Plecanatide

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Plecanatide
Plecanatide sequence.svg
Clinical data
Trade names Trulance
Synonyms SP-304
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C65H104N18O26S4
Molar mass 1681.887 g/mol
3D model (JSmol)

Plecanatide (brand name Trulance), is a drug approved by the FDA for the treatment of chronic idiopathic constipation (CIC)[1] and irritable bowel syndrome with constipation. Plecanatide is an agonist of guanylate cyclase-C. Plecanatide increases intestinal transit and fluid through a buildup of cGMP.[2][3]

Therapeutics[edit]

Indications for use[edit]

As of January 2017, Plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults.[1] The presence of this condition is determined using the Rome III diagnostic criteria for chronic constipation which requires that the patient meet stool frequency, stool consistency, incomplete evacuation, and straining requirements in addition to not being a likely candidate for irritable bowel syndrome.[4] The symptoms should also have been present for at least three of the last six months to establish the chronic nature of the condition before treatment with Plecanatide is indicated.[4]

Contraindications[edit]

Plecanatide has not been shown to be safe or effective in persons 6 years to 18 years of age.[5] Use of Plecanatide by persons under the age of 6 poses a serious dehydration risk and studies have demonstrated Plecanatide can cause death in juvenile mice due to this dehydrating effect.[5]

Use of Plecanatide is also contraindicated in persons who are suspected of having a mechanical gastrointestinal obstruction.[5]

Efficacy[edit]

Plecanatide has been shown to be safe and effective. It has shown to be at least equally as effective as its main competitor, linaclotide (brand name: Linzess), but has been shown to have a lower rate of diarrhea as an adverse drug reaction.[6]

Pharmacology[edit]

Structure and function[edit]

Plecanatide is a 16 amino acid peptide with the amino acid sequence:

H-Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16-OH

Is nearly structurally identical to human uroguanylin, apart from the substitution of Asp3 with Glu3.[7] Disulphide bonds exist between Cys4 and Cys12, as well as Cys7 and Cys15.[8]

Plecanatide has two important motifs. The first being the acidic residues Asp2 and Glu3 which modulate the affinity for its receptor in response to environmental pH.[5][7][9] Simulations predict the optimal activity of Plecanatide to occur at pH 5, making it suitable for targeting cells within the proximal intestine, which has a pH of between 5 and 6.[5] The second is the ACTGC motif (residues Ala11 to Cys15) which is the region responsible for its binding to the receptor, guanylate cyclase-C.[10]

Mechanism of action[edit]

Plecanatide works as a laxative by drawing water in to the gastrointestinal tract thereby softening stool and encouraging its natural passage.

Similar to its endogenous counterpart, Plecanatide activates guanylate cyclase-C on endothelial cells within the gastrointestinal tract.[7] The activation of guanylate cyclase-C catalyses the production of the second messenger guanosine 3’,5’-cyclic monophosphate (cGMP) which leads to the protein kinase A (PKA) and protein kinase G II (PKGII)-mediated phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein.[11][12] CFTR is an anion channel and upon activation it will secrete negatively charged ions, particularly chloride (Cl) and bicarbonate (HCO3) in to the GI tract lumen.[13][14] This disruption to the electrochemical gradient is in part rectified by the passive secretion of positively charged sodium ions in to the lumen and water follows by osmosis.[13]

Plecanatide is also known to have an anti-nociceptive effect in animal models, however the exact mechanism of action is not yet fully elucidated.[5] It has been suggested that this may be in part to the anti-inflammatory action of guanylate cyclase-C by its inhibition of pro-inflammatory cytokines, or through the inhibition of associated sensory neurons.[15]

Pharmacokinetics and metabolism[edit]

As Plecanatide acts on receptors present on the apical side of endothelial cells lining the gastrointestinal tract it is able to impart its effect without ever entering circulation.[7] As with most orally ingested peptides, Plecanatide is degraded by intestinal enzymes and so very little of the active drug enters systemic circulation.[5] Minimal amounts of the drug are expected to be transported in to the body and concentrations of Plecanatide and its metabolites are undetectable in plasma following the recommended dosage of 3 mg.[5][7] It has also been shown that dosages up to 48.6 mg produced no detectable concentration of Plecanatide in human plasma at any time point after ingestion.[7]

Commercialization[edit]

Trulance is manufactured for Synergy Pharmaceuticals, Inc. (NASDAQ: SGYP), which is a biopharmaceutical company focused on gastrointestinal diseases. SGYP was acquired by Pawfect Foods, Inc. in July 2008.[16] Prior to this acquisition, Synergy was a majority-owned subsidiary of Callisto pharmaceuticals. In January 2013, Callisto Pharmaceuticals merged into Synergy Pharmaceuticals (having previously owned about 40% of Synergy's stock.[17] Plecanatide is currently Synergy's only drug on the market.[18]

Manufacturer financials[edit]

In the first quarter of 2017, Synergy reported a net loss of $64.6 million, compared to only $59.9 million net loss in the first quarter of 2016. This is rather expected, as Trulance has just recently come on the market, and with it came substantial costs. This has resulted in a slight drop in stock price in recent months. However, the company has basically no debt. This puts Plecanatide one step above its roughest competition, linaclotide (manufactured by Ironwood Pharmaceuticals), because Ironwood is beholden to enormous amounts of debt and thus is unlikely to turn profits for many years. Synergy plans to reach profitability by 2018. As of March 2017, Synergy had only $16.7 million in convertible debt with $139 million in cash. For comparison, Ironwood remains unprofitable after five years and has $238 million remaining in convertible debt.[19]

Plecanatide is being marketed by a sales force of nearly 250, and marketing is targeting the top 70% of brand name drug prescribers. SGYP reports that 60% of adult patients with CIC and commercial insurance have unrestricted access to Trulance.[20] However, Express Scripts recently announced they would not include Trulance on its 2018 preferred drug formulary and SGYP has since taken a hit.[21]

Intellectual property[edit]

Synergy Pharmaceuticals Inc. has been issued a total of 21 patents from the US Patent and Trademark Office (USPTO) related to its GC agonists, with expiration dates from 2022-2034.[6] Three new patents for method of manufacturing, formulations, and methods of using Plecanatide were issued by the USPTO.[22] Patents for Plecanatide have also been issued by the European Patent Office (EPO). In May 2010, the manufacturer of plecanatide's main competition, Ironwood Pharmaceuticals, filed an anonymous opposition to the patent. After Synergy complained that Ironwood had filed the opposition with falsified and misleading information, the EPO chose to uphold Synergy's right to the patent.[23] In addition, there are also eight foreign patents for Plecanatide.[5]

Regulatory information[edit]

Synergy Pharmaceuticals, Inc. filed an investigational new drug (IND) application to the US FDA on April 2, 2008, and by May 2, 2008 had received notice that its proposed study was safe.[16] The first Phase I clinical trial for Plecanatide (formerly proprietary drug SP-304) began in June 2008. Beginning in February 2010, multiple Phase II clinical trials were initiated, including the CIC3 and National CIC3 trials. The latest Phase II trial for CIC concluded in March 2016.[24] There have also been multiple Phase III trials for Plecanatide in its pursuit of an IBS-C indication, the latest of which was completed in June 2017.[25]

In January 2016, an NDA was filed with the FDA and by April a PDUFA action date had been assigned. As noted above, Plecanatide was approved for use in CIC in January 2017. A sNDA was filed in March 2017 to add an additional indication of irritable bowl syndrome with constipation (IBS-C) and a PDUFA date was set for January 2018.[26]

See also[edit]

References[edit]

  1. ^ a b "FDA approves Trulance for Chronic Idiopathic Constipation". FDA.gov. U.S. Food and Drug Administration. Retrieved 20 January 2017.
  2. ^ "TRULANCE package insert" (PDF). Trulance website. Synergy Pharmaceuticals Inc. 420 Lexington Avenue, Suite 2012 New York, New York 10170. Retrieved 20 January 2017.
  3. ^ Thomas, RH; Luthin, DR (June 2015). "Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents". Pharmacotherapy. 35 (6): 613–30. doi:10.1002/phar.1594. PMID 26016701.
  4. ^ a b Rome III : the functional gastrointestinal disorders. Drossman, Douglas A. (3rd ed.). McLean, Va.: Degnon Associates. 2006. ISBN 9780965683753. OCLC 79476570.
  5. ^ a b c d e f g h i Al-Salama, Zaina T.; Syed, Yahiya Y. (2017-04-01). "Plecanatide: First Global Approval". Drugs. 77 (5): 593–598. doi:10.1007/s40265-017-0718-0. ISSN 0012-6667.
  6. ^ a b "Trulance - FDA prescribing information, side effects and uses". Drugs.com. Retrieved 2017-10-27.
  7. ^ a b c d e f Shailubhai, Kunwar; Comiskey, Stephen; Foss, John A.; Feng, Rong; Barrow, Laura; Comer, Gail M.; Jacob, Gary S. (2013-09-01). "Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses". Digestive Diseases and Sciences. 58 (9): 2580–2586. doi:10.1007/s10620-013-2684-z. ISSN 0163-2116.
  8. ^ Chang, Wen-Chi L; Masih, Shet; Thadi, Anusha; Patwa, Viren; Joshi, Apoorva; Cooper, Harry S; Palejwala, Vaseem A; Clapper, Margie L; Shailubhai, Kunwar. "Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCC mice". World Journal of Gastrointestinal Pharmacology and Therapeutics. 8 (1). doi:10.4292/wjgpt.v8.i1.47. PMC 5292606. PMID 28217374.
  9. ^ Hamra, F. K.; Eber, S. L.; Chin, D. T.; Currie, M. G.; Forte, L. R. (1997-03-18). "Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity". Proceedings of the National Academy of Sciences of the United States of America. 94 (6): 2705–2710. ISSN 0027-8424. PMC 20153. PMID 9122260.
  10. ^ Forte, Leonard Ralph (November 2004). "Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics". Pharmacology & Therapeutics. 104 (2): 137–162. doi:10.1016/j.pharmthera.2004.08.007. ISSN 0163-7258. PMID 15518884.
  11. ^ Hamra, F. K.; Forte, L. R.; Eber, S. L.; Pidhorodeckyj, N. V.; Krause, W. J.; Freeman, R. H.; Chin, D. T.; Tompkins, J. A.; Fok, K. F. (1993-11-15). "Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase". Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10464–10468. ISSN 0027-8424. PMC 47797. PMID 7902563.
  12. ^ Bijvelds, Marcel J. C.; Loos, Michaela; Bronsveld, Inez; Hellemans, Ann; Bongartz, Jean-Pierre; Ver Donck, Luc; Cox, Eric; de Jonge, Hugo R.; Schuurkes, Jan A. J. (2015-12-01). "Inhibition of Heat-Stable Toxin-Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors". The Journal of Infectious Diseases. 212 (11): 1806–1815. doi:10.1093/infdis/jiv300. ISSN 1537-6613. PMID 25999056.
  13. ^ a b Gadsby, David C.; Vergani, Paola; Csanády, László (2006-03-23). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature. 440 (7083): 477–483. doi:10.1038/nature04712. ISSN 0028-0836. PMC 2720541. PMID 16554808.
  14. ^ Park, Hyun Woo; Nam, Joo Hyun; Kim, Joo Young; Namkung, Wan; Yoon, Jae Seok; Lee, Jung-Soo; Kim, Kyung Sik; Venglovecz, Viktoria; Gray, Michael A. (August 2010). "Dynamic regulation of CFTR bicarbonate permeability by [Cl-]i and its role in pancreatic bicarbonate secretion". Gastroenterology. 139 (2): 620–631. doi:10.1053/j.gastro.2010.04.004. ISSN 1528-0012. PMID 20398666.
  15. ^ Eutamene, H.; Bradesi, S.; Larauche, M.; Theodorou, V.; Beaufrand, C.; Ohning, G.; Fioramonti, J.; Cohen, M.; Bryant, A. P. (March 2010). "Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain". Neurogastroenterology & Motility. 22 (3): 312–e84. doi:10.1111/j.1365-2982.2009.01385.x. ISSN 1365-2982. PMID 19706070.
  16. ^ a b Pawfect Foods, Inc. (July 21, 2008). "Form 8-K: Current Report Filing". US Securities Exchange Commission. Retrieved 27 October 2017.
  17. ^ "Synergy Pharmaceuticals Strengthened by Merger Agreement". Seeking Alpha. 23 July 2012. Retrieved 27 October 2017.
  18. ^ "Research and Development :: Synergy Pharmaceuticals Inc. (SGYP)". Synergy Pharmaceuticals Inc. Retrieved 2017-10-27.
  19. ^ Millennial, Life Sciences (2017-08-03). "Synergy Pharmaceuticals: Debt Vs. Equity Financing And The Concept Of Tradeoffs". Seeking Alpha. Retrieved 2017-10-27.
  20. ^ "Synergy Pharmaceuticals Reports First Quarter 2017 Financial Results and Business Update :: Synergy Pharmaceuticals Inc. (SGYP)". Synergy Pharmaceuticals Inc. Retrieved 2017-10-27.
  21. ^ "Express Scripts Stiff-Arms Synergy Pharmaceuticals Inc's (SGYP) Trulance; Canaccord Analyst Comments - Smarter Analyst". Smarter Analyst. 2017-07-31. Retrieved 2017-10-27.
  22. ^ "Synergy Pharmaceuticals Announces Issuance of Three New Patents Expected to Extend TRULANCE™ (Plecanatide) Patent Protection Until 2032". www.businesswire.com. Retrieved 2017-10-27.
  23. ^ "Ironwood Lied To Patent Offices: $500M Suit - Law360". www.law360.com. Retrieved 2017-10-27.
  24. ^ "Open-label Extension (OLE) Study of Plecanatide for Chronic Idiopathic Constipation (CIC)". clinicaltrials.gov. 15 August 2016. Retrieved 27 October 2017.
  25. ^ "Long Term Safety Study of Plecanatide (IBS-C)". clinicaltrials.gov. 5 October 2017. Retrieved 27 October 2017.
  26. ^ "Synergy Pharmaceuticals Announces Acceptance of Supplemental New Drug Application (sNDA) for TRULANCE™ (Plecanatide) for the Treatment of Adults with Irritable Bowel Syndrome with Constipation (IBS-C) :: Synergy Pharmaceuticals Inc. (SGYP)". Synergy Pharmaceuticals Inc. Retrieved 2017-10-27.