Synthetic Porcine Secretin; SecreFlo
Status: marketed in U.S.
Organizations involved:
Repligen Corp. – USA mark.
ChiRhoClin, Inc. – R&D; Tech.; Patent dispute
Chesapeake Biological Labs. – Manuf.
CSL Ltd. - Parent
Cross ref.: See also the entry for ChiRhoStim, a synthetic human secretin. Note, these two products are from the same companies, are approved for the same indications:, and have the same prices.
Description: Synthetic porcine secretin (SecreFlo) is a synthetic (not a biopharmaceutical) lyophilized (freeze-dried) powder acetate salt of secretin, a peptide hormone. Secretin has an amino acid sequence identical to naturally occurring porcine (pig) secretin, a gastrointestinal peptide hormone that aids in the digestive process. Secretin has an 27-amino acid sequence (H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2), a molecular weight of 3055.5 Dalton (3.06 kDa), and an empirical formula of C130H220-N44O41. This is the first synthetic, rather than porcine-derived, version of secretin to receive FDA approval. Solid phase peptide synthesis methods are used to manufacture porcine secretin, with purification including high performance liquid chromatography (HPLC).
Each SecreFlo vial contains 16 µg of purified secretin, 15 mg of L-cysteine hydrochloride, and 20 mg of mannitol. When reconstituted in 8 mL of Sodium Chloride Injection USP, each mL of solution contains 2 µg secretin for intravenous use and a pH of 3-6.5. Vials are stored at -20˚C (frozen). One microgram (µg) of Synthetic Porcine Secretin is approximately equal to five ( 5 ) clinical units ( CU ). Vials are stored at -20°C (in a freezer). [The product insert does not specify a dating/expiration period, but this porcine secretin is definitely less stable than the human secretin product].
Porcine duodenum-derived secretin had long been available, e.g., manufactured and marketed by Ferring Labs., for single dose use in diagnosis of impaired pancreatic function, pancreatic exocrine disease, and gastrinoma-Zollinger-Ellison syndrome; and as an adjunct in obtaining desquamated pancreatic cells for cytopathologic examination.
Note, pharmacological activity, pharmacodynamics, dosing, approved indications:, and prices for synthetic porcine and human secretin are the same.
Nomenclature: Secretin, porcine, synthetic [BIO]; SecreFlo [TR Repligen]; SecreMax [TR ChiRhoClin former]; Synthetic Porcine Secretin [FDA]; secretin (human), 15-L-glutamic acid-16-glycine- [CAS]; L-histidyl-L-seryl-L--aspartylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L--glutamyl-L-leucyl-L-seryl-L-arginyl-L-leucyl-L-arginyl-L--aspartyl-L-seryl-L-alanyl-L-arginyl-L-leucyl-L-glutaminyl-L-arginyl-L-leucyl-L-leucyl-L-glutaminylglycyl-L-leucyl-L-valinamide [CAS]; 17034-35-4 [CAS RN]; RG1068 [SY]
Biological.: Secretin (porcine and human) is produced by the S-cells of the small intestine, and is released when the upper part of the lower intestine (duodenum) is exposed to the acidic contents of the emptying stomach. The hormones primary action is to increase the volume and bicarbonate content of secreted pancreatic juices. Secretin is released into the blood and stimulates the pancreas to discharge bicarbonate, which neutralizes the contents of the intestine. Secretin also augments the release of digestive enzymes from the pancreas and inhibits further production of acid in the stomach.
Secretin is a useful diagnostic tool because of its stimulatory effects on the pancreas. Secretin acts as a hormone to increase pancreatic secretions (required for proper digestion of food), including bicarbonate, and is used to facilitate diagnosis of pancreatic disorders (pancreatic exocrine dysfunction; chronic pancreatitis), and also to increase stomach secretion of gastrins (hormones that increase secretion of hydrochloric acid for digestion) to facilitate diagnosis of gastri-noma (tumors that secrete gastrin, associated with Zollinger-Ellison syndrome).
The standard unit of activity used for SecreFlo is the clinical unit reported in Acta Physiol Scand vol. 66, 316-325, 1966. This validated cat bioassay has been used to define and quantitate the biological activity of secretin (and as the release test for the porcine-derived secretin product). SecreFlo demonstrates a potency of ~5,000 clinical units (CU)/mg of peptide, as opposed to 3,000 CU per mg for porcine-derived secretin. As a pure peptide drug product, SecreFlo dosing is expressed by weight in micrograms (µg), with 0.2 µg = 1 CU.
History: Secretin-Ferring, a natural porcine version extracted from pig intestines, was formerly approved/marketed in the U.S. by Ferring AB (Sweden) for in vivo diagnostic use in pancreatic dysfunction. The product had an excellent safety record (no reported adverse events in over 20 years), but demand was low. Ferring, anticipating the introduction of synthetic secretin, manufactured what should have been enough of the hormone to supply the market for several years and then discontinued the product in 1998. Remaining supplies were rapidly exhausted by off-label use after widespread publicity (anecdotal reports) in Oct. 1998 that secretin reduced the symptoms of autism in several children.
Companies.: SecreFlo was developed by ChiRhoClin, Inc. Repligen exclusively licensed marketing rights for both synthetic porcine and human secretin for diagnostic products from ChiRhoClin in Oct. 1999. ChiRhoClin is responsible for regulatory affairs and manufacturing. Repligen assumed all marketing and distribution after approval. SecreFlo is marketed by Repligen in the U.S. primarily to hospital based gastroenterologists. SecreFlo is manufactured for ChiRho-Clin by Chesapeake Biological Labs., a subsidiary of CSL Ltd.
FDA class: Drug NDA
Approvals: Date = 20020404; NDA; orphan designation (expires 4/4/2007)
Date = 20021101; NDA supplement; Indication = assist in the location and cannulation of the minor pancreatic duct in patients with pancreas divisum undergoing ERCP
Date = 20040103; NDA supplement; Indication = unspecified manufacturing change
Date = 20040301; NDA supplement; Indication = formulation revision
Date = 20040726; NDA supplement; Indication = labeling revision including changing trade name to SecreMax; replacing all mentions of Repligen with ChiRhoClin
Date = 20050912; NDA supplement; Indication = labeling revision including changing trade name back to SecreFlo
Indications: [full text of the "INDICATIONS AND USAGE” section of the product insert/labeling, 4/6/2006]:
SecreFlo is indicated for use in secretin stimulation testing for: (1) Stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of pancreatic exocrine dysfunction; (2) Stimulation of gastrin secretion to aid in the diagnosis of gastrinoma; (3) Stimulation of pancreatic secretions to facilitate the identification of the ampulla of Vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP).
Status: ChiRhoClin filed its NDA in May 1999 (approval time = ~2.9 years). An Approvable Letter was received March 2000; and a second Approvable Letter was received in Nov. 2000. Deficiencies note by FDA were corrected and the NDA was approved on April 5, 2002. SecreFlo was approved with orphan drug status, with U.S. market exclusivity for seven years following FDA approval. Secretin has no FDA-approved therapeutic indications:. It is approved only for uses as a diagnostic aid. SecreFlo was launched in the U.S. on July 28, 2004.
SecreFlo was approved with orphan designation, providing seven years of market exclusivity (unless similar products are classed as New Chemical Entitities, i.e., different products), and was classed by FDA as a New Chemical Entitities (NCE).
SecreFlo has not received centralized European Union approval, and does not appear to be marketed in European countries.
Tech. transfer: Repligen’s licensing of secretin included use patents assigned to (or licensed by) ChiRhoClin Inc. Repligen has received U.S. 6,020,310 covering use of secretin for treatment of autism.
In May 2005, Repligen settled a dispute with ChiRhoClin concerning licensing of its patents, and ChiRhoClin received an award of $750,000. The payment is due to “failed” obligations related to the ChiRhoClin licensing agreement, Repligen had received exclusive rights related to SecreFlo in Oct. 1999. This included paying undisclosed royalties to ChiRhoClin. Repligen terminated this arrangement in Feb. 2004, citing certain deficiencies in ChiRhoClin’s “product and clinical development.” As part of the settlement, Repligen was relieved of having to pay $1.2 million in royalties owed to ChiRhoClin.
In May 2010, Repligen reported that both FDA and EMA had approved the company's proposal for reanalysis of images from a Phase III study of Secretin to improve MRI imaging of pancreas.
Trials: In Sept. 2004, Repligen started an open-label, dose-escalation, U.S. Phase I trial in up to 16 obsessive compulsive disorder (OCD) patients who will receive subcutaneous SecreFlo three times a week for one month.
Medical: Secretin is generally administered as part of a multi-step diagnostic procedure that consists of fasting, oral intubation, administration of test and diagnostic doses of secretin, and collection and evaluation of duodenal fluids. For diagnosis of pancreatic exocrine dysfunction and ERCP procedures, the usual adult dose of secretin is 0.2 µg/kg, administered by slow intravenous injection over one minute. For diagnosis of gastrinoma, the dose is 0.4 µg/kg, infused similarly.
Pancreatic function tests are considered by many to be the most accurate means of diagnosing chronic pancreatitis, particularly when radiological images of the abdomen are normal or inconclusive and when it is necessary to demonstrate exocrine insufficiency for the purpose of determining treatment options. SecreFlo increases the volume and bicarbonate content of digestive juices that are secreted by the pancreas as part of the normal process of digestion. As a stimulant in the pancreatic function test, it aids in the diagnosis of exocrine pancreas dysfunction. The volume and bicarbonate concentration of collected fluids can determine the function level of the pancreas. In trials with SecreFlo, pancreatic exocrine insufficiency typically associated with chronic pancreatitis was indicated in patients with pancreatic fluid bicarbonate concentrations <80 mEq/L in any sample. To stimulate pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction, 0.2 µg/kg body weight of SecreFlo is administered by intravenous injection over 1 minute.
A gastrinoma is a tumor typically found in the pancreas and duodenum and is the hallmark of a relatively rare gastrointestinal disorder known as Zollinger-Ellison Syndrome (ZES). Gastrinomas secrete large quantities of the hormone gastrin, which triggers gastric acid production that can then produce ulcers. ZES constitutes 0.1% or more of cases of peptic ulcer disease . A gastrinoma can be malignant or benign. Although rare, gastrinomas are the most common pancreatic islet cell tumors. Definitive diagnosis of a gastrinoma can be difficult due to the similarities in symptoms with peptic ulcer disease including burning pain in the abdomen, diarrhea, nausea, vomiting, fatigue, weakness and weight loss. SecreFlo administered intravenously stimulates the release of excessive amounts of gastrin into the bloodstream of patients with a gastrinoma. Normal subjects or patients with other peptic ulcer diseases experience only small changes in serum gastrin concentrations. Gastrinoma is strongly suspected in patients showing an increase in serum gastrin concentration of more than 110 pg/mL over basal gastrin levels on any post-SecreFlo injection samples. For stimulation of gastrin secretion to aid in gastrinoma diagnosis, 0.4 µg/kg body weight of SecreFlo is administered by intravenous injection over 1 minute.
Trials: Clinical trials demonstrated that SecreFlo is functionally equivalent to porcine-derived Secretin-Ferring.
In June 2006, Repligen initiated a trial of the diagnostic use of RG1068 for functional magnetic resonance imaging of the pancreas. This is a multi-center, baseline controlled, single-dose study in which 80 patients with a history of pancreatitis will receive a secretin-enhanced MRI and an unenhanced MRI of the pancreas. This study will assess the sensitivity and specificity of secretin-enhanced MRI to improve the ability to detect pancreatic duct abnormalities relative to unenhanced MRI as well as the safety of secretin in combination with MRI. The study is designed to confirm and quantify the clinical observation that patients with pancreatic disease have reduced pancreatic fluid production in response to stimulation by secretin.
Market: The 2007 Average Wholesale Price (AWP) is $390/vial (no change since in 2004) (Red Book, 2007).
Off-label sales of SecreFlo could increase significantly, if secretin shows efficacy in ongoing trials for treatment of autism. Sales would further increase, if approved for autism (a disease occurring with increasing incidence and for which there are currently few effective treatments).
Presumably, like ChiRhoStim (see entry below), SecreFlo is now Medicare-reimbursable with J-Code 2850, effective Jan. 1, 2006.
R&D: In Sept. 2004, Enzon Pharmaceuticals, Inc. and Pharmagene plc concluded an agreement for the development of a PGN0052, a long-acting, pegylated form of secretin using Enzon’s pegylation technology, for treatment for cystic fibrosis and, perhaps, other respiratory disorders. Non-pegylated PGN0052 was then in Phase I and IIa trials, with positive results reported.
Companies involvement:
Full monograph
935 Secretin, porcine, synthetic
Nomenclature:
Secretin, porcine, synthetic [BIO]
SecreFlo [TR Repligen]
SecreMax [TR ChiRhoClin former]]
L-histidyl-L-seryl-L-a-aspartylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-a-glutamyl-L-leucyl-L-seryl-L-arginyl-L-leucyl-L-arginyl-L-a-aspartyl-L-seryl-L-alanyl-L-arginyl-L-leucyl-L-glutaminyl-L-arginyl-L-leucyl-L-leucyl-L-glutaminylglycyl-L-leucyl-L-valinamide [CAS]
17034-35-4 [CAS RN]
porcine secretin, synthetic [SY]
synthetic porcine secretin [FDA]
FDA Class: Drug NDA orphan
Year of approval (FDA) = 2002
Date of 1st FDA approval = 20020404
(in format YYYYMMDD)
Index Terms:
hormones
non-Hodgkin's lymphoma (NHL)
peptides, synthetic
suspension cell culture
cysteine
lyophilized (freeze-dried)
mannitol
pepsin digestion
sodium chloride
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
orphan status
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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