulated GH (P <0.0001). Year 2, 172/271 (73%) in group 1 moved to either group 2 (n = 156) or 3 (n = 16). Year 2 HV SDS was associated with greater year 1 HV SDS (r = 0.045, P <0.0001), greater BMI SDS, taller parents and lower peak GH.For ISS, year 1 HV SDS was associated with greater BMI SDS and lower pre-treatment HV (P ≤0.0001). 109/169 (64%) in group 1 moved to group 2 (n = 90) or group 3 (n = 19). Greater year 2 HV SDS was related to year 1 HV SDS (r = 0.27, P <0.0001).ConclusionFor IGHD, multiple characteristics contributed to best first-year response but for ISS, best first-year HV SDS was associated only with BMI SDS and inversely with pre-treatment HV. For both GHD and ISS, year 1 HV SDS was not a strong enough predictor of year 2 HV SDS to use first-year HV alone to determine GH continuation.