|Image courtesy of Bernard Rimland|
"Birches" by Mark Rimland, an autistic artist.
"There's the possibility of a real public health crisis," warns Marie Bristol-Power, health scientist administrator in the mental retardation and development disabilities branch of the National Institute of Child Health and Human Development in Bethesda, Md. "I spoke to a woman whose child had gotten 15 doses daily, for 15 days in a row."
She adds that the woman only stopped buying the drug when she ran out of money. As secretin supplies grow scarce, vials that wholesale for $179 each are being sold to parents for several thousand dollars in some cases, Bristol-Power says. "You have people calling who are literally mortgaging their houses to get this compound."
The sudden rise of interest in secretin stems from the efforts of Victoria Beck, a New Hampshire mother of an autistic child who suffered from severe gastric problems, a relatively common complaint in autism. In 1996 she and her husband Gary took their son Parker, then aged three, to see Karoly Horvath, director of the pediatric gastroenterology and nutrition laboratory at the University of Maryland School of Medicine. He administered secretin as part of his diagnostic tests. Within days the boy's digestion and sleep patterns improved markedly, and he began speaking, although he had been virtually mute until then.
Beck believes that secretin was responsible for the change in her son, but finding a physician who would prescribe multiple doses off-label was difficult. The doctors expressed concern about possible cross-reactivity with endogenous secretin. The manufactured compound, from Ferring Pharmaceuticals of Tarrytown, N.Y., is derived from pig intestines. Although its chemical configuration is only slightly different from that of human secretin, it is just 60 percent pure. The other 40 percent is unidentified protein fragments.
Beck eventually found a supply of the compound, and on October 6 the television program Dateline aired her story, followed by a Good Morning America segment the next day. By mid-October, Ferring Pharmaceuticals had sold out of secretin. Ironically, the company announced in May that it already had decided in late 1997 to stop production, largely because of low demand. No other form of secretin currently is licensed in the United States.
|Photo courtesy of Raun Melmed|
An autistic child participates in the secretin study.
The two main trials with National Institutes of Health backing will begin next month at the University of Washington and the University of Colorado. Other trials are being conducted at the Universities of Chicago, Utah, Pittsburgh, Pennsylvania, California at Irvine, and Harvard University, as well as Western Carolina Center in Morganton, N.C., Scottish Rite Hospital in Atlanta, Children's Hospital in Philadelphia, and Cleveland Clinic.
Michael G. Chez, a pediatric neurologist at Rush-Presbyterian Medical Center in Chicago, has conducted two trials using the Ferring product, one of them unblinded with 77 subjects, the other double blinded with 44 patients, 25 of whom went through a four-week follow-up. All subjects met criteria for either autism or the wider classification of pervasive developmental disorders. He says, "We came away unconvinced this treatment is worth anything."
Results of the two trials will be published as an abstract in the September Annals of Neurology, to coincide with the Child Neurology Society's annual meeting October 13-16 in Nashville. Chez has submitted a paper on the blinded trial to "a major autism research journal."
The first trial to use a new, synthetic human secretin has just been completed at the nonprofit Southwest Autism Research Center in Scottsdale, Ariz. Thirty children were divided into three groups, one of which received a normal dose, another a high dose, and the third a placebo. Extensive observational analyses were conducted every three weeks of the 12-week, double-blind study.
"The results are going to be a mixed bag, most likely," says developmental pediatrician Raun Melmed, the trial's codirector with obstetrician and gynecologist Cindy Schneider, a mother of two autistic children. "There are going to be clinical nuances involved, and it will be difficult to tease out who are the responders."
Pharmacokineticist Edward D. Purich helped to design the Scottsdale study and several others. He also helped to develop the Ferring product, later leaving the firm to start up ChiRhoClin, a private company in Silver Spring, Md., that makes synthetic forms of both human and porcine secretin. Purich has filed a new drug application for the synthetics, and is providing the compound free of charge for FDA-approved trials. However, only the porcine synthetic is being used in other trials, based on the reasoning that the Ferring biological extract is from pigs. If the porcine synthetic proves to be beneficial, more trials using the human synthetic will be mounted.
"Abatement of autistic symptoms with the use of secretin and other compounds has been reported for years, but [it] has been basically discounted," Purich comments. Secretin does have a physiological effect, stimulating generation of bicarbonate from the pancreas to neutralize gastric acid after meals, but he says any improvements in behavior or speech often have been attributed by physicians to the caregivers' anticipation of good results.
The widely variable symptoms and severity of autism could make it difficult to know what effects, if any, secretin has on the disorder. Characterized by impairments in social interaction and imagination, the most severe cases of autism can be marked by self-injurious or aggressive behavior, whereas the mildest forms resemble a personality disorder associated with a learning disability. There is no cure, although appropriate management may reduce undesirable behaviors.
Secretin's possible mechanism of action on autism is unknown, although there currently are two dominant theories. One is that its effects on digestion exert metabolic changes underlying the disorder. The other is that secretin may mediate serotonin levels in the brain, both hormones being produced in the small intestine. Among serotonin's known effects is improved alertness.
"All the studies being done right now are statistical probes, set up to define questions," Purich says. "There's no reason, on the basis of everything we know now, to think that it is working, and no reason to think it won't work. But we are moving down the road toward closure."
Nevertheless, he thinks it unlikely that a definitive judgment can be made on the hormone's effectiveness without a study that involves between 2,000 and 3,000 patients. Given the expense of such a study and the relatively small number of autism sufferers--the nonprofit Autism Society of America estimates that 500,000 people in the United States have the disorder--Purich doesn't foresee a major pharmaceutical company making such an investment.
|Image courtesy of Bernard Rimland, © Mark Rimland|
Mark Rimland's illustrations reveal attention to detail that is frequently characteristic of autism.
A biochemist and the father of a child with autism, Herlihy says secretin cured her chronic digestive problems and somewhat improved her speech, although those results were secondary in forming his opinion of the hormone's potential. The main reason was phone interviews that Repligen employees conducted with parents of afflicted children as part of FDA's due diligence requirements.
Another repository of such anecdotal evidence is Bernard Rimland, founder and director of the nonprofit Autism Research Institute (ARI) in San Diego. Victoria Beck donated 55 percent of secretin's autism patent rights to ARI, and both parties subsequently sold their rights to Repligen. Rimland, who served as chief technical adviser on the film Rain Man, in which Dustin Hoffman played an autistic savant, has four decades of experience in the field. He also has an autistic adult son.
"There's never been anything that came down the pike that's even nearly like secretin," he declares. He has spoken with about 100 of the approximately 250 doctors who have treated an estimated 3,000 autistic children and adults with secretin. ARI's best information is that 70 percent of patients show benefits, he says.
Psychologist Geraldine Dawson, a codirector of the upcoming NIH trial at the University of Washington, comments, "I feel guarded optimism, because there is a plausible biologic mechanism for this particular drug. And the fact that anecdotal reports say it is operating on specific symptoms of autism rather than associated behaviors is intriguing."
Sally Rogers, a psychiatry professor at University of Colorado Health Sciences Center and codirector of the NIH trial there, adds, "The behavior of children with autism fluctuates." For example, she says, changes in light can affect patient behavior. "You could be getting effects even in the placebo condition that are based on other stimuli."
At each of the two universities, 51 patients will be grouped into 15 who receive the biological extract, 15 who get the synthetic compound, and 21 in the placebo arm. "The clinical literature suggests the placebo response is about 40 percent in autism," Dawson notes. "That was one reason to have a placebo group that is somewhat larger." Only one dose of secretin will be administered, with observational and physiological analyses made at weeks two and four of the four-week trial.
"These infusions are not benign," Dawson cautions. "There's already been a case where a child given repeated doses of the extracted product has developed antibodies."
Purich charges that many of the publicly available secretin supplies are now coming from overseas sources and are being packaged in United States Pharmacopoeia labels without meeting the legally required sterility and purity standards. He warns, "Quite a few patients out there are now getting a drug that they shouldn't be using."