Linaclotide

Linaclotide
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).
Names
Trade namesLinzess, Constella
IUPAC name
  • 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)
Clinical data
Drug classGuanylate cyclase-C (GC-C) agonist[2]
Main usesIBS-C, chronic constipation of unknown cause[2]
Side effectsDiarrhea, abdominal pain, intestinal gas[3][4]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: N (Not classified yet)
    Routes of
    use    		By mouth
    Typical dose72 to 290 mcg OD[4]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa613007
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC59H79N15O21S6
    Molar mass1526.73 g·mol−1
    3D model (JSmol)
    SMILES
    • 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
    • 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 ☒N
    • Key:KXGCNMMJRFDFNR-WDRJZQOASA-N ☒N

    Linaclotide, sold under the brand name Linzess and Constella, is a medication used to treat irritable bowel syndrome with constipation and chronic constipation of unknown cause.[2] It is taken by mouth.[2]

    Common side effects include diarrhea, abdominal pain, and intestinal gas.[3][4] Rarely this may lead to dehydration, low potassium, and low blood pressure with standing.[3] It works by attaching to guanylate cyclase C receptors in the intestines which results in greater fluid release.[3]

    Linaclotide was approved for medical use in the United States and Europe in 2012.[3][2] In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[5][6] In the United Kingdom 4 weeks of medication costs the NHS about £38 as of 2021.[7] This amount in the United States costs about 430 USD.[8]

    Medical use

    Linaclotide is used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.[9][10]

    It has not been tested in pregnant women and it is unknown if it is excreted in breast milk.[10]

    Dosage

    It is taken at a dose of 290 mcg per day for IBS and 72 to 145 mcg for constipation of unknown cause.[4]

    Side effects

    The US label has a black box warning to not use linaclotide in children less than 6 years old and to avoid in people from 6 to 18 years old, due to the risk of serious dehydration.[9]

    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 their colon, rectum, and anus.[10]

    Pharmacology

    Systemic absorption of the globular tetradecapeptide is minimal.[11][12]

    Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C).[11][13][14] The medication binds to the surface of the intestinal epithelial cells.[13] Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses.[11] Activation of GC-C increases cyclic guanosine monophosphate (cGMP).[13] 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.[13][15] This results in increased intestinal fluid and accelerated transit.[13] By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain;[13][12] and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.

    Chemistry

    Linaclotide is a peptide mimic of endogenous guanylin and uroguanylin.[11][14] It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation, or by three-letter abbreviation:[16]

    H–Cys1–Cys2–Glu3–Tyr4–Cys5–Cys6–Asn7–Pro8–Ala9–Cys10–Thr11–Gly12–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;[16] 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:

    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.[16]

    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.[17][18] In 2002 the company hired Mark Currie who had worked at the Searle division of Monsanto and then had gone to Sepracor.[17] 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.[19][20] The company started Phase I trials in 2004.[17]

    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.[21] 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.[22]

    It was approved in the US and Europe in 2012.[23]

    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]

    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 January 2017, plecanatide, a drug marketed under the name Trulance, was approved by the FDA for the treatment of chronic idiopathic constipation (CIC), and is likewise an agonist of guanylate cyclase, except with hexadecapeptide structure.[28]

    It is marketed by Allergan in most of the world and by Astellas in Asia; Ironwood Pharmaceuticals was the originator.[29]

    Society and culture

    Cost

    In 2017, the list price for linaclotide in the US was $378 for 30 pills and plecanatide was priced the same; Allergan and Ironwood increased the price of linaclotide to around $414 in 2018.[29]

    The medication in the U.S. is at a cost of $497 (USD) for 30 capsules, 72 mcg[30] In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[5][6]

    • Linaclotide costs (US)
      Linaclotide costs (US)
    • Linaclotide prescriptions (US)
      Linaclotide prescriptions (US)

    References

    1. ↑ Oh, See Arr (August 17, 2011). "Macrocycle Milestone for Ironwood Pharma". The Haystack. Archived from the original on 5 June 2019. Retrieved 11 February 2017 – via CENBlog.org.
    2. 1 2 3 4 5 "Linaclotide Monograph for Professionals". Drugs.com. Archived from the original on 19 October 2021. Retrieved 23 November 2021.
    3. 1 2 3 4 5 "Constella". Archived from the original on 22 June 2021. Retrieved 23 November 2021.
    4. 1 2 3 4 "DailyMed - LINZESS- linaclotide capsule, gelatin coated". dailymed.nlm.nih.gov. Archived from the original on 29 March 2021. Retrieved 23 November 2021.
    5. 1 2 "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 11 April 2020.
    6. 1 2 "Linaclotide - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 11 April 2020.
    7. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 52. ISBN 978-0857114105.
    8. ↑ "Linaclotide Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 23 November 2021.
    9. 1 2 "US label for linaclotide" (PDF). FDA. January 2017. Archived (PDF) from the original on 20 March 2021. Retrieved 15 April 2018. For label updates see FDA index page for NDA 202811 Archived 2017-06-28 at the Wayback Machine
    10. 1 2 3 "UK label: Linaclotide Summary of Product Characteristics". Electronic Medicines Compendium. September 2017. Archived from the original on 15 April 2018. Retrieved 15 April 2018.
    11. 1 2 3 4 Hussain ZH, Everhart K, Lacy BE (2015). "Treatment of Chronic Constipation: Prescription Medications and Surgical Therapies". Gastroenterol Hepatol (NY). 11 (2): 104–114, esp. 108f. PMC 4836568. PMID 27099579.
    12. 1 2 Corsetti M, Tack J (2013). "Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation". United European Gastroenterol J. 1 (1): 7–20. doi:10.1177/2050640612474446. PMC 4040778. PMID 24917937.{{cite journal}}: CS1 maint: uses authors parameter (link)
    13. 1 2 3 4 5 6 Linzess package insert Archived 2016-05-10 at the Wayback Machine, Allergan, plc, revised November 2015. Accessed August 18, 2016.
    14. 1 2 Love, Bryan L.; Johnson, Audrey; Smith, Lisa S. (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. ISSN 1079-2082. PMID 24939497.
    15. ↑ Yu SW, Rao SS (2014). "Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide". Therap Adv Gastroenterol. 7 (5): 193–205. doi:10.1177/1756283X14537882. PMC 4107700. PMID 25177366.{{cite journal}}: CS1 maint: uses authors parameter (link)
    16. 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 February 11, 2017. Retrieved February 10, 2017.{{cite journal}}: CS1 maint: uses authors parameter (link)
    17. 1 2 3 Withers, Melissa (September 22, 2004). "Druhunters". Paradigm Magazine, Whitehead Institute. Archived from the original on August 28, 2021. Retrieved April 15, 2018.
    18. ↑ Timmerman, Luke (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.
    19. ↑ Hornby, PJ (2015). "Drug discovery approaches to irritable bowel syndrome". Expert Opinion on Drug Discovery. 10 (8): 809–24. doi:10.1517/17460441.2015.1049528. PMID 26193876. S2CID 207494271.
    20. ↑ "Director profile: Mark Currie, Ph.D." MUSC Foundation for Research Development. Archived from the original on 16 April 2018. Retrieved 15 April 2018.
    21. ↑ FDA News Staff (September 17, 2007). "Daily International Pharma Alert". FDA News. 4 (182). Archived from the original on July 10, 2011. Retrieved September 15, 2010.
    22. ↑ Pollack, Andrew (September 13, 2010). "Drug for Irritable Bowel Achieves Goals in Trial". The New York Times. Archived from the original on December 20, 2011. Retrieved September 14, 2010.
    23. ↑ Yu, Siegfried W.B.; Rao, Satish S.C. (11 February 2017). "Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide". Therap Adv Gastroenterol. 7 (5): 193–205. doi:10.1177/1756283X14537882. PMC 4107700. PMID 25177366.
    24. ↑ Jones, Stacy; Burdette, kacy; Wieczner, Jen (July 30, 2015). "From Actavis to Allergan: One pharma company's wild dealmaking journey". Fortune. Archived from the original on September 27, 2020. Retrieved April 15, 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, Lisa. "How DTC got things moving for Linzess". BioPharma Dive. Archived from the original on 2018-04-15. Retrieved 2018-04-15.
    28. ↑ "FDA approves Trulance for Chronic Idiopathic Constipation". FDA.gov. U.S. Food and Drug Administration. Archived from the original on 20 January 2017. Retrieved 20 January 2017.
    29. 1 2 Nocera, Joe (9 January 2018). "How Allergan Continues to Make Drug Prices Insane". Bloomberg News. Archived from the original on 2018-04-15. Retrieved 2018-04-15.
    30. ↑ "Linzess Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 7 August 2020. Retrieved 3 April 2021.
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