title: Long-Acting C-Terminal Peptide–Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children Comparative pharmacokinetics and pharmacodynamics of a new sustained-release growth hormone (GH), LB03002, versus daily GH in adults with GH deficiency. Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. Circulating concentrations of insulin-like growth factor I and risk of breast cancer Three-year efficacy and safety of LB03002, a once-weekly sustained-release growth hormone (GH) preparation, in prepubertal children with GH deficiency (GHD). Somapacitan, a once‐weekly reversible albumin‐binding GH derivative, in children with GH deficiency: A randomized dose‐escalation trial Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study 24-month use of once-weekly GH, LB03002, in prepubertal children with GH deficiency.
abstract: Context Daily injections are required for growth hormone ( GH ) replacement therapy , which may cause low compliance as a result of inconvenience and distress in patients . Objective C-terminal peptide-modified human GH ( MOD-4023 ) is developed for once-a-week dosing regimen in GH-deficient ( GHD ) adults and children . The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children . Design A multicenter , open-label , r and omized , controlled phase 2 study in children with GHD , evaluating the safety , tolerability , pharmacokinetics/pharmacodynamics , and efficacy of three different weekly MOD-4023 doses , compared with daily recombinant human GH ( r-hGH ) . Setting The trial was conducted in 14 endocrinology centers in Europe . Patients Fifty-three prepubertal children with GHD completed 12 months of treatment with either MOD-4023 ( N = 42 ) or r-hGH ( N = 11 ) . Interventions C-terminal peptide-modified hGH ( MOD-4023 ) was administered weekly at a dose of either 0.25 , 0.48 , or 0.66 mg/kg/wk and compared with daily hGH at a dose of 0.24 mg/kg/wk . Results MOD-4023 showed an estimated half-life approximately fivefold to 10-fold longer when compared with daily r-hGH . Insulin-like growth factor (IGF)-I and IGF-binding peptide 3 showed a dose-dependent increase during MOD-4023 treatment . IGF-I st and ard deviation score for MOD-4023 did not exceed + 2 . All MOD-4023 cohorts demonstrated adequate catch-up growth . The 0.66 mg/kg/wk dose demonstrated efficacy closest to daily r-hGH . No serious adverse events were observed during MOD-4023 treatment , and its tolerability was consistent with known properties of r-hGH . Conclusions This study confirms the long-acting properties of MOD-4023 and shows a promising safety and tolerability profile . This provides support for initiation of a phase 3 study in GHD children using a single weekly injection of MOD-4023 Context TransCon Growth Hormone ( GH ) ( Ascendis Pharma ) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency ( GHD ) . Objective To compare the pharmacokinetics , pharmacodynamics , safety , and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD . Design R and omized , open-label , active-controlled study of three doses of weekly TransCon GH versus daily Genotropin ( Pfizer ) . Setting Thirty-eight centers in 14 European countries and Egypt . Patients Prepubertal male and female treatment-naïve children with GHD ( n = 53 ) . Interventions Subjects received one of three TransCon GH doses ( 0.14 , 0.21 , or 0.30 mg GH/kg/wk ) or Genotropin 0.03 mg GH/kg/d for 26 weeks . Main Outcome Measures GH and insulinlike growth factor-1 ( IGF-1 ) levels , growth , adverse events , and immunogenicity . Results Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses . A dose response was observed , with IGF-1 st and ard deviation scores increasing into the normal range for all three TransCon GH doses . Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm , which was not statistically different from 11.6 cm for Genotropin . Adverse events were mild to moderate , and most were unrelated to the study drug . Injection site tolerance was good . One TransCon GH subject developed a low-titer , nonneutralizing antibody response to GH . Conclusions The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH ( pharmacokinetics ) and IGF-1 ( pharmacodynamics ) levels , safety , and efficacy and support advancement into phase 3 development Background / Aims : MOD-4023 is a long-acting human growth hormone ( hGH ) in clinical trials for the treatment of growth hormone deficiency ( GHD ) . A key goal is maintenance of serum concentrations of insulin-like growth factor ( IGF ) 1 within normal range throughout GH dosing . The study aim ed to develop a pharmacokinetic model for MOD-4023 and a pharmacodynamic model for the effect of MOD-4023 on IGF-1 to allow estimation of peak and mean IGF-1 and to identify the optimal IGF-1 sampling day . Methods : MOD-4023 ( 0.25 , 0.48 , or 0.66 mg/kg ) was administered weekly for 12 months to 41 GH-naive GHD children ( age 3–11 years ) . The control group ( n = 11 , age 4–9 years ) received daily recombinant human growth hormone ( r-hGH ; 34 µg/kg ) . Sparse sample s ( 4/subject ) were obtained to determine serum concentrations of MOD-4023 or r-hGH and IGF-1 . Results : A 2-compartment pharmacokinetic model with first-order absorption fit MOD-4023 data well ; a 1-compartment model was appropriate for r-hGH . For both , weight-normalized systemic parameters were preferred over allometric scaling . For MOD-4023 , an indirect model fit IGF-1 SDS data well ; baseline IGF-1 increased over time . At steady state , sample s obtained 4 days following dose administration predicted mean IGF-1 SDS during the dosing interval well . Conclusion : The IGF-1 profile is consistent with the weekly dosing interval . Sampling 4 days following dose administration allows estimation of mean IGF-1 SDS during the dosing interval in GHD patients CONTEXT LB03002 is a novel sustained-release GH preparation administered once weekly . OBJECTIVE Our objective was to examine the pharmacokinetics , pharmacodynamics , and safety of LB03002 vs. daily GH . DESIGN AND SETTING This open-label , crossover study compared the pharmacokinetics and pharmacodynamics of LB03002 and daily GH . PATIENTS AND OTHER PARTICIPANTS Six male and three female patients with adult GH deficiency participated in the single-center study . INTERVENTION Subjects were on stable daily GH treatment  before the study . After a 4-wk washout with no GH , five weekly doses of LB03002 were given . MAIN OUTCOME MEASURE GH and IGF-I concentrations were measured during the last dose of daily GH and during the first and fifth weekly doses of LB03002 . RESULTS The observed maximal serum GH concentration was approximately doubled after LB03002 ( 6.1 + /- 3.2 and 4.5 + /- 2.2 microg/liter at first and fifth doses ) compared with daily GH ( 2.7 + /- 2.2 microg/liter ) . A sustained increase in GH concentration for more than 48 h was observed with LB03002 , such that dose-normalized area under the curve ( AUC ) was not significantly different between daily GH and LB03002 . Mean maximal serum IGF-I concentration was 34 - 41 % greater with LB03002 than with daily GH , and AUC was 7-fold greater . However , normalized to GH dose , AUC for IGF-I was comparable . Adverse events and local reactions were acceptable , and there were no evident safety concerns with LB03002 . CONCLUSIONS Multiple weekly doses of LB03002 appeared safe and well tolerated . Comparable GH bioavailability and sustained IGF-I elevations support the use of once-weekly LB03002 to replace daily GH therapy Objective We assessed the efficacy and safety of a weekly pegylated human growth hormone ( PEG-rhGH ) ( Jintrolong ) vs daily rhGH for children with growth hormone deficiency ( GHD ) . Design Phase II and III , multicenter , open-label , r and omized controlled trials . Methods 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively . Patients in the phase II study were r and omized 1:1:1 to weekly Jintrolong ( 0.1 mg/kg/week PEG-rhGH complex ) , weekly Jintrolong ( 0.2 mg/kg/week PEG-rhGH complex ) or daily rhGH ( 0.25 mg/kg/week ) for 25 weeks . Patients in the phase III study were r and omized in a 2:1 ratio to weekly Jintrolong ( 0.2 mg/kg/week ) or daily rhGH ( 0.25 mg/kg/week ) for 25 weeks . The primary endpoint for both studies was height velocity ( HV ) increase at the end of treatment . Other growth-related parameters , safety and compliance were also monitored . Results The phase II study established the preliminary efficacy , safety and recommended dose of Jintrolong PEG-rhGH . In the phase III study , we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment ( from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year ) vs daily rhGH ( from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year ) at the end of treatment ( P < 0.05 ) . Additionally , significantly greater improvement in the height st and ard deviation scores was associated with Jintrolong throughout the treatment ( P < 0.05 ) . Adverse event rates and treatment compliance were comparable between the two groups . Conclusion Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH Objective Growth hormone ( GH ) replacement therapy currently requires daily injections , which may cause distress and low compliance . C-terminal peptide (CTP)-modified growth hormone ( MOD-4023 ) is being developed as a once-weekly dosing regimen in patients with GH deficiency ( GHD ) . This study ’s objective is to evaluate the safety , pharmacokinetics ( PK ) , pharmacodynamics ( PD ) and efficacy of MOD-4023 administered once-weekly in GHD adults . Design 54 adults with GHD currently treated with daily GH were normalized and r and omized into 4 weekly dosing cohorts of MOD-4023 at 18.5 % , 37 % , 55.5 % or 123.4 % of individual cumulative weekly molar hGH dose . The study included 2 stages : Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023 . Stage B was an extension period of once-weekly MOD-4023 administration ( 61.7 % molar hGH content ) to collect further safety data and confirm the results from Stage A. Results Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment . Insulin-like growth factor I ( IGF-I ) SDS levels were maintained within normal range . The 18.5 % cohort was discontinued due to low efficacy . MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts . The reported adverse events were consistent with known GH-related side effects . Conclusions Once-weekly MOD-4023 administration in GHD adults was found to be clinical ly effective while maintaining a favorable safety profile and may obviate the need for daily injections . Weekly GH injections may improve compliance and overall outcome . The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial , which is currently ongoing BACKGROUND Insulin-like growth factor-I ( IGF-I ) is a potent mitogen for normal and neoplastic cells , whereas IGF-binding protein-3 ( IGFBP-3 ) inhibits cell growth in many experimental systems . Acromegalics , who have abnormally high levels of growth hormone and IGF-I , have higher rates of colorectal cancer . We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospect i ve case-control study nested in the Physicians ' Health Study . METHODS Plasma sample s were collected at baseline from 14916 men without diagnosed cancer .  IGF-I , IGF-II , and IGFBP-3  were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects . All P values are two-sided . RESULTS IGFBP-3 levels correlated with IGF-I levels ( r=.64 ) and with IGF-II levels ( r=.90 ) . After controlling for IGFBP-3 , age , smoking , body mass index ( weight in kg/[height in m]2 ) , and alcohol intake , men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile ( relative risk [RR]=2.51 ; 95 % confidence interval [CI]=1.15 - 5.46 ; P for trend = .02 ) . After controlling for IGF-I and other covariates , men with higher IGFBP-3 had a lower risk ( RR=0.28 ; 95 % CI=0.12 - 0.66 ; P for trend = .005 , comparing extreme quintiles ) . The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men . IGF-II was not associated with risk . CONCLUSIONS Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer BACKGROUND Insulin-like growth factor (IGF)-I , a mitogenic and antiapoptotic peptide , can affect the proliferation of breast epithelial cells , and is thought to have a role in breast cancer . We hypothesised that high circulating IGF-I concentrations would be associated with an increased risk of breast cancer . METHODS We carried out a nested case-control study within the prospect i ve Nurses ' Health Study cohort .  Plasma concentrations of IGF-I and IGF binding protein 3 ( IGFBP-3 )  were measured in blood sample s collected in 1989 - 90 . We identified 397 women who had a diagnosis of breast cancer after this date and 620 age-matched controls .  IGF-I concentrations were compared by logistic regression with adjustment for other breast-cancer risk factors . FINDINGS There was no association between IGF-I concentrations and breast-cancer risk among the whole study group . In postmenopausal women there was no association between IGF-I concentrations and breast-cancer risk ( top vs bottom quintile of IGF-I , relative risk 0.85 [ 95 % CI 0.53 - 1.39 ] ) . The relative risk of breast cancer among premenopausal women by IGF-I concentration ( top vs bottom tertile ) was 2.33 ( 1.06 - 5.16 ; p for trend 0.08 ) . Among premenopausal women less than 50 years old at the time of blood collection , the relative risk was 4.58 ( 1.75 - 12.0 ; p for trend 0.02 ) . After further adjustment for plasma IGFBP-3 concentrations these relative risks were 2.88 and 7.28 , respectively . INTERPRETATION A positive relation between circulating IGF-I concentration and risk of breast cancer was found among premenopausal but not postmenopausal women . Plasma IGF-I concentrations may be useful in the identification of women at high risk of breast cancer and in the development of risk reduction strategies . Additional larger studies of this association among premenopausal women are needed to provide more precise estimates of effect BACKGROUND GH treatment currently requires daily sc injections , result ing 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 GH-deficient , GH-naive prepubertal children were r and omized 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 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 To evaluate the safety , local tolerability , pharmacodynamics and pharmacokinetics of escalating single doses of once‐weekly somapacitan , a reversible , albumin‐binding GH derivative , vs once‐daily GH in children with GH deficiency ( GHD ) Background / Aims : To determine the optimal dose of LB03002 , a sustained-release , once-weekly formulation of recombinant human growth hormone ( rhGH ) , and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature ( ISS ) . Methods : This multicenter , r and omized , open-label , phase II study included GH-naïve , prepubertal children with ISS , r and omized to receive daily rhGH 0.37 mg/kg/week ( control , n = 16 ) , LB03002 0.5 mg/kg/week ( n = 14 ) , or LB03002 0.7 mg/kg/week ( n = 16 ) . The primary endpoint was height velocity ( HV ) change at week 26 . Results : At week 26 , the least square ( LS ) means for HV change ( cm/year ) with control , LB03002 0.5 mg/kg/week , and LB03002 0.7 mg/kg/week were 5.08 , 3.65 , and 4.38 , and the LS means for the change in height st and ard deviation score were 0.65 , 0.49 , and 0.58 , respectively . The lower bound of the 90 % confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change ( –1.72 ) satisfied the noninferiority margin ( –1.75 ) . Adverse events were generally mild and short-lived . Conclusion : A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments . LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH 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 We conducted a phase III , 12-month , multinational , r and omized , open-label , comparator-controlled trial with a 12-month uncontrolled extension . PATIENTS Prepubertal GH treatment-naive GH-deficient children ( mean age , 7.8 y ) participated in the study . INTERVENTION 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 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 c and i date for long-term GH replacement in GH-deficient children
target: Conclusions There is no evidence to support differences in the effects of long-acting GH compared with those of daily GH .
background: Purpose Long-acting growth hormone ( GH ) has been developed to address the noncompliance and decreased efficacy associated with daily GH injections .
  We aim ed to evaluate the efficacy and safety of long-acting GH replacement therapy in children with short stature .