Lixisenatide

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Lixisenatide
Clinical data
Trade names Lyxumia (Europe), Adlyxin (US)
License data
Routes of
administration
Subcutaneous injection
ATC code A10BX10 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Identifiers
CAS Number 827033-10-3
PubChem (CID) 16139342
IUPHAR/BPS 7387
ChemSpider 17295846
ChEBI CHEBI:85662
Chemical and physical data
Formula C215H347N61O65S
Molar mass 4858.49 g/mol
3D model (Jmol) Interactive image

Lixisenatide (trade name Lyxumia in the Europe and Adlyxin in the U.S.) is a once-daily injectable GLP-1 receptor agonist for the treatment of diabetes type II.

Medical use[edit]

Lixisenatide is used as adjunct to diet and exercise to treat diabetes type II.[1] In Europe, its use is limited to complementing insulin therapy.[2] It is provided in an autoinjector containing fourteen doses and is injected subcutaneusly.[1]

Lixisenatide should not be used for people who have problems with stomach emptying.[1]

Lixisenatide delays emptying of the stomach, which may change how quickly other drugs that are taken by mouth take effect.[1]

The drug has not been studied in pregnant women well enough to draw conclusions and it is unknown if lixisenatide is secreted in breast milk; in animal studies the drug harmed the fetus of pregnant animals.[1]

Adverse effects[edit]

In about .1% of cases people have had anaphylactic reactions to lixisenatide and in about .2% of cases the drug has caused pancreatitis.[1] Use with insulin or sulfonylurea may cause hypoglycemia.[1] In some cases, people with no kidney disease have had acute kidney injury and in some people with existing kidney disease the condition has gotten worse.[1] Because lixisenatide is a peptide people can and do develop an immune response to it that will eventually make the drug ineffective; people who have developed antibodies to lixisenatide tend to have more inflammation at the injection site.[1]

At least 5% of people had nausea, vomiting, diarrhea, headache, or dizziness after taking lixisenatide.[1]

Mechanism of action[edit]

Lixisenatide is a member of the class of Glucagon-like peptide-1 receptor agonist drugs, each of which activates the GLP-1 receptor. GLP-1 is a hormone that helps pancreatic beta cells to secrete insulin in response to high blood sugar. Because it works like the normal hormone, insulin is only secreted when blood sugar is high. Like GLP-1, it also slows gastric emptying.[2]

Chemistry[edit]

Lixisenatixe is a peptide made of 44 amino acids, with an amide group on its C terminus.[1]

has been described as "des-38-proline-exendin-4 (Heloderma suspectum)-(1–39)-peptidylpenta-L-lysyl-L-lysinamide", meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, that was isolated from the Gila monster venom, omitting proline at position 38 and adding six lysine residues. Its complete sequence is:[3]

H–HisGlyGlu–Gly–ThrPhe–Thr–SerAspLeu–Ser–LysGlnMet–Glu–Glu–Glu–AlaValArg–Leu–Phe–Ile–Glu–Trp–Leu–Lys–Asn–Gly–Gly–Pro–Ser–Ser–Gly–Ala–Pro–Pro–Ser–Lys–Lys–Lys–Lys–Lys–Lys–NH2

History[edit]

It was created by Zealand Pharma A/S of Denmark;[4] in 2003 Zealand licensed it to Sanofi which developed the drug.[5] Lixisenatide was approved by the European Commission on February 1, 2013.[2] Sanofi submitted an NDA in the US, which was accepted for review by the US FDA in February 2013[6] but after discussions with the FDA about the cardiovascular safety data included in the package (starting in 2008, the FDA had required stronger CV safety data for new anti-diabetes drugs, following the controversy around the risks of Avandia)[7] Sanofi decided to withdraw the NDA and wait for the results of a Phase III study that was scheduled to be completed in 2015.[8][9] Because the drug was the first GLP-1 agonist that could be taken once a day, sales projections in 2013 were €500M per year by 2018.[9] Sanofi resubmitted the application which the FDA accepted in September 2015, by which time Sanofi had lost the lead in the field of anti-diabetic drugs to Novo Nordisk.[10] Lixisenatide received FDA approval on July 28, 2016.[11]

In 2010, Zeland and Sanofi extended their license agreement to allow Sanofi to develop a combination therapy of lixisenatide with insulin glargine, which was Sanofi's best selling drug at the time, with sales of around €3 billion in 2009.[12] Sanofi planned to start the Phase III trial that year.[12] Sanofi submitted the NDA in December 2015 for the combination, called LixiLan and it was considered by the same Endocrinologic and Metabolic Drugs Advisory FDA Committee that was considering lixisenatide as a single agent.[13][14] In May 2016 by a vote of 12-2, with several members of the committee expressing reservations about Sanofi's plans to offer two pens with different ratios of insulin glargine and lixisenatide - one for people who had never taken insulin before and one for people who had; there was also concern about how to handle dosing when switching people from a single drug regimen to the combination drug.[13][15][16] In August 2016 the FDA told Sanofi that it was delaying a final decision for three months, and asked Sanofi for more data on how people used the delivery devices.[17]

Patent protection for lixisenatide expires in 2020.[18]

References[edit]

  1. ^ a b c d e f g h i j k "US Lixisenatide label" (PDF). FDA. July 2016. Retrieved September 21, 2016. 
  2. ^ a b c "Lyxumia 10 micrograms solution for injection - Summary of Product Characteristics (SPC)". UK Electronic Medicines Compendium. 2 May 2016. Retrieved 21 September 2016. 
  3. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 61" (PDF). WHO Drug Information. 23 (1): 66f. 2009. 
  4. ^ Christensen, M; Knop, FK; Holst, JJ; Vilsboll, T (2009). "Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus". IDrugs : the investigational drugs journal. 12 (8): 503–13. PMID 19629885. 
  5. ^ Terry, Mark (November 5, 2015). "In Attempt to Bolster Sagging Diabetes Revenue Sanofi Inks Deal with Hanmi Pharma Worth 4 2 Billion". Biospace. 
  6. ^ "Sanofi New Drug Application for Lixisenatide Accepted for Review by FDA". Drugs.com/PR Newsire. 19 February 2013. 
  7. ^ Hughes, Sue (July 3, 2008). "FDA Advisory Committee Recommends Cardiovascular Safety Studies for Diabetes Drugs". Medscape. 
  8. ^ Nainggolan, Lisa (September 12, 2013). "Sanofi Withdraws US NDA for GLP-1 Agonist Lixisenatide". Medscape. 
  9. ^ a b Humphreys, Andrew (December 1, 2013). "Reaching Epic Proportions 2013". PharmaLive. 
  10. ^ Taylor, Phil (September 30, 2015). "Sanofi's lixisenatide is back under FDA review". PM Live. 
  11. ^ "FDA approves Adlyxin to treat type 2 diabetes". FDA. 28 July 2016. Retrieved 28 July 2016. 
  12. ^ a b "Zealand extends Lixisenatide licence with S-A". PMLive. June 8, 2010. 
  13. ^ a b Farooq, Raheel (May 24, 2016). "Sanofi SA (ADR) and Diabetes: Things Are Not Working Out". Business Finance News. 
  14. ^ "FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting" (PDF). FDA. May 25, 2016. 
  15. ^ Nainggolan, Lisa (August 25, 2016). "Sanofi's GLP-1/Insulin Combo LixiLan Faces 3-Month Delay in US". Medscape. 
  16. ^ "Summary Minutes of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting" (PDF). FDA. May 25, 2016. 
  17. ^ Staton, Tracy (August 21, 2016). "With FDA delay, Sanofi loses head start in diabetes combo-med rivalry with Novo". FiercePharma. 
  18. ^ Elkinson, S; Keating, GM (March 2013). "Lixisenatide: first global approval.". Drugs. 73 (4): 383–91. PMID 23558600.