Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults

Ku, Cheol Ryong; Brue, Thierry; Schilbach, Katharina; Ignatenko, Stanislav; Magony, Sándor; Chung, Yoon‐Sok; Kim, Byung Joon; Hur, Kyu Yeon; Kang, Hee Yoon; Kim, Jung Hee; Kim, Min Seon; Kowalska, Aldona; Bolanowski, Marek; Ruchała, Marek; Damjanović, Svetozar; Payer, Juraj; Choi, Yun Jung; Heo, Su Jin; Kim, Tae Kyoung; Heo, Min Kyu; Lee, Joon; Lee, Mi Kyung

doi:10.1530/eje-18-0185

Cited by 11 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HyTropin (Produced by Genexine and Handok of South Korea) is fused to the Fc-domain of immunoglobulin. A Phase II study in Europe demonstrated efficacy and apparent safety in adults with GH deficiency ( 187 ).…”

Section: Non-covalent Albumin Binding Ghmentioning

confidence: 99%

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future

2021

View full text Add to dashboard Cite

Since antiquity Man has been fascinated by the variations in human (and animal) growth. Stories and art abound about giants and little people. Modern genetics have solved some of etiologies at both extremes of growth. Serious study began with the pathophysiology of acromegaly followed by early attempts at treatment culminating in modern endoscopic surgery and multiple pharmacologic agents. Virtually at the same time experiments with the removal of the pituitary from laboratory animals noted the slowing or stopping of linear growth and then over a few decades the extraction and purification of a protein within the anterior pituitary that restored, partially or in full, the animal’s growth. Human growth hormone was purified decades after those from large animals and it was noted that it was species specific, that is, only primate growth hormone was metabolically active in primates. That was quite unlike the beef and pork insulins which revolutionized the care of children with diabetes mellitus. A number of studies included mild enzymatic digestion of beef growth hormone to determine if those “cores” had biologic activity in primates and man. Tantalizing data showed minimal but variable metabolic efficacy leading to the “active core” hypothesis, for these smaller peptides would be amenable to peptide synthesis in the time before recombinant DNA. Recombinant DNA changed the landscape remarkably promising nearly unlimited quantities of metabolically active hormone. Eight indications for therapeutic use have been approved by the Food and Drug Administration and a large number of clinical trials have been undertaken in multiple other conditions for which short stature in childhood is a sign. The future predicts other clinical indications for growth hormone therapy (and perhaps other components of the GH?IGF-1 axis), longer-acting analogues and perhaps a more physiologic method of administration as virtually all methods at present are far from physiologic.

show abstract

Section: Non-covalent Albumin Binding Ghmentioning

confidence: 99%

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future

2021

View full text Add to dashboard Cite

show abstract

“…A Phase 2 randomized, openlabel study was conducted in 16 endocrinology centers in Europe and Korea among 45 adult participants with growth hormone deficiency. With twice-monthly administration, the drug demonstrated comparable efficacy and acceptable tolerability without significant immunogenicity (35). The manufacturer is planning a Phase 3 study with a longer treatment period and more patients in the United States.…”

Section: Growth Hormone Fusion Proteinsmentioning

confidence: 99%

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

Lal¹,

Hoffman²

2019

Archives of Endocrinology and Metabolism

View full text Add to dashboard Cite

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.

show abstract

“…Furthermore, the rest of the Fc protein of HL2351 is engineered from the human immunoglobulin G4, which is less susceptible to antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity than other antibody isotypes . The hybrid Fc‐fusion technology has been successfully applied to other endogenous peptides and proteins such as human growth hormone and erythropoietin to extend their short half‐lives. Because the role of IL‐1ra has is well known in the blocking of the signal mediated through the IL‐1 receptor, HL2351 could be a more practical, if not a better, option than a new monoclonal antibody with a new epitope for the IL‐1 receptor, which needs to be newly developed from scratch.…”

Section: Introductionmentioning

confidence: 99%

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc‐fused interleukin‐1 receptor antagonist, in healthy subjects: A first‐in‐human study

Huh

Cho

et al. 2020

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims We performed a first‐in‐human study with HL2351, a novel hybrid Fc‐fused interleukin (IL)‐1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. Methods A randomized, double‐blind, placebo‐ and active‐controlled, dose‐escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active‐controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex‐vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL‐1β. Anti‐HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. Results HL2351 was eliminated more slowly than anakinra (terminal half‐life: 27.21–45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose‐proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL‐6 expression varied widely (range: 0–92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. Conclusion HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7‐11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

show abstract

Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults

Abstract: GX-H9 has the potential for up to twice-monthly administration.

Cited by 11 publications

References 23 publications

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future

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

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc‐fused interleukin‐1 receptor antagonist, in healthy subjects: A first‐in‐human study

Contact Info

Product

Resources

About