|Chemical and physical data|
|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) 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.
- 1 Therapeutics
- 2 Pharmacology
- 3 Commercialization
- 4 See also
- 5 References
Indications for use
As of January 2017, Plecanatide is approved in the United States for the treatment of chronic idiopathic constipation in adults. 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. 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.
Plecanatide has not been shown to be safe or effective in persons 6 years to 18 years of age. 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.
Use of Plecanatide is also contraindicated in persons who are suspected of having a mechanical gastrointestinal obstruction.
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.
Structure and function
Plecanatide is a 16 amino acid peptide with the amino acid sequence:
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. 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. The second is the ACTGC motif (residues Ala11 to Cys15) which is the region responsible for its binding to the receptor, guanylate cyclase-C.
Mechanism of action
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. 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. 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. 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.
Plecanatide is also known to have an anti-nociceptive effect in animal models, however the exact mechanism of action is not yet fully elucidated. 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.
Pharmacokinetics and metabolism
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. As with most orally ingested peptides, Plecanatide is degraded by intestinal enzymes and so very little of the active drug enters systemic circulation. 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. 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.
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. 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. Plecanatide is currently Synergy's only drug on the market.
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.
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. However, Express Scripts recently announced they would not include Trulance on its 2018 preferred drug formulary and SGYP has since taken a hit.
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. Three new patents for method of manufacturing, formulations, and methods of using Plecanatide were issued by the USPTO. 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. In addition, there are also eight foreign patents for Plecanatide.
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. 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. 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.
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.
- Linaclotide, another guanylate cyclase-C agonist
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