Linaclotide

Linaclotide, (sold under the brand name Linzess in the US and Mexico, and as Constella elsewhere)[2] is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.[3][4] It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others are gastrointestinal.[3]

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).
Clinical data
Trade namesLinzess
AHFS/Drugs.comMonograph
MedlinePlusa613007
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
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)
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.243.239
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
 NY (what is this?)  (verify)

It is an oligo-peptide agonist of guanylate cyclase 2C and remains in the GI tract after it is taken orally. It was approved in the US and Europe in 2012.[5]

It is marketed by Allergan in most of the world and by Astellas in Asia; Ironwood Pharmaceuticals was the originator.[6] In 2017, it was the 257th most commonly prescribed medication in the United States, with more than one million prescriptions.[7][8]

Medical use

Linaclotide is used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.[3][4]

It has not been tested in pregnant women and it is unknown if it is excreted in breast milk.[4]

Adverse 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.[3]

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.[4]

Pharmacology

Systemic absorption of the globular tetradecapeptide is minimal.[9][10]

Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C).[9][11][12] The medication binds to the surface of the intestinal epithelial cells.[11] Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses.[9] Activation of GC-C increases cyclic guanosine monophosphate (cGMP).[11] 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.[11][13] This results in increased intestinal fluid and accelerated transit.[11] By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain;[11][10] and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.

Chemistry

Linaclotide is a hybrid peptide design of the E.coli heat-stable enterotoxin (STa) and the endogenous peptide hormones endogenous guanylin and uroguanylin.[14][9][12] It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation, or by three-letter abbreviation:[15]

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;[15] 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.[15]

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.[16][17] In 2002 the company hired Mark Currie who had worked at the Searle division of Monsanto and then had gone to Sepracor.[16] 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.[18][19] The company started Phase I trials in 2004.[16]

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.[20] 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.[21]

It was approved in the US and Europe in 2012.[5]

Forest was acquired in 2014 and eventually became part of Allergan.[22] Allergan acquired rights from Almirall in 2015[23] and in 2017 acquired remaining rights in most of the rest of the world, excluding North America, Japan, and China.[24]

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%.[25]

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.[26]

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.[6]

In April 2022, the list price for linaclotide in the US was $501-$515 with discount for 30 capsules at the big chain pharmacies.

References
  1. Oh SA (August 17, 2011). "Macrocycle Milestone for Ironwood Pharma". The Haystack. Archived from the original on 27 November 2018. Retrieved 11 February 2017 – via CENBlog.org.
  2. "Linaclotide - Ironwood Pharmaceuticals". AdisInsight. Retrieved 15 April 2018.
  3. "US label for linaclotide" (PDF). FDA. January 2017. Retrieved 15 April 2018. For label updates see FDA index page for NDA 202811
  4. "UK label: Linaclotide Summary of Product Characteristics". Electronic Medicines Compendium. September 2017. Retrieved 15 April 2018.
  5. 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.
  6. Nocera J (9 January 2018). "How Allergan Continues to Make Drug Prices Insane". Bloomberg News.
  7. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
  8. "Linaclotide - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
  9. 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.
  10. 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.
  11. Linzess package insert, Allergan, plc, revised November 2015. Accessed August 18, 2016.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Withers M (September 22, 2004). "Druhunters". Paradigm Magazine, Whitehead Institute.
  17. Timmerman L (23 February 2009). "Xconomy: Renewables Aren't Just for Biofuels: Microbia Makes Industrial Chemicals a Bit Greener". Xconomy.
  18. 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.
  19. "Director profile: Mark Currie, Ph.D." MUSC Foundation for Research Development. Retrieved 15 April 2018.
  20. FDA News Staff (September 17, 2007). "Daily International Pharma Alert". FDA News. 4 (182). Retrieved September 15, 2010.
  21. Pollack, Andrew (September 13, 2010). "Drug for Irritable Bowel Achieves Goals in Trial". The New York Times. Retrieved September 14, 2010.
  22. Jones S, Burdette K, Wieczner J (July 30, 2015). "From Actavis to Allergan: One pharma company's wild dealmaking journey". Fortune.
  23. "Press release: Allergan Acquires Rights To Ironwoods Constella (Linaclotide) From Almirall In More Than 40 Countr". Allergan. 27 October 2015.
  24. "8-K" (PDF). Ironwood. 31 January 2017.
  25. LaMotta L. "How DTC got things moving for Linzess". BioPharma Dive.
  26. "FDA approves Trulance for Chronic Idiopathic Constipation". FDA.gov. U.S. Food and Drug Administration. Retrieved 20 January 2017.
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