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PROFILE

Is Autism's Answer in the Gut?

Repligen Corporation

by Jane Salodof MacNeil

Posted August 31, 2001 · Issue 109

Abstract

Repligen Corporation recently announced progress in developing a drug for

children with autism. With no other drugs on the market, Repligen could reap

enormous rewards - if it succeeds.

On June 18, a biotechnology company in Needham, Massachusetts, announced

progress in developing a drug for children with autism, a developmental

disorder for which there is no drug or even a known cause. Ordinarily, talk

of new treatments mobilizes desperate parents and investigators committed to

helping these children. Repligen Corporation's statement on secretin

generated more surprise than hosannas, as it was thought that both the

company and the drug had already had their day in the sun.

Controlled studies don't support Repligen's enthusiasm for secretin.

A gastrointestinal hormone, secretin stimulates the pancreas to release

bicarbonate in response to gastric acid. It became the next great hope for

autism following a 1998 television report that, serendipitously, a severely

autistic three-year-old started speaking after receiving secretin in a

diagnostic test for gastric problems. Since then, at least four

placebo-controlled studies have reported that secretin didn't deliver

behavioral changes. One suggested it might even make some children worse.

Twenty-year-old Repligen is a downsized biotech that nearly went out of

business in the mid-nineties. It invested heavily in searching,

unsuccessfully, for an AIDS vaccine, and has yet to bring even one drug to

market or make a profit. Walter C. Herlihy, Repligen's president and CEO

since 1996, had brought the publicly traded company's finances under control

when his wife read the buzz about secretin on the Internet. Both are

biochemists, but their interest was personal. Their two daughters have

pervasive developmental disorder (PDD), an umbrella term that includes

autism. Herlihy licensed rights to market the hormone and secured a patent

to develop synthetic secretin as a treatment for autism and its symptoms.

Autism affects 1 in 500 children.

Undaunted by secretin's bad marks in the medical journals, Herlihy says, in

hindsight, that he made a wise business decision, one that could reap

enormous rewards for Repligen if it succeeds in bringing the first drug for

autism to market. Once considered rare, the disorder today has an incidence

of 1 in 500 - half a million children in the United States alone, according

to the Autism Society of America. " Here's an opportunity to do good and

reward investors, " says Herlihy, who has since remade Repligen's mission

into finding new therapies for debilitating pediatric diseases.

The company has two other potential drugs in clinical trials. It is starting

a phase II clinical trial of uridine therapy for mitochondrial diseases,

which affect about 20,000 people in the United States and often cause death

by the age of 10. Investigators theorize that these diseases occur when

mitochondria do not produce enough uridine, a precursor for RNA and DNA

synthesis. If they are right and create the first drug for mitochondrial

diseases to win Food and Drug Administration (FDA) approval, Repligen will

have orphan drug advantages.

Repligen's income producer is Protein A.

Repligen is also testing an injectable form of CTLA4 (CTLA4-Ig), a highly

specific T cell regulatory protein, in cancer patients undergoing stem cell

transplantation. CTLA4 is an old project and does not fit into the company's

new model. It would have a huge market, however, if it succeeds in

inhibiting graft-versus-host disease by only turning off cells that are

initiating an unwanted immune response. The stakes are sufficiently high

that Repligen and the University of Michigan are engaged in a joint lawsuit

over patent rights awarded to the Bristol-Meyers Squibb Company. Meanwhile,

Repligen's only income producer is Protein A, which it cloned in 1982.

Protein A products are used to make monoclonal antibodies, and other firms'

sales are soaring with more than 100 Protein-A-derived drugs in clinical

trials.

Secretin is the heart of the new Repligen, however, and in the gut,

literally, of a new way of thinking about autism. About half of all autistic

children appear to have gastrointestinal problems such as chronic diarrhea,

gas, and bloating. As a result, gastroenterologists often see autistic

children, and some have begun to study their problems.

Wakefield thinks immunological abnormalities play a role in autism.

Wakefield, a surgeon at the Royal Free Hospital in London, created an

international controversy when he reported finding traces of measles virus

in autistic children in the immune cells of inflamed lymphoid tissue.

Several major epidemiological studies dispute his hypothesis that the

measles-mumps-rubella vaccine caused the rise in autism. Wakefield also

theorized that a subset of autistic children has a condition he labeled

autistic enterocololitis.

In the United States, Karoly Horvath, a gastrointestinal specialist at the

University of land, began researching secretin after it caused

surprising changes in the child featured on NBC Dateline. In 1999, he

reported that secretin produced a response in 27 of 36 autistic children

with gastrointestinal symptoms. By then an unknown number of parents were

giving the hormone off-label to their children, and concerned physicians

were engaged in placebo-controlled trials. Although these were phase I

studies to determine whether secretin is safe for children, each reported

that various assessments failed to show more patients responding to secretin

than to a placebo.

Repligen found two biomarkers for responsiveness to secretin.

In June, Repligen announced results of a double-blind, placebo-controlled

phase II trial during which 126 autistic children, ages 3 to 6, were given

three doses of secretin at three-week intervals at five centers. Not only

was a larger response reported in the secretin group versus the children on

placebo, but Repligen also said it found two biomarkers that separated

responders from nonresponders.

Calprotectin is a sign of colitis and had been identified by Wakefield as a

possible biomarker for autistic enterocolitis, according to Herlihy.

Chymotrypsin is a pancreatic enzyme released by secretin. When a subset of

children with elevated levels of these two proteins was removed from the

sample, 64 patients were left and the secretin cohort had more responders.

Herlihy says a meta-analysis of the four phase I studies shows benefits.

Repligen's leader followed up with a meta-analysis of the four phase I

studies, which he presented at the Autism Society of America's annual

meeting in July. Herlihy argued that the negative studies were too small and

that when he adds the results together, the secretin cohorts had

significantly more responders: 29 percent versus 16 percent. Herlihy also

raised the possibility that some nonresponders might be responders. The

normal behavior of some autistic children fluctuates from day to day, he

said, and subtle changes would be difficult to detect or measure in the

midst of dramatic swings in behavior.

Herlihy has developed a theory as to why secretin - a 27-amino acid peptide

hormone produced by the S cells of the small intestine - would affect

children with a neurological condition. " Secretin stimulates the vagus

nerve, a four-lane highway across the blood-brain barrier, " he says,

suggesting an overlap in which the same parts of the brain that regulate

emotional behavior also regulate the gastrointestinal tract. While he's not

sure how this plays out and suggests it could affect children in many

different ways, Herlihy says, " It's brain-gut, not gut-brain. "

Sandler asks, " Where are the published data from the meta-analysis? "

Sandler, medical director at the Olson Huff Center for Child

Development in North Carolina and chair of the American Academy of

Pediatrics' panel on children with disabilities, conducted the first of the

trials to deflate secretin. He describes theories about the leaky gut and

the effects of peptides on the brain as tantalizing, and says it's possible

the investigators missed some evidence in support of secretin. But he wants

to see Herlihy's studies. " Where are the published data from the

meta-analysis to demonstrate that? " he asks. " If someone has done a

meta-analysis . . . that should be written up and published. It would be

very surprising. "

, medical director of the Child Development Centre at the

University of Toronto and the Hospital for Sick Children in Toronto, Canada,

headed the fourth negative trial. Her group could find no efficacy for

secretin, even when they broke the children into various subgroups. Although

she expresses concern that secretin had negative effects on some children

and does not plan any further investigation, she does not rule out the

possibility that Herlihy will succeed. " There's something different about

the gut in some kids with autism, " she says, suggesting that Repligen's

greatest contribution may be that it is doing research into what makes an

autistic population different biologically from a nonautistic population.

The goal is to produce " a fingerprint of autism versus normal. "

The company is recruiting between 400 and 500 children for a bioprofiling

database, according to Ariane Marolewski, Repligen's senior director of

biochemistry. Various methods will be used to test samples of the children's

plasma, urine, and stool for proteins, peptides, and small molecules. The

goal is to produce what Marolewski calls " a fingerprint of autism versus

normal. "

Repligen has formed a relationship with an organization called Cure Autism

Now to raise funds for autism research. It hopes to draw income from sales

of diagnostic secretin once the FDA approves its synthetic product. At the

moment, no commercial secretin has been available since the original

manufacturer stopped production.

" It's not a magical cure. I agree with that. "

In the long run, Herlihy says Repligen's investment in secretin will be

worthwhile even if it relieves symptoms for only a small portion of the

children with PDD. " It's not a magical cure. I agree with that, " he says.

" Our position is that if this helps - I said help, not cure - 20 percent of

the children with autism, it is a mega breakthrough. "

Jane Salodof MacNeil is a freelance editor and writer. She frequently writes

about health and medicine for Oncology News International, CBS HealthWatch,

and other media.

Wolsborn is Web designer of HMS Beagle.

Tell us what you think.

Endlinks

Autism: Cognitive Deficit or Cognitive Style? - argues that progress in

understanding autism will by exploring what people with autism are good at.

>From Trends in Cognitive Sciences, 1999, 3:6:216-222. Full text available

from BioMedNet.

The Biological Basis of Autism - focuses on advances in understanding the

pathogenesis of the disorder. From Current Opinion in Neurobiology, 1997,

7:708-712. Full text available from BioMedNet.

Genetic Clues to the Biological Basis of Autism - reviews recent work on the

genetic basis of autism and the implications for future research, diagnosis

and management. From Molecular Medicine Today, 2000, 6:6:238-244. Full text

available from BioMedNet.

So, What's Not To Like About Wakefield - a Spectrum interview with

Dr. Wakefield.

Center for the Study of Autism - provides information on various topics

related to or about autism. Includes a special section on Secretin and

Autism.

Autism Research Instititute - offers information, links, and editorials

including several on secretin: A Negative Placebo Effect?, Secretin:

Positive, Negative Reports in the " Top of the First Inning, " and The Safety

Issue.

Autism Resources - offers a gateway to information.