Status: marketed in U.S.

Organizations involved:

Repligen Corp. – USA mark.

ChiRhoClin, Inc. – R&D; Tech.

Chesapeake Biological Labs. – Manuf.

CSL Ltd. - Parent

Cross ref.: See the entry above concerning synthetic porcine secretin for further background information about secretin. Note, these two products are from the same companies, are approved for the same indications:, and have the same prices.

Description: Synthetic human secretin (ChiRhoStim) is a synthetic (not a biopharmaceutical) lyophilized (freeze-dried) formulation of secretin, a peptide hormone. Secretin has an amino acid sequence identical to naturally occurring human secretin, a gastrointestinal peptide hormone that aids in the digestive process. Human secretin has the amino acid sequence His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Glu-Gly-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH2, a molecular weight of 3039.4 Dalton (3.04 kDa), and an empirical formula of C130H220N44O40. Solid phase peptide synthesis methods are used to manufacture human secretin, with purification including high performance liquid chromatography (HPLC).

Each vial contains 16 µg of purified synthetic human secretin, 1.5 mg of L-cysteine hydrochloride, 20 mg of mannitol, and 0.9 mg of sodium chloride. When reconstituted in 8 mL of Sodium Chloride Injection USP, each mL of solution contains 2 mcg synthetic human secretin for intravenous use in the pH range 3 to 6.5. ChiRhoStim has a dating period of 24 months when stored at –20˚C (in a freezer). It may be “temporarily” stored at 2-8˚C (refrigerated) for up to one year, and up to six months at room temperature.

Note, pharmacological activity, pharmacodynamics, dosing, approved indications:, and prices for synthetic human and porcine secretin are the same. The human product offers advantages in terms of stability and storage.

Nomenclature: Secretin, human, synthetic [BIO]; ChiRhoStim [TR]; Human Secretin [FDA]; secretin [USAN INN]; 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--glutamylglycyl-L-alanyl-L-arginyl-L-leucyl-L-glutaminyl-L-arginyl-L-leucyl-L-leucyl-L-glutaminylglycyl-L-leucyl-L-valinamide [CAS]; 108153-74-8 [CAS]; RG1068 [SY]; synthetic human secretin [SY]; human secretin, synthetic [SY]; NDC 67066-002-01 [NDC]

Companies.: ChiRhoStim 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. ChiRhoStim is marketed by Repligen in the U.S. to hospital based gastroenterologists. ChiRhoStim is manufactured for ChiRho-Clin by PolyPeptide Laboratories, Chesapeake Biological Labs., a subsidiary of CSL Ltd.

Approvals: Date = 20040409; NDA 21-256

Date = 20051026; NDA supplement; Indication = approval of ChiRhoStim as proprietary name for use in labeling

Indications: [full text of the "INDICATIONS AND USAGE” of product insert/labeling, 4/25/2006]:

ChiRhoStim is indicated 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, and (3) Stimulation of pancreatic secretions to facilitate the identification of the ampulla of Vater and accessory papilla during endoscopic retrograde cholangiopancreatography (ERCP).

See DOSAGE AND ADMINISTRATION Section for proper methodologies for performing the secretin pancreatic stimulation test as well as its use to facilitate identification of the pancreatic duct papillae and gastrin stimulation test.

Status: The NDA was submitted by ChiRhoClin, Inc. on June 14, 2001. An NDA amendment was filed in June 2001. An Approvable Letter was received on Dec. 14, 2001. Deficiencies in the NDA were corrected, and the NDA was approved on April 9, 2004. FDA has granted RG1068 Orphan Drug status and Fast Track Designation.

Both ChiRhoStim and SecreFlo have orphan designation, and both are classed by FDA as New Chemical Entitities (NCEs).

Marketing: Vials have been reported to cost the same as SecreFlo (see entry above).

The Average Wholesale Price (AWP) is not available (not in 2007 Red Book).

ChiRhoStim is Medicare-reimbursable with J-Code 2850, effective Jan. 1, 2006.

In June 2010, Repligen reported, "Recently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved our proposal to re-analyze the images from our Phase 3 study to establish the utility of RG1068, synthetic human secretin, in improving magnetic resonance imaging (MRI) of the pancreas (Phase 3 re-read). The FDA and EMA have agreed to the Phase 3 re-read based on the numerous deficiencies with the analysis of the radiographic images by the contract research organization hired to oversee analysis of the Phase 3 data. A successful re-read of the Phase 3 data may support registration of RG1068 for MRI imaging of the pancreas. The goal of the Phase 3 study is to evaluate the sensitivity and specificity of RG1068 in combination with MRI to improve the detection of structural abnormalities of the pancreatic ducts relative to MRI alone. Detailed visual assessment of the pancreatic ducts is important in the assessment, diagnosis and treatment of diseases such as acute and chronic pancreatitis. There are more than 300,000 MRI procedures conducted in the U.S. and Europe each year that could directly benefit from the addition of RG1068."

In March 2012, Repligen reported positive top-line results from a Phase iii study to evaluate the safety and efficacy of RG1068, synthetic human secretin, to improve magnetic resonance imaging (MRI) of the pancreas in patients with pancreatic disease using endoscopy (ERCP) as a diagnostic reference. Repligen reported, "This was a multi-center, baseline controlled, single dose study in which 258 patients enrolled at 29 clinical sites within the U.S. and Canada received an MRI of the pancreas with and without RG1068, and separately an ERCP. The MRI images were randomized and independently reviewed by three radiologists for evaluation of the presence or absence of 10 pre-specified pancreatic duct abnormalities, image quality, visualization of the main pancreatic duct and confidence in diagnostic findings. The study’s co-primary endpoints were an improvement in sensitivity of detection of structural abnormalities of the pancreatic ducts using RG1068 in combination with MRI compared to MRI alone with minimal loss in specificity (<7.5%). The study design used ERCP as the diagnostic reference for determination of structural abnormalities. The analysis of the Phase 3 radiographic images was a “re-read” which was agreed to by the Food and Drug Administration and European Medicines Agency based on the determination that the original analysis was flawed and therefore inconclusive due to deficiencies in performance by the contract research organization overseeing the original analysis. A new contract research organization and three new radiologists were hired to conduct the re-read."