Secretin Data Presented at World Congress of Pediatric Gastroenterology Five Studies Characterize Effects of Secretin in Children with Autism NEEDHAM, MA - August 9, 2000 - Five research groups presented results at the World Congress of Pediatric Gastroenterology in Boston, August 5-9, on studies which evaluated the effects of secretin in autistic children. These studies, which characterized the safety, changes in gastrointestinal symptoms, changes in the symptoms of autism, or changes in the biology of secretin-treated children, are described below. A study presented by researchers from Repligen Corporation characterized changes in the metabolic profiles in autistic children treated with secretin through a detailed urine analysis. This study found that a subset of children show changes in their urinary metabolic profiles as a result of secretin treatment. "These five studies provide important data relevant to the development of secretin in autism and expand the effort to understand gastrointestinal symptoms in these patients and their potential connection to the core symptoms of autism," stated Walter C. Herlihy, Ph.D., President and CEO of Repligen. "A consistent theme in these Phase 1 studies is the observation that there may be a subset of children whose gastrointestinal or behavioral symptoms are particularly responsive to secretin." Secretin Improves Intestinal Permeability in Autistic Children. K Horvath, RH Zielke, RM Collins, A Rabsztyn, LA Medeiros, J Perman, Dept. of Pediatrics, University of Maryland School of Medicine, Baltimore, MD. Prior studies have reported that a significant fraction of autistic children suffer from a form of intestinal dysfunction characterized by elevated intestinal permeability ("leaky gut"). This study examined the intestinal permeability of 25 autistic children and measured the changes following a single secretin injection. Initially, 76% (19/25) of the patients had abnormally elevated intestinal permeability prior to treatment. The effect of secretin on intestinal permeability in autistic children was evaluated in a double-blind, placebo-controlled study which included one placebo and one porcine secretin (Ferring) injection for each patient. Urine specimens were collected one week prior to and three weeks after the secretin/placebo injections. Analysis of urine samples from 20 children demonstrated a significant decrease in the level of intestinal permeability at the end of the trial (p=0.012). A decrease in permeability was observed in 13 out of the 20 patients (65%), there were no changes noted in 2 patients (10%) and an increase in permeability was seen in 5 patients (25%). The authors concluded that a significant percentage of autistic children have abnormal intestinal permeability which may be improved by a single secretin injection. Evaluation of Gastrointestinal Symptoms in Autistic Children Before and Following Secretin Infusion. JR Lightdale, C Hayer, B Siegel, GR Elliott, MB Heyman, Dept. of Gastroenterology and Nutrition, Children's Hospital, Boston, MA; Psychiatry; Pediatrics, University of California, San Francisco, CA. This study enrolled 20 autistic children (18 male), aged 3-6 with a confirmed diagnosis of autism, and reported GI symptoms for an open- label trial of secretin. Children were monitored in the clinic for 24- hours for stool collection. Clinical observations confirmed parental reports that 16/20 (80%) of the children were documented to have loose stools during the 24-hour period. A 3 CU/Kg dose of porcine secretin (Ferring) was then administered. At the one-week follow-up visit, 7/16 (44%) of children with previously noted diarrhea brought diapers containing formed stool to the clinic. A majority of the parents (15/20) also reported fewer and more formed stools during the 5-week follow-up period. The authors conclude that potential pancreatic dysfunction and/or the role of secretin in GI symptoms in autism require further investigation. The authors also recorded changes in expressive language in this same clinical study using the Preschool Language Scale-3 (PLS-3). No statistically significant difference (p between baseline and follow-up evaluations at 1, 2 ,3 and 5 weeks post-treatment. Parents were also surveyed and 83% reported moderate to significant language improvement following secretin. The authors conclude that previously reported language gains could not be confirmed with the PLS-3 and that parental observations differ significantly from the PLS-3 test results. Without a placebo group it is not possible to determine to what extent the parental reports are due to a placebo effect or whether parents are more sensitive observers of language than the PLS-3 test. Synthetic Human Secretin in the Treatment of Pervasive Developmental Disorders. CK Schneider, RD Melmed, CL Martin, RA Fabes, M Balhorn, Southwest Autism Research Center, Phoenix; AZ, Family Resources and Human Development, Arizona State University, Tempe, AZ. This study assessed the efficacy of synthetic human secretin in the treatment of pervasive developmental disorders using a double-blind, placebo controlled design in which participants were followed for 12 weeks after a single infusion of secretin or saline placebo. Thirty autistic children aged 2 to10 were randomly assigned to one of three groups to receive either high dose (0.4 mg/kg) secretin, low dose (0.2mg/kg) secretin, or saline placebo. Psychological and language assessments and gastrointestinal histories were obtained at baseline and at 3, 6, and 12 weeks post-infusion. The average scores on the Childhood Autism Rating Scale, Vineland Adaptive Behavior Scales, Gilliam Autism Rating Scale, and the Preschool Language Scale-3 improved over time in all three treatment groups. Upon further analysis, it was found that greater severity of autistic symptoms at baseline correlated with greater improvement at 6 and 12 weeks as the dosage of secretin increased. In contrast, single dose secretin therapy was generally ineffective in children who presented with mild or moderate levels of autism. The authors conclude that secretin was somewhat more effective when the symptoms of autism were more severe, and this effectiveness was greater with higher dose secretin therapy suggesting that future studies focus on this patient subset and dose. Safe Use of Intravenous Secretin in Autistic Children. R Sockolow, D Meckes, K Hewitson, V Atluru, Dept. of Pediatrics, Winthrop-University Hospital, Mineola, NY. The safety of secretin was assessed in 34 autistic children for immediate clinical reactions and post injection side effects within the 6 weeks following two doses of porcine secretin (Ferring). There were no immediate life threatening side effects. Analysis of blood samples showed that 25 of the 34 had low secretin levels just before the first dose. None had secretin antibodies before or after the secretin injection. A dramatic change in their sociability was noted by parents and therapists/ doctors in 4 of the 34 (12%) patients. All 4 had low baseline secretin levels and a positive anti-gliadin IgG. The authors conclude that two doses of intravenous secretin is safe to use in children provided that they are observed for at least 1 hour and that a small subset of children who are anti-gliadin IgG positive and have low secretin levels have a greater chance for significant improvement in their autistic symptoms. Analysis of Compounds in the Urine of Autistic Children with HPLC and Mass Spectrometry. J Zhang, G Rivers, J Peyser, B Zack, K Horvath, J Rusche, Repligen Corporation, Needham, MA; Pediatrics, U. of Maryland School of Medicine, Baltimore, MD. Previous studies have reported opioid peptides in urine and altered amounts of some urinary metabolites. Urine samples were collected from 40 autistic children aged 3-12 and 44 healthy children and analyzed by HPLC-MS/MS. The most significant difference in the two groups was a significant fraction (47%) of the autistic patients with undetectable levels of 7- methylxanthine in their urine. In a double- blind, placebo-controlled, crossover clinical study in 20 children the effect of placebo vs. secretin was evaluated on urinary metabolites. There was a significant increase in urinary 7- methylxanthine following secretin which was not observed following placebo administration. Four autistic children who had no detectable levels of 7-methylxanthine at the beginning of the study showed an increase of greater than 100-fold following secretin. The authors concluded that additional studies are warranted to determine if a lack of urinary 7-methylxanthine defines a subset of autistic children who may be more responsive to secretin. Repligen is currently conducting a Phase 2, placebo-controlled clinical trial of three doses of secretin in young children with autism at five sites in the United States: the Mayo Clinic (Rochester, MN), Southwest Autism Research Center (Phoenix), Rochester Institute for Digestive Diseases (Rochester, NY), University of Maryland Medical Center (Baltimore) and University of California, Davis/MIND Institute (Sacramento). Repligen Corporation develops new drugs for debilitating pediatric disorders including autism, organ transplant and cancer. Repligen also manufactures and markets a set of patented products based on Protein A, which are used by the pharmaceutical industry to produce therapeutic antibodies. Its corporate headquarters are located at 117 Fourth Avenue, Needham MA, 02494. Additional information may be requested from www.repligen.com. This press release contains forward-looking statements based on current management expectations. There are certain key factors which could cause future results to differ materially from those anticipated by management. Such factors include, but are not limited to: uncertainty in the realization of future revenues, the uncertain timeline for clinical activity, results of pending or future clinical trials, the Company's ability to continue to establish collaborative arrangements with third parties, the Company's ability to maintain financial stability, the technical risks associated with development and manufacture of clinical products, the fact that there can be no assurances that patents relating to the Company's potential products will afford adequate protection to the Company, the risks of technological change and competition, and the competitive environment of the biotechnology and pharmaceutical industries. These factors are more fully discussed in the Company's periodic filings with the Securities and Exchange Commission. reposted byAngela