Linaclotide
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| Systematic (IUPAC) name | |
|---|---|
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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 | |
| Trade names | Linzess |
| License data |
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| Pregnancy category |
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| Routes of administration | Oral |
| Legal status | |
| Legal status |
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| Identifiers | |
| CAS Number |
851199-59-2  |
| ATC code | A06AX04 (WHO) |
| PubChem | CID 16158208 |
| IUPHAR/BPS | 5017 |
| ChemSpider |
17314504  |
| UNII |
N0TXR0XR5X |
| KEGG |
D09355 |
| Chemical data | |
| Formula | C59H79N15O21S6 |
| Molar mass | 1526.74 g/mol |
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Linaclotide (marketed under the trade name Linzess and Constella) is a peptide agonist of guanylate cyclase 2C. It was approved by the FDA in August 2012 for the treatment of chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) in adults.[1]
Background
The National Institutes of Health (NIH) estimate 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 do not treat pain, while use of opiates 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.[2]
Linaclotide is a peptide agonist of guanylate cyclase 2C (GC-C). The medication binds to the surface of the intestinal epithelial cells. Activation of GC-C results in increased cyclic guanosine monophosphate (cGMP). Elevation of cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. By elevating cGMP, linaclotide reduces activation of colonic sensory neurons, reducing pain; and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.[3]
Clinical trials
The approved dose for constipation-predominant irritable bowel syndrome IBS-C is 290 micrograms daily; the approved dose for chronic idiopathic constipation CIC is 145 mcg daily.[1] The package insert contains the details of the medications response rates and side effects.[3]
In Phase I trials mentioned in January 2009 in The American Journal of Gastroenterology, the medication was well tolerated. In 42 patients with chronic constipation who participated in a randomized, double-blind, placebo-controlled study there was symptom relief and that the medication was well tolerated.[4] In a Phase III clinical trial announced in September 2010, Ironwood Pharmaceuticals studied approximately 800 patients over 12 weeks who were given linaclotide or a placebo in a randomized double-blind trial. 34% of those receiving linaclotide experienced relief of pain and constipation, compared to 21% of patients who had taken the placebo. 50% of those receiving linaclotide saw a significant reduction in pain, versus 37% with the placebo, with pain reduction starting in the first week on the medication. 6% of patients left the study after experiencing diarrhea, the most commonly reported side effect.[2]
Distribution and licensing
Under a partnership agreement announced in 2007 between Forest Laboratories and Microbia (as Ironwood was then known), Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies.[5] Distribution rights in the United States will be shared with Forest Laboratories, with Almirall distributing linaclotide in Europe and Astellas Pharma in Asia.[2]
Chemistry
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.[6]
References
- 1 2 "FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation" Food and Drug Administration news release, August 30, 2012. Accessed April 28, 2016.
- 1 2 3 Pollack, Andrew. "Drug for Irritable Bowel Achieves Goals in Trial", The New York Times, September 13, 2010. Accessed September 14, 2010.
- 1 2 Linzess package insert, Allergan, Plc, revised November 2015. Accessed April 28, 2016.
- ↑ Johnston, Jeffrey M; Kurtz, Caroline B.; Drossman, Douglas A.; Lembo, Anthony J.; Jeglinski, Brenda I.; MacDougall, James E.; Antonelli, Stephen M.; and Currie, Mark G. "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.
- ↑ Staff. "Daily International Pharma Alert", FDANews, September 17, 2007, Vol. 4 No. 182. Accessed September 15, 2010.
- ↑ Albericio, F; Giraud, M; Gongora, M; Paradis, M; Tulla-Puche, J; Werbitzky, O. "Solid-Phase Synthesis of the Cys-rich Peptide Linaclotide" (PDF).
External links
- Linzess information Drugs com Accessed October 23, 2013.
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