Lixisenatide

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Lixisenatide
Clinical data
Trade names Lyxumia (EU), Adlyxin (US)
AHFS/Drugs.com Monograph
MedlinePlus a617005
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.210.612 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C215H347N61O65S
Molar mass 4858.56 g·mol−1
3D model (JSmol)
  • CCC(C)C(C(=O)NC(CCC(=O)O)C(=O)NC(Cc1c[nH]c2c1cccc2)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NCC(=O)NCC(=O)N3CCCC3C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N4CCCC4C(=O)N5CCCC5C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)N)NC(=O)C(Cc6ccccc6)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc7ccccc7)NC(=O)C(C(C)O)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(Cc8cnc[nH]8)N
  • InChI=1S/C215H347N61O65S/c1-16-115(10)173(210(337)256-141(68-74-170(299)300)194(321)261-148(94-122-98-232-126-50-24-23-49-124(122)126)199(326)258-143(89-111(2)3)196(323)247-134(58-32-40-83-223)189(316)262-149(96-160(226)285)180(307)235-100-161(286)233-104-165(290)274-85-42-60-156(274)207(334)267-154(108-280)206(333)265-151(105-277)181(308)237-101-162(287)239-117(12)213(340)276-87-44-62-158(276)214(341)275-86-43-61-157(275)208(335)268-153(107-279)204(331)249-132(56-30-38-81-221)187(314)246-131(55-29-37-80-220)186(313)245-130(54-28-36-79-219)185(312)244-129(53-27-35-78-218)184(311)243-128(52-26-34-77-217)183(310)242-127(176(227)303)51-25-33-76-216)272-201(328)146(92-120-45-19-17-20-46-120)260-197(324)144(90-112(4)5)257-190(317)135(59-41-84-231-215(228)229)255-209(336)172(114(8)9)271-177(304)116(11)240-182(309)138(65-71-167(293)294)251-192(319)139(66-72-168(295)296)252-193(320)140(67-73-169(297)298)253-195(322)142(75-88-342-15)254-191(318)137(63-69-159(225)284)250-188(315)133(57-31-39-82-222)248-203(330)152(106-278)266-198(325)145(91-113(6)7)259-200(327)150(97-171(301)302)263-205(332)155(109-281)269-212(339)175(119(14)283)273-202(329)147(93-121-47-21-18-22-48-121)264-211(338)174(118(13)282)270-164(289)103-236-179(306)136(64-70-166(291)292)241-163(288)102-234-178(305)125(224)95-123-99-230-110-238-123/h17-24,45-50,98-99,110-119,125,127-158,172-175,232,277-283H,16,25-44,51-97,100-109,216-224H2,1-15H3,(H2,225,284)(H2,226,285)(H2,227,303)(H,230,238)(H,233,286)(H,234,305)(H,235,307)(H,236,306)(H,237,308)(H,239,287)(H,240,309)(H,241,288)(H,242,310)(H,243,311)(H,244,312)(H,245,313)(H,246,314)(H,247,323)(H,248,330)(H,249,331)(H,250,315)(H,251,319)(H,252,320)(H,253,322)(H,254,318)(H,255,336)(H,256,337)(H,257,317)(H,258,326)(H,259,327)(H,260,324)(H,261,321)(H,262,316)(H,263,332)(H,264,338)(H,265,333)(H,266,325)(H,267,334)(H,268,335)(H,269,339)(H,270,289)(H,271,304)(H,272,328)(H,273,329)(H,291,292)(H,293,294)(H,295,296)(H,297,298)(H,299,300)(H,301,302)(H4,228,229,231)/t115-,116-,117-,118+,119+,125-,127-,128-,129-,130-,131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,172-,173-,174-,175-/m0/s1
  • Key:XVVOERDUTLJJHN-IAEQDCLQSA-N

Lixisenatide (trade name Lyxumia in the European Union and Adlyxin in the U.S. and manufactured by Sanofi) is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.

Contents

Medical use

Lixisenatide is used as adjunct to diet and exercise to treat type 2 diabetes. [3] In the European Union, its use is limited to complementing insulin therapy. [2] [4] As of 2017 it is unclear if they affect a person's risk of death. [5]

It is provided in an autoinjector containing fourteen doses and is injected subcutaneously. [3]

Lixisenatide should not be used for people who have problems with stomach emptying. [3] Lixisenatide delays emptying of the stomach, which may change how quickly other drugs that are taken by mouth take effect. [3]

Lixisenatide in neurodegenerative diseases

Results from a research work which was done by McClean PL et al. demonstrated that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of Alzheimer disease AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the measured parameters after ten weeks of daily intraperitoneal injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed. When analyzing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug, with more effectiveness accomplished with lixisenatide. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the two drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex were reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments. [6]

Cai HY et al. demonstrated in a study that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. So, lixisenatide might have the potential to be developed as a novel therapy for AD. [7] Liu Wet al found an interesting results when comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen, while both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The previous results demonstrate that both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of Parkinson disease. [8]

Another study done by Kerry Hunter et al. profiled the GLP-1 receptor agonists liraglutide and lixisenatide. The kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis were evaluated. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. The previous results suggest that these novel incretin analogues cross the BBB showing physiological activity and neurogenesis in the brain, which makes them good candidates to be used as a treatment of neurodegenerative diseases. [9]

Adverse effects

In about 0.1% of cases people have had anaphylactic reactions to lixisenatide and in about 0.2% of cases the drug has caused pancreatitis. [3] Use with insulin or sulfonylurea may cause hypoglycemia. [3] 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. [3] 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. [3]

At least 5% of people had nausea, vomiting, diarrhea, headache, or dizziness after taking lixisenatide. [3]

Mechanism of action

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

Lixisenatide is a peptide made of 44 amino acids, with an amide group on its C terminus. [3]

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: [10]

H–His–Gly–Glu–Gly–Thr–Phe–Thr–Ser–Asp–Leu–Ser–Lys–Gln–Met–Glu–Glu–Glu–Ala–Val–Arg–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

It was created by Zealand Pharma A/S of Denmark; [11] in 2003 Zealand licensed it to Sanofi which developed the drug. [12] Lixisenatide was approved by the European Commission in February 2013. [2] Sanofi submitted an NDA in the US, which was accepted for review by the US FDA in February 2013, [13] 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) [14] Sanofi decided to withdraw the NDA and wait for the results of a Phase III study that was scheduled to be completed in 2015. [15] [16] 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. [16] 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. [17] Lixisenatide received FDA approval in July 2016. [18]

In 2010, Zealand 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. [19] Sanofi planned to start the Phase III trial that year. [19] 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. [20] [21] 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. [20] [22] [23] 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. [24]

Patent protection for lixisenatide expired in 2020. [25]

Related Research Articles

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merged with Aventis and renamed to Sanofi-Aventis, which were each the product of several previous mergers. It changed its name back to Sanofi in May 2011. The company is a component of the Euro Stoxx 50 stock market index. In 2023, the company’s seat in Forbes Global 2000 was 89.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

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

Pramlintide is an injectable amylin analogue drug for diabetes, developed by Amylin Pharmaceuticals. Pramlintide is sold as an acetate salt.

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

Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. 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.

<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">Benznidazole</span> Chemical compound

Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. While it is highly effective in early disease, the effectiveness decreases in those who have long-term infection. It is the first-line treatment given its moderate side effects compared to nifurtimox. It is taken by mouth.

<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, Inc. 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.

Albiglutide is a glucagon-like peptide-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. GSK has announced that it intends to withdraw the drug from the worldwide market by July 2018 for economic reasons.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, 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.

<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.

<span class="mw-page-title-main">Semaglutide</span> Anti-diabetic and anti-obesity medication

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 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 and Rybelsus 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.

Insulin glargine/lixisenatide, sold under the brand name Soliqua 100/33 among others, is a fixed-dose combination medication that combines insulin glargine and lixisenatide and is used to treat diabetes.

<span class="mw-page-title-main">Injector pen</span> Drug storage and delivery device

An injector pen is a device used for injecting medication under the skin. First introduced in the 1980s, injector pens are designed to make injectable medication easier and more convenient to use, thus increasing patient adherence. The primary difference between injector pens and traditional vial and syringe administration is the easier use of an injector pen by people with low dexterity, poor vision, or who need portability to administer medicine on time. Injector pens also decrease the fear or adversity towards self-injection of medications, which increases the likelihood that a person takes the medication.

<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 via subcutaneous injections.

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

References

  1. ↑ "Diabetic health". Health Canada . May 8, 2018. Retrieved April 13, 2024.
  2. 1 2 3 4 "Lyxumia 10 micrograms solution for injection - Summary of Product Characteristics (SPC)". UK Electronic Medicines Compendium. May 2, 2016. Archived from the original on September 23, 2016. Retrieved September 21, 2016.
  3. 1 2 3 4 5 6 7 8 9 10 11 "Adlyxin- lixisenatide kit Adlyxin- lixisenatide injection, solution". DailyMed. January 11, 2019. Retrieved September 7, 2020.
  4. 1 2 "Lyxumia EPAR". European Medicines Agency (EMA). September 17, 2018. Retrieved September 7, 2020.
  5. ↑ 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.
  6. ↑ McClean PL, Hölscher C (November 2014). "Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease". Neuropharmacology. 86: 241–58. doi:10.1016/j.neuropharm.2014.07.015. PMID   25107586. S2CID   24550291.
  7. ↑ Cai HY, Yang JT, Wang ZJ, Zhang J, Yang W, Wu MN, Qi JS (January 2018). "Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease". Biochemical and Biophysical Research Communications. 495 (1): 1034–1040. doi:10.1016/j.bbrc.2017.11.114. PMID   29175324.
  8. ↑ Liu W, Jalewa J, Sharma M, Li G, Li L, Hölscher C (September 2015). "Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease" (PDF). Neuroscience. 303: 42–50. doi:10.1016/j.neuroscience.2015.06.054. PMID   26141845. S2CID   35297066.
  9. ↑ Hunter K, Hölscher C (March 2012). "Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis". BMC Neuroscience. 13 (1): 33. doi: 10.1186/1471-2202-13-33 . PMC   3352246 . PMID   22443187.
  10. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 61" (PDF). WHO Drug Information. 23 (1): 66f. 2009.
  11. ↑ Christensen M, Knop FK, Holst JJ, Vilsboll T (August 2009). "Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus". IDrugs. 12 (8): 503–13. PMID   19629885.
  12. ↑ Terry M (November 5, 2015). "In Attempt to Bolster Sagging Diabetes Revenue Sanofi Inks Deal with Hanmi Pharma Worth 4 2 Billion". Biospace.
  13. ↑ "Sanofi New Drug Application for Lixisenatide Accepted for Review by FDA". Drugs.com/PR Newsire. February 19, 2013.
  14. ↑ Hughes S (July 3, 2008). "FDA Advisory Committee Recommends Cardiovascular Safety Studies for Diabetes Drugs". Medscape.
  15. ↑ Nainggolan L (September 12, 2013). "Sanofi Withdraws US NDA for GLP-1 Agonist Lixisenatide". Medscape.
  16. 1 2 Humphreys A (December 1, 2013). "Reaching Epic Proportions 2013". PharmaLive.
  17. ↑ Taylor P (September 30, 2015). "Sanofi's lixisenatide is back under FDA review". PM Live.
  18. ↑ "FDA approves Adlyxin to treat type 2 diabetes". FDA. July 28, 2016. Retrieved July 28, 2016.
  19. 1 2 "Zealand extends Lixisenatide licence with S-A". PMLive. June 8, 2010.
  20. 1 2 Farooq R (May 24, 2016). "Sanofi SA (ADR) and Diabetes: Things Are Not Working Out". Business Finance News. Archived from the original on September 23, 2016.
  21. ↑ "FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting" (PDF). FDA. May 25, 2016.
  22. ↑ Nainggolan L (August 25, 2016). "Sanofi's GLP-1/Insulin Combo LixiLan Faces 3-Month Delay in US". Medscape.
  23. ↑ "Summary Minutes of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting" (PDF). FDA. May 25, 2016.
  24. ↑ Staton T (August 21, 2016). "With FDA delay, Sanofi loses head start in diabetes combo-med rivalry with Novo". FiercePharma.
  25. ↑ Elkinson S, Keating GM (March 2013). "Lixisenatide: first global approval". Drugs. 73 (4): 383–91. doi:10.1007/s40265-013-0033-3. PMID   23558600. S2CID   23612106.
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