A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist

2007 ◽  
Vol 13 (9) ◽  
pp. 1108-1113 ◽  
Author(s):  
Ian R Wilkinson ◽  
Eric Ferrandis ◽  
Peter J Artymiuk ◽  
Marc Teillot ◽  
Chantal Soulard ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Long Acting ◽  
Acting Agonist

Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand–receptor fusions

2010 ◽  
Vol 119 (11) ◽  
pp. 483-491 ◽  
Author(s):  
Eric Ferrandis ◽  
Sarbendra L. Pradhananga ◽  
Caroline Touvay ◽  
Carol Kinoshita ◽  
Ian R. Wilkinson ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Weight Gain ◽  
Repeated Administration ◽  
Pharmacokinetic Profile ◽  
The Other ◽  
Repeated Administrations ◽  
Potent Agonist ◽  
Long Acting ◽  
Acting Agonist ◽  
Immunogenic Response

A fundamental concern for all new biological therapeutics is the possibility of inducing an immune response. We have recently demonstrated that an LR-fusion (ligand–receptor fusion) of growth hormone generates a potent long-acting agonist; however, the immunogenicity and toxicity of these molecules have not been tested. To address these issues, we have designed molecules with low potential as immunogens and undertaken immunogenicity and toxicology studies in Macaca fascicularis and pharmacokinetic and pharmacodynamic studies in rats. Two variants of the LR-fusion, one with a flexible linker (GH–LRv2) and the other without (GH–LRv3), were tested. Comparison was made with native human GH (growth hormone). GH–LRv2 and GH–LRv3 demonstrated similar pharmacokinetics in rats, showing reduced clearance compared with native GH and potent agonist activity with respect to body weight gain in a hypophysectomized rat model. In M. fascicularis, a low level of antibodies to GH–LRv2 was found in one sample, but there was no other evidence of any immunogenic response to the other fusion protein. There were no toxic effects and specifically no changes in histology at injection sites after two repeated administrations. The pharmacokinetic profiles in monkeys confirmed long half-lives for both GH–LRv2 and GH–LRv3 representing exceptionally delayed clearance over rhGH (recombinant human GH). The results suggest that repeated administration of a GH LR-fusion is safe, non-toxic, and the pharmacokinetic profile suggests that two to three weekly administrations is a potential therapeutic regimen for humans.

scholarly journals Absorption, metabolism and excretion of once-weekly somapacitan, a long-acting growth hormone derivative, after single subcutaneous dosing in human subjects

2021 ◽  
pp. 106030
Author(s):  
Hans Helleberg ◽  
Mads Bjelke ◽  
Birgitte Bentz Damholt ◽  
Palle Jacob Pedersen ◽  
Michael Højby Rasmussen
Keyword(s):  
Growth Hormone ◽  
Human Subjects ◽  
Long Acting

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS AND PATIENTS TRANSITIONING FROM PEDIATRIC TO ADULT CARE

2019 ◽  
Vol 25 (11) ◽  
pp. 1191-1232 ◽  
Author(s):  
Kevin C. J. Yuen ◽  
Beverly M. K. Biller ◽  
Sally Radovick ◽  
John D. Carmichael ◽  
Sina Jasim ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Growth Hormone Deficiency ◽  
American Association ◽  
Hormone Deficiency ◽  
Insulin Like Growth Factor ◽  
Glucagon Stimulation Test ◽  
Adult Care ◽  
Stimulation Tests ◽  
Long Acting

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Methods: Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence). Conclusion: This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH–stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document. LAY ABSTRACT This updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH–stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH–stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH–stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement. Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AHSG = alpha-2-HS-glycoprotein; AO-GHD = adult-onset growth hormone deficiency; ARG = arginine; BEL = best evidence level; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CO-GHD = childhood-onset growth hormone deficiency; CPG = clinical practice guideline; CRP = C-reactive protein; DM = diabetes mellitus; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = Food and Drug Administration; FD-GST = fixed-dose glucagon stimulation test; GeNeSIS = Genetics and Neuroendocrinology of Short Stature International Study; GH = growth hormone; GHD = growth hormone deficiency; GHRH = growth hormone–releasing hormone; GST = glucagon stimulation test; HDL = high-density lipoprotein; HypoCCS = Hypopituitary Control and Complications Study; IGF-1 = insulin-like growth factor-1; IGFBP = insulin-like growth factor–binding protein; IGHD = isolated growth hormone deficiency; ITT = insulin tolerance test; KIMS = Kabi International Metabolic Surveillance; LAGH = long-acting growth hormone; LDL = low-density lipoprotein; LIF = leukemia inhibitory factor; MPHD = multiple pituitary hormone deficiencies; MRI = magnetic resonance imaging; P-III-NP = procollagen type-III amino-terminal pro-peptide; PHD = pituitary hormone deficiencies; QoL = quality of life; rhGH = recombinant human growth hormone; ROC = receiver operating characteristic; RR = relative risk; SAH = subarachnoid hemorrhage; SDS = standard deviation score; SIR = standardized incidence ratio; SN = secondary neoplasms; T3 = triiodothyronine; TBI = traumatic brain injury; VDBP = vitamin D-binding protein; WADA = World Anti-Doping Agency; WB-GST = weight-based glucagon stimulation test

Development of a long acting human growth hormone analog suitable for once a week dosing

2013 ◽  
Vol 23 (2) ◽  
pp. 402-406 ◽  
Author(s):  
Moorthy S.S. Palanki ◽  
Abhijit Bhat ◽  
Ben Bolanos ◽  
Florence Brunel ◽  
Joselyn Del Rosario ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Human Growth Hormone ◽  
Human Growth ◽  
Hormone Analog ◽  
Long Acting
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