Drug: Linzess
Generic molecule: linaclotide
Company: Ironwood Pharmaceuticals
Approval date: Aug. 30,2012

851199-59-2 CAS NO

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)

Linaclotide is a peptide consisting of 14 amino acids. The sequence is

H–Cys¹–Cys²–Glu³–Tyr⁴–Cys⁵–Cys⁶–Asn⁷–Pro⁸–Ala⁹–Cys¹⁰–Thr¹¹–Gly¹²–Cys¹³–Tyr¹⁴–OH

There are three disulfide bonds: Between Cys¹ and Cys⁶, between Cys² and Cys¹⁰, and between Cys⁵ and Cys¹³.^[8]

Linaclotide (marketed under the trade name Linzess) is an experimentalpeptide agonist of guanylate cyclase 2C that is undergoing clinical trials for use in treating abdominal pain in patients with irritable bowel syndrome (IBS) accompanied by constipation. The drug also looks promising in the treatment of gastroparesis, chronic intestinal pseudo-obstruction (CIPO), andinertia coli as well.^[1] The drug was developed by Ironwood Pharmaceuticals, based in Cambridge, Massachusetts.

Linaclotide was approved by the FDA on August 30, 2012 for the treatment of chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults.^[2] It became available in US pharmacies on December 17, 2012. ^[3] That same month, it was forecast by market research firm Decision Resources to achieve blockbuster status by 2021.^[4]

The National Institutes of Health (NIH) estimates that as many as 20% of Americans may experience signs of irritable bowel syndrome, with approximately one-third of those affected experiencing constipation often accompanied by abdominal pain, affecting as many as 10 million Americans.Laxatives can assist with constipation but don’t treat pain, while use ofopiates to treat pain can aggravate constipation. While low-cost laxatives and pain killers would likely be tried first, linaclotide targets both associated conditions in a once-daily pill and could be used if standard treatments are unsuccessful in treating symptoms, though it would likely cost as much as several dollars per day.^[5]

The approval of partner Ironwood’s linaclotide in late August is one of many reasons Forest Labs has been oft-cited as a takeover target in biopharma. Forest markets the drug, which is OK’d for chronic idiopathic constipation and to treat irritable bowel syndrome with constipation. Morgan Stanley has estimated potential peak sales at $2 billion.

1. Tadataka Yamada, ed. (2011). Textbook of Gastroenterology. John Wiley & Sons. ISBN 9781444359411.
2.  “FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation”. 30 Aug 2012.
3.  “Ironwood and Forest Announce U.S. Availability of LINZESS”. 17 Dec 2012.
4.  “Constella/Linzess Will Achieve Blockbuster Sales of $1.2 Billion in 2021 in the Irritable Bowel Syndrome Drug Market”. 19 Dec 2012.
5. Pollack, Andrew. “Drug for Irritable Bowel Achieves Goals in Trial”, The New York Times, September 13, 2010. Accessed September 14, 2010.
6. Jeffrey M Johnston , Caroline B Kurtz , Douglas A Drossman , Anthony J Lembo , Brenda I Jeglinski , James E MacDougall , Stephen M Antonelli & Mark G Currie . “Pilot Study on the Effect of Linaclotide in Patients With Chronic Constipation”, The American Journal of Gastroenterology 104, 125–132 (1 January 2009) | doi:10.1038/ajg.2008.59. Accessed September 15, 2010.
7. Staff. “Daily International Pharma Alert”, FDANews, September 17, 2007, Vol. 4 No. 182. Accessed September 15, 2010.
8. Albericio, F; Giraud, M; Gongora, M; Paradis, M; Tulla-Puche, J; Werbitzky, O. Solid-Phase Synthesis of the Cys-rich Peptide Linaclotide.