Linaclotide

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Linaclotide
Linaclotide structure.svg
Linaclotide structure. A 2D line-angle schematic of linaclotide (sequence CCEYCCNPACTGCY). [1] The phenolic ring of terminal tyrosine (Y) is in the lower left corner. Exaggerated bond lengths emphasize 3 disulfide (-S—S-) bonds between 6 cysteines (C's).
Clinical data
Trade names Linzess
AHFS/Drugs.com Monograph
MedlinePlus a613007
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Identifiers
  • L-Cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclo(1-6),(2-10),(5-13)-tris(disulfide)
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.243.239 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C59H79N15O21S6
Molar mass 1526.73 g·mol−1
3D model (JSmol)
  • O=C(O)[C@@H](NC(=O)[C@H]4NC(=O)CNC(=O)[C@@H](NC(=O)[C@H]2NC(=O)[C@@H](NC(=O)[C@H]5N(C(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CSSC1)CSSC2)CCC(=O)O)Cc3ccc(O)cc3)CSSC4)CC(=O)N)CCC5)C)[C@H](O)C)Cc6ccc(O)cc6
  • InChI=1S/C59H79N15O21S6/c1-26-47(82)69-41-25-101-99-22-38-52(87)65-33(13-14-45(80)81)49(84)66-34(16-28-5-9-30(76)10-6-28)50(85)71-40(54(89)72-39(23-97-96-20-32(60)48(83)70-38)53(88)67-35(18-43(61)78)58(93)74-15-3-4-42(74)56(91)63-26)24-100-98-21-37(64-44(79)19-62-57(92)46(27(2)75)73-55(41)90)51(86)68-36(59(94)95)17-29-7-11-31(77)12-8-29/h5-12,26-27,32-42,46,75-77H,3-4,13-25,60H2,1-2H3,(H2,61,78)(H,62,92)(H,63,91)(H,64,79)(H,65,87)(H,66,84)(H,67,88)(H,68,86)(H,69,82)(H,70,83)(H,71,85)(H,72,89)(H,73,90)(H,80,81)(H,94,95)/t26-,27+,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1 X mark.svgN
  • Key:KXGCNMMJRFDFNR-WDRJZQOASA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Linaclotide, (sold under the brand name Linzess in the US and Mexico, and as Constella elsewhere) [6] is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause. [4] [2] It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others include diarrhea. [4]

Contents

It is an oligo-peptide agonist of guanylate cyclase 2C and remains in the GI tract after it is taken by mouth. It was approved in the US and the European Union in 2012. [7]

It is marketed by Abbvie (formerly Allergan) in the United states and by Astellas in Asia;[ citation needed ] Ironwood Pharmaceuticals was the originator. [8] [ failed verification ] In 2021, it was the 246th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [9] [10]

Medical use

Linaclotide is indicated to treat irritable bowel syndrome with constipation and chronic constipation with no known cause. [4] [2]

In June 2023, the indication was expanded in the US to include the treatment of functional constipation. [4] [11]

Adverse effects

The US label has a black box warning to not use linaclotide in children less than six years old and to avoid in people from 6 to 18 years old, due to the risk of serious dehydration. [4]

More than 10% of people taking linaclotide have diarrhea. Between 1% and 10% of people have decreased appetite, dehydration, low potassium, dizziness when standing up too quickly, nausea, vomiting, urgent need to defecate, fecal incontinence, and bleeding in the colon, rectum, and anus. [2]

It has not been tested in pregnant women and it is unknown if it is excreted in breast milk. [2]

Pharmacology

Systemic absorption of the globular tetradecapeptide is minimal. [12] [13]

Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C). [12] [4] [14] The medication binds to the surface of the intestinal epithelial cells. [4] Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses. [12] Activation of GC-C increases cyclic guanosine monophosphate (cGMP). [4] Elevated cGMP stimulates secretion of chloride and bicarbonate and water into the intestinal lumen, mainly by way of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel activation. [4] [15] This results in increased intestinal fluid and accelerated transit. [4]

Chemistry

Linaclotide is a hybrid peptide design of the E.coli heat-stable enterotoxin (STa) and the endogenous peptide hormones endogenous guanylin and uroguanylin. [16] [12] [14] It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation,[ citation needed ] or by three-letter abbreviation: [17]

H–Cys 1–Cys2–Glu 3–Tyr 4–Cys5–Cys6–Asn 7–Pro 8–Ala 9–Cys10–Thr 11–Gly 12–Cys13–Tyr14–OH

However, the actual structure of linaclotide is not fully specified without the three disulfide (R-S-S-R) bonds it contains, which are between Cys1 and Cys6, between Cys2 and Cys10, and between Cys5 and Cys13; [17] these are shown in exaggerated fashion in the line-angle graphic showing the chemical bonds within and between each amino acid (and their stereochemistries, see the infobox, above right), and are represented using a one-letter abbreviations in the following additional schematic:[ citation needed ]

Linaclotide schematic.svg

A study in discovery synthesis reported that 2 of 14 strategies available to synthesize linaclotide were successful—the successful ones involving trityl protection of all cysteines, or trityl protection of all cysteines except Cys1 and Cys6, which were protected with tert-butylsulphenyl groups. The study also reported that solution-phase oxidation (disulfide formation) was advisable over solid-supported synthesis for linaclotide, and that the Cys1–Cys6 disulfide bridge was the most favored energetically. [17]

History

The drug was discovered at Microbia, Inc, which had been spun out of the Whitehead Institute in 1998 by postdocs from the lab of Gerald Fink to commercialize the lab's know-how and inventions related to microbial pathogens and biology. [18] [19] In 2002 the company hired Mark Currie who had worked at the Searle division of Monsanto and then had gone to Sepracor. [18] Currie directed the efforts that led to the discovery of linaclotide, which was based on an enterotoxin produced by some strains of Escherichia coli that cause traveler's diarrhea. [20] [21] The company started Phase I trials in 2004. [18]

Under a partnership agreement announced in 2007, between Forest Laboratories and Microbia, Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies in the US; Forest obtained exclusive rights to market in Canada and Mexico. [22] By 2010, Microbia had changed its name to Ironwood Pharmaceuticals and had licensed rights to distribute the drug in Europe to Almirall and had licensed Asian rights to Astellas Pharma. [23]

It was approved in the United States and in the European Union in 2012. [7]

Forest was acquired in 2014 and eventually became part of Allergan. [24] Allergan acquired rights from Almirall in 2015, [25] and in 2017, acquired remaining rights in most of the rest of the world, excluding North America, Japan, and China. [26]

Society and culture

Economics

In 2014, Ironwood and Forest then Allergan began running direct-to-consumer advertising which raised sales by 21%; campaigns in 2015 and 2016 raised sales by 27% and 30%. [27]

In 2017, the list price for linaclotide in the US was US$378 for 30 pills; Allergan and Ironwood increased the price of linaclotide to around $414 in 2018. [8]

Related Research Articles

<span class="mw-page-title-main">Constipation</span> Bowel dysfunction

Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement. Complications from constipation may include hemorrhoids, anal fissure or fecal impaction. The normal frequency of bowel movements in adults is between three per day and three per week. Babies often have three to four bowel movements per day while young children typically have two to three per day.

<span class="mw-page-title-main">Laxative</span> Agents that relax and loosen the bowels and stools

Laxatives, purgatives, or aperients are substances that loosen stools and increase bowel movements. They are used to treat and prevent constipation.

<span class="mw-page-title-main">Irritable bowel syndrome</span> Functional gastrointestinal disorder

Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating and changes in the consistency of bowel movements. These symptoms may occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.

Functional constipation, known as chronic idiopathic constipation (CIC), is constipation that does not have a physical (anatomical) or physiological cause. It may have a neurological, psychological or psychosomatic cause. A person with functional constipation may be healthy, yet has difficulty defecating.

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

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

Tegaserod is a 5-HT4 agonist manufactured by Novartis and sold under the names Zelnorm and Zelmac for the management of irritable bowel syndrome and constipation. Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects. Before then, it was the only drug approved by the United States Food and Drug Administration to help relieve the abdominal discomfort, bloating, and constipation associated with irritable bowel syndrome. Its use was also approved to treat chronic idiopathic constipation.

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

Renzapride is a prokinetic agent and antiemetic which acts as a full 5-HT4 agonist and partial 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors.

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<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

<span class="mw-page-title-main">Olsalazine</span> Pharmaceutical drug

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

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<span class="mw-page-title-main">Lubiprostone</span> Medication used for constipation

Lubiprostone, sold under the brand name Amitiza among others, is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company.

Alverine is a drug used for functional gastrointestinal disorders. Alverine is a smooth muscle relaxant. Smooth muscle is a type of muscle that is not under voluntary control; it is the muscle present in places such as the gut and uterus.

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<span class="mw-page-title-main">Naldemedine</span> Medication used in the treatment of Opioid-Induced Constipation

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References

  1. ↑ Oh SA (17 August 2011). "Macrocycle Milestone for Ironwood Pharma". The Haystack. Archived from the original on 27 November 2018. Retrieved 11 February 2017– via CENBlog.org.
  2. 1 2 3 4 5 "UK label: Linaclotide Summary of Product Characteristics". Electronic Medicines Compendium. September 2017. Archived from the original on 15 April 2018. Retrieved 15 April 2018.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. 1 2 3 4 5 6 7 8 9 10 11 "Linzess- linaclotide capsule, gelatin coated". DailyMed. 31 August 2021. Archived from the original on 29 March 2021. Retrieved 12 June 2023.
  5. ↑ "Constella EPAR". European Medicines Agency. 24 May 2023. Archived from the original on 22 June 2021. Retrieved 12 June 2023.
  6. ↑ "Linaclotide - Ironwood Pharmaceuticals". AdisInsight. Archived from the original on 7 October 2017. Retrieved 15 April 2018.
  7. 1 2 Yu SW, Rao SS (September 2014). "Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide". Therapeutic Advances in Gastroenterology. 7 (5): 193–205. doi:10.1177/1756283X14537882. PMC   4107700 . PMID   25177366.
  8. 1 2 Nocera J (9 January 2018). "How Allergan Continues to Make Drug Prices Insane". Bloomberg News. Archived from the original on 15 April 2018. Retrieved 15 April 2018.
  9. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  10. ↑ "Linaclotide - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  11. ↑ "FDA approves first treatment for pediatric functional constipation". U.S. Food and Drug Administration (FDA) (Press release). 12 June 2023. Retrieved 12 June 2023.
  12. 1 2 3 4 Hussain ZH, Everhart K, Lacy BE (February 2015). "Treatment of Chronic Constipation: Prescription Medications and Surgical Therapies". Gastroenterology & Hepatology. 11 (2): 104–114. PMC   4836568 . PMID   27099579.
  13. ↑ Corsetti M, Tack J (February 2013). "Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation". United European Gastroenterology Journal. 1 (1): 7–20. doi:10.1177/2050640612474446. PMC   4040778 . PMID   24917937.
  14. 1 2 Love BL, Johnson A, Smith LS (July 2014). "Linaclotide: a novel agent for chronic constipation and irritable bowel syndrome". American Journal of Health-System Pharmacy. 71 (13): 1081–1091. doi:10.2146/ajhp130575. PMID   24939497.
  15. ↑ Yu SW, Rao SS (September 2014). "Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide". Therapeutic Advances in Gastroenterology. 7 (5): 193–205. doi:10.1177/1756283X14537882. PMC   4107700 . PMID   25177366.
  16. ↑ Braga Emidio N, Tran HN, Andersson A, Dawson PE, Albericio F, Vetter I, Muttenthaler M (June 2021). "Improving the Gastrointestinal Stability of Linaclotide". Journal of Medicinal Chemistry. 64 (12): 8384–8390. doi:10.1021/acs.jmedchem.1c00380. PMC   8237258 . PMID   33979161.
  17. 1 2 3 Góngora-Benítez M, Tulla-Puche J, Paradís-Bas M, Werbitzky O, Giraud M, Albericio F (2011). "Optimized Fmoc solid-phase synthesis of the cysteine-rich peptide linaclotide" (PDF). Biopolymers. 96 (1): 69–80. doi:10.1002/bip.21480. PMID   20560145. S2CID   46150263. Archived from the original (PDF) on 11 February 2017. Retrieved 10 February 2017.
  18. 1 2 3 Withers M (22 September 2004). "Druhunters". Paradigm Magazine, Whitehead Institute. Archived from the original on 28 August 2021. Retrieved 15 April 2018.
  19. ↑ Timmerman L (23 February 2009). "Xconomy: Renewables Aren't Just for Biofuels: Microbia Makes Industrial Chemicals a Bit Greener". Xconomy. Archived from the original on 16 April 2018. Retrieved 15 April 2018.
  20. ↑ Hornby PJ (2015). "Drug discovery approaches to irritable bowel syndrome". Expert Opinion on Drug Discovery. 10 (8): 809–824. doi:10.1517/17460441.2015.1049528. PMID   26193876. S2CID   207494271.
  21. ↑ "Director profile: Mark Currie, Ph.D." MUSC Foundation for Research Development. Archived from the original on 16 April 2018. Retrieved 15 April 2018.
  22. ↑ "Microbia, Forest Laboratories Announce Linaclotide Collaboration". FDA News. 17 September 2007. Archived from the original on 20 August 2016. Retrieved 15 September 2010.
  23. ↑ Pollack, Andrew (13 September 2010). "Drug for Irritable Bowel Achieves Goals in Trial". The New York Times . Archived from the original on 20 December 2011. Retrieved 14 September 2010.
  24. ↑ Jones S, Burdette K, Wieczner J (30 July 2015). "From Actavis to Allergan: One pharma company's wild dealmaking journey". Fortune. Archived from the original on 27 September 2020. Retrieved 15 April 2018.
  25. ↑ "Press release: Allergan Acquires Rights To Ironwoods Constella (Linaclotide) From Almirall In More Than 40 Countr". Allergan. 27 October 2015. Archived from the original on 15 April 2018. Retrieved 15 April 2018.
  26. ↑ "8-K" (PDF). Ironwood. 31 January 2017. Archived from the original (PDF) on 15 April 2018. Retrieved 15 April 2018.
  27. ↑ LaMotta L. "How DTC got things moving for Linzess". BioPharma Dive. Archived from the original on 15 April 2018. Retrieved 15 April 2018.
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