Albiglutide

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.

Albiglutide
Clinical data
Trade namesEperzan (Europe), Tanzeum (US)
Other namesGSK-716155
AHFS/Drugs.comtanzeum
License data
Routes of
administration		Subcutaneous (SC)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingProbably none
MetabolismMost likely proteolysis
Elimination half-life5 (4–7) days
Identifiers
CAS Number
PubChem SID
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC3232H5032N864O979S41
Molar mass72971.34 g·mol−1

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]

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.[5][6] 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][7]

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.[8]

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.[9] In April 2014, the US FDA approved albiglutide under the name Tanzeum.[10]

In August 2017, GSK announced that it intended to withdraw the drug from the worldwide market by July 2018 for economic reasons.[11]

References
  1. Liu, J; Li, L; Deng, K; Xu, C; Busse, JW; Vandvik, PO; Li, S; Guyatt, GH; Sun, X (8 June 2017). "Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis". BMJ (Clinical Research Ed.). 357: j2499. doi:10.1136/bmj.j2499. PMC 5463186. PMID 28596247.
  2. "Eperzan: EPAR — Product Information" (PDF). European Medicines Agency. 2017-08-04.
  3. Madsbad, S (2015). "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. Drugs.com: FDA Professional Drug Information on Tanzeum.
  5. Matthews JE, Stewart MW, De Boever EH, 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". J. Clin. Endocrinol. Metab. 93 (12): 4810–4817. doi:10.1210/jc.2008-1518. PMID 18812476.
  6. Baggio; et al. (2008). "Glucagon-like Peptide-1 Analogs Other Than Exenatide".
  7. KEGG: Albiglutide.
  8. Matthew Herper for Forbes. 16 July 2012. Three Lessons From GlaxoSmithKline's Purchase Of Human Genome Sciences
  9. "Glaxo Gets EU Marketing Approval for Diabetes Drug Eperzan". Wall Street Journal. 26 March 2014.
  10. "FDA Approves Weekly Injectable Diabetes Drug: Albiglutide".
  11. "Typ-2-Diabetes: Albiglutid geht weltweit vom Markt". Pharmazeutische Zeitung Online (in German). 2017-08-02.
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