Long-Acting C-Terminal Peptide–Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children

Zelinska, Nataliya; Iotova, Violeta; Skorodok, Julia; Malievsky, Oleg; Peterkova, Valentina; Самсонова, Л. Н.; Rosenfeld, Ron G.; Zadik, Zvi; Jaron-Mendelson, Michal; Koren, Ronit; Amitzi, Leanne; Raduk, Dmitri; Hershkovitz, Oren; Hart, Gili

doi:10.1210/jc.2016-3547

Cited by 49 publications

(52 citation statements)

References 22 publications

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“…Our PEG-rhGH’s molecular weight is 58–66 kDa (14). The treatment dosage of the long-acting weekly PEG-rhGH is not equivalent to a simple accumulation of daily dosage of the daily rhGH, and it has been suggested that for a long-acting rhGH formula, comparing its biological/physiological effects with those of daily rhGH would be more appropriate than a simple molar comparison (19). The long-term efficacy of PEG-rhGH in children with GHD needs to be explored further to assess its potential superiority.…”

Section: Discussionmentioning

confidence: 99%

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Luo

Hou

et al. 2017

European Journal of Endocrinology

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ObjectiveWe 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).DesignPhase II and III, multicenter, open-label, randomized controlled trials.Methods108 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 randomized 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 randomized 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.ResultsThe 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 standard deviation scores was associated with Jintrolong throughout the treatment (P < 0.05). Adverse event rates and treatment compliance were comparable between the two groups.ConclusionJintrolong 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.

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Section: Discussionmentioning

confidence: 99%

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Luo

Hou

et al. 2017

European Journal of Endocrinology

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“…Other inclusion and exclusion criteria are reported by Zelinska et al [5]. Children (Tables 1, 2) were randomized to 1 of 3 weekly doses of MOD-4023 (0.25, 0.48, or 0.66 mg/kg weekly; n = 41; 27 boys, 14 girls) or daily r-hGH (Genotropin, 0.034 mg/kg/day; n = 11; 8 boys, 3 girls).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children

Fisher¹,

Rosenfeld²,

Jaron-Mendelson³

et al. 2017

Horm Res Paediatr

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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 aimed 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 samples (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, samples 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.

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“…The dose selection for this study was based on previous nonclinical and clinical studies . The data obtained from a phase 1 study in healthy adult men, a phase 2 study in adults with GHD, and a phase 2 study in GHD children provided a favorable safety profile and confirmed the adequacy of a weekly regimen of MOD‐4023, as reflected by normalizing IGF‐1 standard deviation score (SDS) values. The average effective dose that was shown to maintain adult men with GHD within the IGF‐1 SDS normal range was 2.5 mg. On the basis of these results and assuming a similar response in the Japanese population, the lowest dose in the present study (2.5 mg) was also used as the initial dose in an ongoing phase 3 study in GHD adults, whereas the middle and high doses potentially provided 3‐ and 6‐fold exposure margins, respectively, over the initial clinical dose.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Safety of a Long‐Acting Human Growth Hormone (MOD‐4023) in Healthy Japanese and Caucasian Adults

Kramer

Jaron-Mendelson²,

Koren³

et al. 2017

Clinical Pharm in Drug Dev

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Daily injections of growth hormone (GH) as replacement therapy in GH-deficient (GHD) patients may cause poor compliance and inconvenience. C-terminal peptide-modified human GH (MOD-4023) has been developed for once-weekly administration in GHD adults and children. In the present study, the pharmacokinetics (PK) and pharmacodynamics (PD) of a single subcutaneous dose of MOD-4023 were evaluated in healthy Caucasian and Japanese adults, using a phase 1 double-blind, vehicle-controlled, randomized study design. The study was conducted in 42 healthy Japanese (n = 21) and Caucasian (n = 21) men receiving either MOD-4023 at a dose of 2.5, 7.5, or 15 mg or vehicle. In the 2.5-and 7.5-mg cohorts, no differences in mean MOD-4023 serum concentration were found between Japanese and Caucasian subjects. A comparison of PK parameters in the 15-mg group suggests a slower absorption rate of MOD-4023 in Japanese subjects. PD analysis showed no apparent differences in IGF-1 and IGFBP-3 plasma concentrations between the Japanese and Caucasian subjects and indicated that a dose of 15 mg achieved the maximal effect in both ethnic groups. MOD-4023 demonstrated a favorable safety profile and local tolerance following single-dose subcutaneous administration. This study provides additional support for the development of MOD-4023 as a long-acting human growth hormone formulation for once-weekly administration. Keywords insulin-like growth factor 1 (IGF-1), growth hormone deficiency (GHD), weekly GH, Japanese, MOD-4023Growth hormone deficiency (GHD) leads to inadequate levels of circulating insulin-like growth factor-1 (IGF-1) and, in children, to abnormal linear growth. GHD in adults results in decreased lean body mass, increased fat mass, weakness, reductions in exercise capacity, muscle mass/strength, cardiac performance, bone density, and neuropsychological disturbances. 1,2Growth hormone (GH) replacement therapy has been the standard of care for more than 50 years in tens of thousands of patients and has proved to be safe and effective.3,4 The majority of currently available human growth hormone (hGH) products require daily subcutaneous injections to maintain hGH blood levels within the effective therapeutic window. The main therapeutic aim of growth hormone treatment in children with GHD is to enable short children to achieve normal height, whereas the goal of replacement therapy in adults is to correct the metabolic, functional, and psychological abnormalities associated with adult GHD. The recommended starting dose of GH in young men and women is 0.2 and 0.3 mg/day, respectively (or 0

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Long-Acting C-Terminal Peptide–Modified hGH (MOD-4023): Results of a Safety and Dose-Finding Study in GHD Children

Abstract: 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.

Cited by 49 publications

References 22 publications

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies

Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children

Pharmacokinetics, Pharmacodynamics, and Safety of a Long‐Acting Human Growth Hormone (MOD‐4023) in Healthy Japanese and Caucasian Adults

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