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GLP-1

GLP-1

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GLP-1

GLP-1 is a hormone consisting of 37 amino acids. Intact biologically active GLP-1 is dependent on GLP-1 (7-36) amide and GLP-1 (7-37). To increase the secretion of insulin and somatostatin, GLP-1 (7-36) amide and GLP-1 (7-37) bind and affect the identified GLP-1 receptor (GLP1R) on pancreatic islet β-cells, δ-cells and α-cells. Moreover, GLP-1 and GLP-1R agonists also contribute to lowering blood glucose and losing weight with a variety of extrapancreatic effects.

The half-life of human GLP-1 in body is short. So, GLP-1 analogs (as GLP-1R agonists) are developed through modifications of its structure to improve the stability of this hormone while maintaining its potency and pharmacological effects.

GLP-1 Analogs for Therapeutic Use

There are various GLP-1 receptor agonists available, including exenatide, exenatide extended-release (ER), lixisenatide, liraglutide, dulaglutide, semaglutide, and oral semaglutide. But due to declining sales, albiglutide was discontinued in 2017. In 2005, FDA approved the first GLP-1 receptor agonist, exenatide. All GLP-1 analogs except oral semaglutide (approved by the FDA in 2019) are administered subcutaneously.

In addition, semaglutide have been approved by the FDA for chronic weight management in 2021 and it has shown efficacy in weight loss studies when injected once-weekly with high-dose of 2.4 mg doses. Other GLP-1 receptor agonists, with the exception of high-dose liraglutide and semaglutide, have also been shown to have a good effect of losing weight but have not been approved by the FDA for this indication.

Name Types Structure Features
Exenatide Short-acting Exenatide is a 39-amino acid peptide amide with 53% amino acid sequence identity to human GLP-1. A key amino acid substitution at position 2 confers complete resistance to DPP-4.
Liraglutide Short-acting With 97% amino acid residue identity, Liraglutide is structurally similar to natural GLP-1 (7-37). The differences between Liraglutide and human GLP-1 are that Lys is replaced by Arg at position 28; glutamate spacer at Lys in position 20 conjugates palmitic acid. Through binding to serum albumin and self-binding in the subcutaneous space, fatty acid conjugation prolongs the duration of action.
Albiglutide Long-acting Albiglutide is a tandem fusion of two GLP-1(7-36) molecules with human serum albumin. The peptide sequence is shifted from Gly to Ala at position 8, which increases resistance to DPP-4 mediated protein aggregation. In addition, fusion of this peptide with albumin prolongs its half-life in humans by 6-8 days.
Dulaglutide Long-acting Dulaglutide is a GLP-1 (7-37) polypeptide analog consisting of recombinant DNA covalently fused to IgG Fc. The structure of dulaglutide improves solubility, reduces immunogenicity and decreases renal clearance.
Lixisenatide Short-acting Lixisenatide includes a 44-amino acid peptide with a similar structure to exenatide (differing only by one amino acid). The original exenatide sequence was extended by adding six lysine residues to the C-terminus and removing proline from the C-terminus. This modification slightly extended the half-life of exenatide to 3-4 hours, allowing it to be injected subcutaneously once a day and, more importantly, quadrupling its binding to the GLP-1 receptor.
NN9535 Long-acting As a long-acting GLP-1 agonist, semaglutide differs from liraglutide in two sites. Pos2 is replaced by Aib(U)-a modification that significantly protects it from enzymatic degradation by the DPP-4. In addition, the modified fatty acid chain and the two PEG2 intermediates have been shown to be optimal for prolonged efficacy both in vitro and in vivo.
Beinaglutide Short-acting Benalutide is a recombinant human GLP-1 polypeptide (rhGLP-1) that is almost 100% homologous to human GLP-1 (7-36).
PEG-Loxenatide Long-acting Polyethylene glycol loxenatide (PEG-Loxe) is a novel PEG linked GLP-1 analogs. Loxenatide is derived from exendin-4, with 53% homology to human GLP-1.

LY3298176

 Long-acting A dual receptor agonist targeting GLP-1 receptor and insulinotropic polypeptide (GIP) receptor.
Yaohai Bio-Pharma Offers One-Stop CDMO Solution for GLP-1
GLP-1 or GLP-1 Analogs Pipelines
Generic Name Brand Name/ Altermative name Expression System Indications Manufacturer Latest stage
Liraglutide Recombinant Saxenda,Victoza, 诺和力 Yeast (Saccharomyces cerevisiae) Cardiovascular diseases, Obesity, Overweight, Type 2 diabetes mellitus Novo Nordisk Approval
Semaglutide (Injection) Ozempic, Wegovy, 诺和泰 Yeast Type 2 diabetes mellitus, Overweight, Obesity, Heart failure, Nonalcoholic Steatohepatitis, Novo Nordisk Approval
Semaglutide (Oral) Rybelsus Yeast Type 2 diabetes mellitus, Overweight, Obesity, Alzheimer's disease Novo Nordisk Approval
Albiglutide Albugo, Eperzan, Syncria Yeast (Saccharomyces cerevisiae) Type 2 diabetes mellitus GSK Withdraw
Bydureon, Byetta Exenatide N.A. (Chemical synthesis) Type 2 diabetes mellitus Amylin Pharmaceutical,AstraZeneca Approval
Dulaglutide trulicity CHO cell Type 2 diabetes mellitus Eli Lilly Approval
Beinaglutide 谊生泰, 菲塑美 Escherichia coli (E. coli) Type 2 diabetes mellitus, Obesity , Overweight Shanghai Benemae Pharmaceutical Approval
Liraglutide Biosimilar 利鲁平 Escherichia coli (E. coli) Type 2 diabetes mellitus, Obesity, Overweight, Diabetes Hangzhou Zhongmei, Jiuyuan Gene Engineering Approval
Liraglutide Biosimilar 统博力 Pending Update Type 2 diabetes mellitus Tonghua Dongbao Approval
Ecnoglutide XW003 Escherichia coli (E. coli) Type 2 diabetes mellitus | Obesity | Nonalcoholic Steatohepatitis（nonalcoholic steatohepatitis，NASH） Sciwind Biosciences Phase III
Exendin-4 Recombinant exenatide, active substance Pending Update Type 2 diabetes mellitus Dongguan Baolijian Bioengineering Phase III
Recombinant exendin 4 UNI RE4 Pending Update Type 2 diabetes mellitus Uni-Bio Science Group Phase III
rExenatide-4 Recombinant exenatide-4, RE-4 Pending Update Type 2 diabetes mellitus CSPC Zhongqi Pharmaceutical Technology Phase III
Liraglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus SL Pharmaceutica,Protein-Way Biotechnology Phase III
Liraglutide biosimilar Pending Update Pending Update Obesity | Overweight | Type 2 diabetes mellitus Wanbang Biopharmaceuticals Phase III
Liraglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus Zhuhai United Laboratories Phase III
Semaglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus Livzon Group Phase III
Avexitide Avexitide (USAN),Avexitide acetate,Exendin 9-39 Pending Update Post-Bariatric Hypoglycemia (PBH), Congenital Hyperinsulinism (HI) Cambridge University Press, Eiger BioPharmaceuticals, Stanford University Phase II
Efinopegdutide JNJ-64565111, HM12525A, MK-6024 Pending Update Nonalcoholic Steatohepatitis | Type 2 diabetes mellitus Hanmi Pharmaceutical, MSD Phase II
Oxyntomodulin Pending Update Pending Update Type 2 diabetes mellitus, Obesity Xenetic Biosciences, Pharmsynthez PJSC Phase II
PB-1023 Glymera, GLP-1-ELP-120 Pending Update Type 2 diabetes mellitus PhaseBio harmaceuticals, ImmunoForge Phase II
Retatrutide LY 3437943 Pending Update Obesity | Overweight, Type 2 diabetes mellitus Eli Lilly Phase II
GZR-18 GZR18 Pending Update Type 2 diabetes mellitus | Obesity, Overweight Gan & Lee Pharmaceuticals  Phase I / II
E2HSA Recombinant exenatide-human serum albumin fusion protein Pending Update Diabetes Zhejiang Huayang Phase I
GLP-1 analogue fusion protein Recombinant human GLP-1 analog fusion protein, human serum albumin（HSA） Pending Update Diabetes Jiangsu T-Mab Biopharma Phase I
HB 1085 Insulinotropic Hormone Secretion Peptide Fusion Protein Pending Update Type 2 diabetes mellitus, Obesity Wuxi Hebang Phase I
Exendin-9,39 Exenatide9-39 Pending Update Diabetes | Obesity Mayo Clinic Phase I
GLP-1 Pending Update Pending Update Type 1 diabetes mellitus, Insulin Resistance University of Virginia Foundation Phase I
NN-9277 Pending Update Pending Update Overweight Novo Nordisk A/S Phase I
Oxyntomodulin peptide analogs OXM Pending Update Diabetes, Obesity Imperial College London Phase I
VTC-G15 Pending Update Pending Update Type 1 diabetes mellitus Mass General Brigham, Inc. Phase I
XW-004 Oral GLP-1 analog Pending Update Type 2 diabetes mellitus, Nonalcoholic Steatohepatitis, Obesity Sciwind Biosciences Phase I
XW-014 XW-014 Pending Update Type 2 diabetes mellitus, Nonalcoholic Steatohepatitis, Obesity Sciwind Biosciences Phase I
Liraglutide biosimilar TQZ2451 Pending Update Type 2 diabetes mellitus Chia Tai Tianqing Pharmaceutical Submit for Approval
Liraglutide biosimilar 4P-004、4P004 Pending Update Knee Arthritis 4Moving Biotech Phase I
Liraglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus Sciwind Biosciences, Etinpro Phase I
Semaglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus Chongqing Chenan Biopharmaceutical, Shanghai Bovax Biotechnology Phase I
Semaglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus Hangzhou Zhongmei Huadong, Chongqing Paijin Biotechnology Phase I
Semaglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus, Alzheimer's disease, Nonalcoholic Steatohepatitis, Obesity Zhuhai United Laboratories, Zhongshan Branch Phase I
Semaglutide Biosimilar PJ-007 Pending Update Type 2 diabetes mellitus, Obesity Huadong Medicine, Chongqing Peg-Bio Biopharma Phase I
Liraglutide biosimilar Pending Update Pending Update Type 2 diabetes mellitus Nobot Biotechnology Clinical trial Application
Semaglutide biosimilar Pending Update Pending Update Pending Update Zhuhai United Clinical trial Application

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