Repligen's SecreFlo is approved as a diagnostic tool and is being studied for treating autism
Few pharmacists know much about secretin, a hormone produced by the small intestine, but a lot of parents of autistic children do. During the past five years, this hormone has made headlines on several occasions, and now it is back in the news once again. What is secretin and why the hype?
Under normal circumstances, secretin is a hormone produced in the gastrointestinal tract that is involved in several different aspects of food digestion. For example, when acidic foods enter the small bowel, secretin is released by the S cells of the duodenum. Secretin then gets transported to the pancreas where it stimulates the release of bicarbonate, water, and small amounts of digestive enzymes into the small intestine. These components, especially bicarbonate, mix with acidic foods and aid in digestion.
Another role for secretin in the digestive tract involves stimulation of gastrin. When gastrin is released, it triggers the secretion of stomach acid, mucin, and pepsinogenother important chemicals for food digestion.
Several years ago, Ferring Pharmaceuticals of Sweden marketed a porcine-derived secretin product as a diagnostic tool to identify some gastrointestinal diseases, but in 1999 the manufacturer halted production. Since then, supplies have dwindled and the product has been available only to patients enrolled in clinical trials. However, with the recent Food & Drug Administration approval of a synthetic secretin (SecreFlo, RepliGen Corp.), the product is available once again.
The newly approved secretin is the first synthetic porcine-derived secretin formulation. It consists of 27 amino acids that are identical to the naturally occurring porcine peptide. The product was granted orphan drug status by the FDA since it is estimated that only about 15,000 patients will need the product each year. It is indicated as a diagnostic aid for pancreatitis and gastrinoma.
Rosemary Berardi, Pharm.D., professor of pharmacy and a clinical pharmacist with the University of Michigan, said, "The diagnosis of pancreatitis or Zollinger Ellis syndrome [hypersecretion of gastrin, e.g., when a gastrinoma is present] may be made with secretory studies and other kinds of abdominal tests, such as CT scans. Secretin is a test that can be used to help make the diagnosis."
Tracy Normandin, a sales and marketing representative for RepliGen, acknowledged that secretin is intended to be used as a diagnostic aid with other abdominal studies. She said that even after pancreatitis has already been diagnosed, it is sometimes useful for clinicians to determine to what extent the exocrine functions of the pancreas are still intact. This may be assessed by administering secretin intravenously to patients with chronic pancreatitis. The bicarbonate output from the pancreatic duct (secreted in response to secretin) can be collected and analyzed. If there is less than 80 mEq/L bicarbonate secreted in response to a secretin challenge, this indicates a deficit in pancre-atic function.
Likewise, secretin can also be used to diagnose gastrinomas, or rare tumors that secrete excess gastrin. Gastrinomas lead to stomach ulcerations and erosions. Roughly half of these tumors are malignant. If gastrin levels rise to greater than 110 pg/ml following a challenge with secretin, this suggests the presence of a gastrinoma.
When secretin is used as a diagnostic tool, it appears to be remarkably safe. In fact, Normandin said that in clinical trials, "side effects are occasional and mild. There were no reports of allergies." However, since the product is a porcine derivative, allergic reactions are possible. As a result, it is recommended that a small IV test dose be administered prior to infusing the agent. Another synthetic secretin productidentical to human secretinis also under evaluation by RepliGen for diagnostic use and would be suitable for people with porcine allergies. FDA approval may come in as little as 18 months.
Currently approved indications for secretin are limited to diagnosis of pancreatic dysfunction and gastrinomas. However, perhaps the most interesting thing about secretin is that in addition to its activities in the gut, it also appears to play a role in the brain. Secretin receptors, especially those in the amygdala, may be the next targets of secretin's therapeutic actions, as RepliGen evaluates another secretin formulation for efficacy in autistic children.
According to Laura Whitehouse, senior director, market development at RepliGen, "This product is different from the diagnostic products in that its specifications [purity, testing, characterization, etc.] are different, the formulation is different, the amount of secretin in the vial is different, and it has undergone much more extensive preclinical testing as would be expected for a multidose therapeutic that is being developed in a pediatric indication."
This other secretin formulation is currently in phase III clinical trials in children with autism. Autism is a severe psychiatric disorder, usually diagnosed before three years of age, in which children have difficulties with social interactions, display deficits in language and communication, and exhibit repetitive and limited behavioral patterns. Although several studies have failed to demonstrate a positive correlation in autistic behaviors following secretin therapy, according to RepliGen president and CEO, Walter Herlihy, Ph.D., there is a subset of childrenthose three and four years oldwho exhibit a robust response to secretin as measured by the Autism Diagnostic Observation Schedule, the current gold standard in assessing function in autistic children.
Although some children in phase II trials demonstrated improvements in emotional expressions, sharing enjoyment, and making eye contact while receiving the medication, partial regression in these areas was noted after completing the study. This suggests that while secretin may modify symptoms of autism, it probably does not significantly change the course of the disease.
The first phase III study is currently under way and expected to be completed in early 2003. In the study, six injections of either secretin or placebo are given to approximately 300 children aged three to six with moderate to severe symptoms over 18 weeks. If RepliGen secures FDA approval for this indication, it will be the first product approved for treating autism.
Kelly Karpa. Multiple uses may be likely for secretin. Drug Topics 2002;10:HSE17.