Albiglutide

Last updated
Albiglutide
Clinical data
Trade names Eperzan (Europe), Tanzeum (US)
Other namesGSK-716155
AHFS/Drugs.com tanzeum
License data
Routes of
administration 		Subcutaneous (SC)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding Probably none
Metabolism Most likely proteolysis
Elimination half-life 5 (4–7) days
Identifiers
CAS Number
PubChem SID
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C3232H5032N864O979S41
Molar mass 72971.34 g·mol−1

Albiglutide (trade names Eperzan in Europe and Tanzeum in the US) is a glucagon-like peptide-1 agonist (GLP-1 agonist) drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. [1] GSK has announced that it intends to withdraw the drug from the worldwide market by July 2018 for economic reasons.

Contents

Medical uses

Albiglutide is used for the treatment of type 2 diabetes in adults. It can be used alone (if metformin therapy is ineffective or not tolerated) or in combination with other antidiabetic drugs, including insulins. [2]

According to a 2015 analysis, albiglutide is less effective than other GLP-1 agonists for lowering glycated hemoglobin (HbA1c, an indicator for long-term blood glucose control) and weight loss. It also seems to have fewer side effects than most other drugs of this class, except for reactions at the injection site which are more common under albiglutide than, for example, under liraglutide. [3]

Contraindications

The US approval lists the thyroid C cell cancers medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN 2) as contraindications because other GLP-1 agonists are known to cause such cancers in rodents. Albiglutide causes immunogenicity in rodents, so its cancer risk could not be assessed. [4] The European approval mentions the uncertainty about C cell cancers, but not as a contraindication. [2]

Side effects

Common side effects (in more than 10% of patients) in clinical trials were diarrhoea, nausea, and, unsurprisingly, hypoglycaemia (low blood glucose levels) and reactions at the injection site. Upper respiratory tract infections were also common, but only slightly more so than under placebo. Uncommon but potentially severe side effects included acute pancreatitis (in 0.3% of patients) and hypersensitivity reactions (in fewer than 0.1%). [2] [4]

Interactions

No clinically relevant interactions have been found in studies with a number of drugs that are known for their interaction potential (simvastatin, warfarin, digoxin, and oral contraceptives). Nonetheless, since albiglutide slows gastric emptying, it could conceivably increase absorption of other drugs if taken at the same time. [2] [4]

Pharmacology

Mechanism of action

Albiglutide acts as an agonist at the GLP-1 receptor, which makes it a type of incretin mimetic. This causes an increase of insulin secretion, predominantly in the presence of high blood glucose, and also slows down gastric emptying. [2]

Unlike other GLP-1 agonists, due to its structure it has difficulty in crossing the blood-brain barrier. This means that it does not affect the central nervous system as much as other GLP-1 agonists and may be responsible for the limited weight loss seen in the drug. [5]

Pharmacokinetics

Following subcutaneous injection, albiglutide reaches highest blood concentrations after three to five days. Steady-state concentrations are achieved after three to five weeks. The substance is most likely broken down by protease enzymes to small peptides and amino acids. [2] Being resistant to dipeptidyl peptidase-4 (DPP-4), [4] the enzyme that breaks down GLP-1, albiglutide has a biological half-life of five (four to seven) days, which is considerably longer than the older GLP-1 analogs exenatide and liraglutide. [6] [7] This allows for a once-weekly administration, [2] unlike liraglutide but like the extended-release form of exenatide.

Chemistry

Albiglutide is a peptide consisting of 645 proteinogenic amino acids with 17 disulfide bridges. Amino acids 1–30 and 31–60 constitute two copies of modified human GLP-1, the alanine at position 2 having been exchanged for a glycine for better DPP-4 resistance. [4] The remaining sequence is human albumin. The complete sequence is

HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR (2 copies of modified GLP-1, modifications underlined) DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA KTCVADESAE (albumin starts at the beginning of this line) NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY EIARRHPYFY APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK ASSAKQRLKC ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK VHTECCHGDL LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI AEVENDEMPA DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD YSVVLLLRLA KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ NCELFEQLGE YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH PEAKRMPCAE DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA LEVDETYVPK EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT KEQLKAVMDD FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGL

with disulfide bridges linking amino acids 113-122, 135-151, 150-161, 184-229, 228-237, 260-306, 305-313, 325-339, 338-349, 376-421, 420-429, 452-498, 497-508, 521-537, 536-547, 574-619, 618-627. [2] [8]

Synthesis

It is bioengineered in the yeast Saccharomyces cerevisiae using recombinant DNA technology. [2]

History

The drug was invented by Human Genome Sciences and was developed in collaboration with GSK. [9]

GSK filed for US FDA approval on 14 January 2013 and for European Medicines Agency (EMA) approval on 7 March 2013. In March 2014, GSK received approval from the European Commission to market albiglutide under the name Eperzan. [10] In April 2014, the US FDA approved albiglutide under the name Tanzeum. [11]

In August 2017, GSK announced that it intended to withdraw the drug from the worldwide market by July 2018 for economic reasons. [12]

Related Research Articles

Drugs used in diabetes treat diabetes mellitus by decreasing the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Glucose-dependent insulinotropic polypeptide</span> Mammalian protein found in Homo sapiens

Glucose-dependent insulinotropic polypeptide, abbreviated as GIP, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion.

Enteroglucagon is a peptide hormone derived from preproglucagon. It is a gastrointestinal hormone, secreted from mucosal cells primarily of the colon and terminal ileum. It consists of 37 amino acids. Enteroglucagon is released when fats and glucose are present in the small intestine; which decrease the motility to allow sufficient time for these nutrients to be absorbed.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin twice daily or once weekly.

<span class="mw-page-title-main">Dipeptidyl peptidase-4 inhibitor</span> Enzyme blocker and diabetes treatment drug

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone Involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Saxagliptin</span> Chemical compound

Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Amylin Pharmaceuticals</span> Biopharmaceutical company

Amylin Pharmaceuticals is a biopharmaceutical founded in 1987 that was based in San Diego, California. The company was engaged in the discovery, development, and commercialization of drug candidates for the treatment of diabetes, obesity, and other diseases. Amylin produced three drugs: Symlin, Byetta (exenatide) and Bydureon.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand names Victoza and Saxenda among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, are a class of drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

Taspoglutide is a former experimental drug, a glucagon-like peptide-1 agonist, that was under investigation for treatment of type 2 diabetes and being codeveloped by Ipsen and Roche.

Lixisenatide is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It was developed by Novo Nordisk in 2012 and approved for use in the US in 2017. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic (injectable) and Rybelsus (pill) for diabetes, and under the brand name Wegovy for weight loss.

Insulin degludec/liraglutide, sold under the brand name Xultophy, is a fixed-dose combination medication for the treatment of adults with type 2 diabetes to improve glycemic control in combination with diet and exercise. It contains insulin degludec and liraglutide. It is administered by subcutaneous injection.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic medication

Tirzepatide, sold under the brand name Mounjaro among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered through subcutaneous injection.

Glucagon receptor agonists are a class of drugs under development for the treatment of obesity, non-alcoholic fatty liver disease, and congenital hyperinsulinism.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

References

  1. ↑ Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, et al. (June 2017). "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis". BMJ. 357: j2499. doi:10.1136/bmj.j2499. PMC   5463186 . PMID   28596247.
  2. 1 2 3 4 5 6 7 8 9 "Eperzan: EPAR — Product Information" (PDF). European Medicines Agency. 2017-08-04.
  3. ↑ Madsbad S (April 2016). "Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists". Diabetes, Obesity & Metabolism. 18 (4): 317–332. doi:10.1111/dom.12596. PMC   5064617 . PMID   26511102.
  4. 1 2 3 4 5 "Tanzeum". Drugs.com .
  5. ↑ Yu M, Benjamin MM, Srinivasan S, Morin EE, Shishatskaya EI, Schwendeman SP, Schwendeman A (May 2018). "Battle of GLP-1 delivery technologies". Advanced Drug Delivery Reviews. 130: 113–130. doi:10.1016/j.addr.2018.07.009. PMC   6843995 . PMID   30009885.
  6. ↑ Matthews JE, Stewart MW, De Boever EH, Dobbins RL, Hodge RJ, Walker SE, et al. (December 2008). "Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes". The Journal of Clinical Endocrinology and Metabolism. 93 (12): 4810–4817. doi: 10.1210/jc.2008-1518 . PMID   18812476.[ permanent dead link ]
  7. ↑ Baggio LL, Drucker DJ (2008). "Glucagon-like Peptide-1 Analogs Other Than Exenatide".
  8. ↑ KEGG: Albiglutide.
  9. ↑ Matthew Herper for Forbes. 16 July 2012. Three Lessons From GlaxoSmithKline's Purchase Of Human Genome Sciences
  10. ↑ Gallivan R, Plumridge H (26 March 2014). "Glaxo Gets EU Marketing Approval for Diabetes Drug Eperzan". Wall Street Journal.
  11. ↑ Busko M (15 April 2014). "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide". Medscape.
  12. ↑ "Typ-2-Diabetes: Albiglutid geht weltweit vom Markt" [Type 2 diabetes: Albiglutide is being withdrawn from the market worldwide]. Pharmazeutische Zeitung Online (in German). 2017-08-02.
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