http://news.bmn.com/hmsbeagle/109/notes/profile
|
Is Autism's Answer in the Gut? by |
|
|
|
|
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.
|
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. |
Andrew 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 Maryland, 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?" |
Adrian 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."
Wendy Roberts, 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."
ALL
INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR
GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE
KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED
AS PROVIDING MEDICAL OR LEGAL ADVICE. THE DECISION WHETHER OR NOT TO
VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU
ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.