A long‐acting pegylated recombinant human growth hormone (Jintrolong
            <sup>®</sup>
            ) in healthy adult subjects: Two single‐dose trials evaluating safety, tolerability and pharmacokinetics

Guan, Yanping; He, Fan; Wu, Junyan; Zhao, Lizi; Wang, X.; Zeng, Guangtao; Ren, Bin; Chen, J.; Liao, Xianghai; Ma, Zhenzhen; Chen, X.; Zhong, Guoping; Huang, Min; Zhao, Xin

doi:10.1111/jcpt.12732

Cited by 14 publications

(7 citation statements)

References 17 publications

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“…PEG-rhGH (Jintrolong ® ) has been recently approved for the treatment of children with GHD by China National Medical Products Administration (NMPA). Previous pharmacokinetics (PK) study showed that PEG-rhGH had a half-life of 32 ± 5 h and still maintained a high concentration (7.9 ng/ml) in circulation after five half-lives, supporting a weekly dosing schedule ( 3 ). A phase III trial in 343 children with GHD demonstrated the safety and efficacy of weekly Jintrolong ® (0.2 mg/kg/week) for 25 weeks that is non-inferior to daily rhGH (0.25 mg/kg/week).…”

Section: Introductionmentioning

confidence: 93%

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

et al. 2021

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ContextLong-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.ObjectiveWe studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.Design, Setting, and PatientsThis multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.InterventionSubjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks.Main Outcome MeasureThe primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes.ResultsAt week 26, the median HtSDSCA changed from −2.75, −2.82, and −2.78 to −2.31, −2.43, and −2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%–90.34% and 76.08%–90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups.ConclusionsAlthough notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions.Clinical Trial Registrationclinicaltrials.gov, identifier NCT02976675.

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Section: Introductionmentioning

confidence: 93%

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

et al. 2021

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“…Doses up to 0.8mg/kg were well tolerated. Pharmacokinetic profiles and plasma growth hormone concentrations supported potential for weekly administration (24).…”

Section: Pegylated Formulationsmentioning

confidence: 97%

Perspectives on long-acting growth hormone therapy in children and adults

Lal¹,

Hoffman²

2019

Archives of Endocrinology and Metabolism

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Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world.

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“…A 24-month follow-up study demonstrated that Jintrolong ® is effective, well-tolerated, and convenient to administer in Chinese children with GHD (8). Additionally, the safety, tolerability, and pharmacokinetics of Jintrolong ® in adult subjects were also evaluated to be well tolerated (22).…”

Section: Introductionmentioning

confidence: 99%

PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients

Zhou²,

et al. 2022

Front. Endocrinol.

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Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.

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A long‐acting pegylated recombinant human growth hormone (Jintrolong ^® ) in healthy adult subjects: Two single‐dose trials evaluating safety, tolerability and pharmacokinetics

Abstract: Single-dose Jintrolong injection was well tolerated in healthy adult subjects, and the maximum tolerable dose was no lower than 0.8 mg/kg. Jintrolong was long-acting with the potential for weekly administration.

Cited by 14 publications

References 17 publications

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

Perspectives on long-acting growth hormone therapy in children and adults

PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients

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A long‐acting pegylated recombinant human growth hormone (Jintrolong ® ) in healthy adult subjects: Two single‐dose trials evaluating safety, tolerability and pharmacokinetics

Abstract: Single-dose Jintrolong injection was well tolerated in healthy adult subjects, and the maximum tolerable dose was no lower than 0.8 mg/kg. Jintrolong was long-acting with the potential for weekly administration.

Cited by 14 publications

References 17 publications

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

Perspectives on long-acting growth hormone therapy in children and adults

PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients

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A long‐acting pegylated recombinant human growth hormone (Jintrolong ^® ) in healthy adult subjects: Two single‐dose trials evaluating safety, tolerability and pharmacokinetics