Bio Markers for Response to Secretin in Autism Found/ Repligen Extends Study

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June 21, 2002 Search www.feat.org/search/news.asp

SCIENCE

Also: * Repligen Announces Extension of Phase 2 Clinical Trial of

Secretin in Autism

* Lenny Schafer Speaking at ASA Conference 2000

Biological Markers for Response to Secretin in Autism Found

Three Independent Endpoints Show Significant Treatment Effect in Defined

Patient Subset

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104 & STORY=/www/story/06-18

-2001/0001516473 & EDATE= <-- address ends here.

PRNewswire - Repligen Corporation (Nasdaq: RGEN) announced today that

it has found abnormal levels of two gastrointestinal biomarkers in a subset

of the patients who participated in its recently completed Phase 2 clinical

trial of secretin in autism. Analysis of patients in the trial with normal

levels of these two biological markers showed a statistically significant

effect of secretin treatment in three endpoints including two assessments

carried out by a clinical psychologist and one parental assessment.

Secretin-treated patients with normal levels of both biomarkers showed a

statistically significant improvement (p=0.016) in social function in

evaluations carried out by a trained clinical evaluator utilizing the Autism

Diagnostic Observation Schedule ( " ADOS " ). Additionally, observations of

secretin-related improvements by psychologists using the Clinical Global

Impression Scale ( " CGI " ) were statistically significant (p=0.02) in patients

with normal levels of both biomarkers. A statistically significant

improvement (p<0.001) was also found in the CGI assessments by parents of

secretin-treated patients compared to those who received a placebo.

This represents the first successful use of biological markers to

define a set of autistic patients capable of responding to a specific

therapy.

" These biological markers have enabled us to document the response to

secretin with assessments carried out by both psychologists and parents, "

stated Walter C. Herlihy, President and CEO of Repligen. " This combination

of a global assessment of improvement and a quantitative measurement of

social deficits is a potential strategy for assessing secretin in pivotal

clinical trials. " The Phase 2 trial evaluated 126 children, 3 to 6 years

of age, with moderate to severe symptoms of autism and reported

gastrointestinal symptoms.

A stool sample was collected from each patient at the beginning of the

trial and subsequently analyzed for two proteins: calprotectin, a marker of

gastrointestinal inflammation and chymotrypsin, an enzyme released from the

pancreas during digestion. For each protein, 25-30% of the patients had an

abnormal value prior to treatment with secretin or a placebo. The ability

to demonstrate a secretin-related treatment effect was dramatically improved

in the 64 patients, or 51% of the total patient population, with normal

levels of both proteins. Patients with abnormal levels of one or both of

these biomarkers accounted for most of the " placebo responders " in the

trial, indicating that they had a high degree of symptom variability over

the eight week duration of the trial. These results indicate that it is

important to control for gastrointestinal and other non-neurological disease

processes in order to reliably measure changes in behavior in young children

with autism.

Calprotectin and Chymotrypsin

Calprotectin is a protein with anti-microbial and immunoregulatory

properties found in high concentrations in neutrophils, a type of white

blood cell. Calprotectin released by neutrophils in the gut is stable and

can be detected in stool. Elevated levels of calprotectin in stool have

been reported in diseases characterized by intestinal inflammation such as

ulcerative colitis and Crohn's disease. It has previously been reported to

be elevated in autistic children with gastrointestinal symptoms. Levels of

calprotectin did not correlate with severity of gastrointestinal symptoms in

these patients.

Chymotrypsin is one of several enzymes released by the pancreas in

response to stimulation by secretin and other hormones. Its function is to

degrade proteins as part of the digestive process. It is relatively stable

in the gut and can be detected in a stool sample. Low levels of

chymotrypsin in stool have been used as an indication of pancreatic

insufficiency in patients with cystic fibrosis. The reason for low

chymotrypsin levels in these patients is currently unknown since other

indications of pancreatic insufficiency are absent in this population.

Autism Diagnostic Observation Schedule and Clinical Global Impression

DOS is a standardized clinical instrument for the diagnosis of autism

based on a structured interaction between a psychologist and the child. The

interaction consists of a series of tasks designed to assess deficits in

communication and social interaction. ADOS is widely accepted as the " gold

standard " for the diagnosis of autism in clinical research. The ADOS social

domain is a series of activities which enable a clinician to evaluate eye

contact, facial expressions, shared enjoyment in interaction, showing of

toys or objects, the initiation of joint attention, the response to joint

attention and the quality of social overtures. The ADOS produces a score

that reflects the number and severity of the social deficits characteristic

of autism. All patients were evaluated with ADOS prior to treatment and two

weeks after the third administration of secretin or a placebo.

CGI is a standardized assessment of the global change in symptoms in

which a patient is rated as " very much improved, " " much improved, "

" minimally improved, " etc. It has been used as a primary endpoint in the

FDA approval process for many drugs that target behavioral or cognitive

symptoms including drugs approved for Alzheimer's disease, depression and

schizophrenia. All patients were evaluated with a CGI two weeks after the

third administration of secretin or a placebo by a psychologist and

independently by their parent.

The clinical trial was carried out at the Southwest Autism Research

Center/Phoenix Children's Hospital (Phoenix, AZ), the Rochester Institute

for Digestive Diseases and Sciences (Rochester, NY), the University of

land Medical Center (Baltimore, MD), the Mayo Clinic (Rochester, MN) and

the MIND Institute/University of California, (Sacramento, CA).

Repligen Corporation develops new drugs for debilitating pediatric

diseases including autism, cancer, and immune and metabolic disorders.

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 http://www.repligen.com.

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* * *

Repligen Announces Extension of Phase 2 Clinical Trial of Secretin in Autism

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104 & STORY=/www/story/06-18

-2001/0001516488 & EDATE= <-- address ends here.

PRNewswire - Repligen Corporation announced today that it has

initiated an open label extension of its recently completed Phase 2 clinical

trial of human synthetic secretin in children with autism. In the extension

phase of the study, all patients who completed the Phase 2 trial will be

offered six doses of secretin over an 18-week period. The goal of this

study is to collect additional, longer term safety data and to extend the

biological and behavioral observations of the Phase 2 trial.

The Phase 2 trial enrolled 126 children, 3 to 6 years of age, with

moderate to severe symptoms of autism and reported gastrointestinal

symptoms. There were 66 patients in the secretin group who received three

administrations of secretin or a total of 198 doses. There were no " serious

adverse events " in either the secretin or placebo-treated groups and no

difference in the number of adverse behaviors including hyperactivity, sleep

disruption, increased irritability or aggressiveness between the two groups.

Extensive analysis of blood and urine chemistries has shown no indication of

toxicity associated with three doses of human synthetic secretin.

In the extension study, 124 eligible patients will be offered six

additional administrations of secretin at three week intervals or a total of

up to 744 dose administrations (6 x 124). Multiple blood, urine and stool

samples will also be analyzed for safety as well as for a variety of

biological markers including calprotectin, an indicator of gut inflammation

and chymotrypsin, an indicator of pancreatic function. In the Phase 2

study, patients whose calprotectin or chymotrypsin levels were abnormal

showed a higher variability in their symptoms of autism making it more

difficult to document the effect of secretin treatment in this subgroup.

" We are pleased with the safety profile of secretin observed in the

Phase 2 study, " stated Walter C. Herlihy, President and CEO of Repligen.

" We are extending this study at our own initiative to gain valuable longer

term safety data which we believe will be useful in accelerating the

development of this drug. "

* * *

** AUTISM SOCIETY OF AMERICA **

Presents

JULY 22 8:30 am

LENNY SCHAFER

Editor of the FEAT Daily Newsletter

ASA Conference 2001 “Millennium of Hope” San Diego

SPEAKING ON: The Politics of Autism - 2002

Please Join Lenny Schafer at his presentation on current events that effect

Professionals, parents, and individuals dealing with Autism

TOPICS: The growth in the number of children diagnosed as full-fledged

autistic has progressed from ripples of concern by students of public health

to predictions of Tsunami proportions of an epidemic. Epidemics are public

health matters, and by definition are political matters. How do we prepare

for an epidemic or near-epidemic of a disorder that can cost $60,000 a year

to treat, per person? This fast growing population of autism threatens to

break the back of disability and education legislation by sucking them dry

of resources. The Individuals with Disabilities Education Act means nothing

if Congress fails to fund it. Even now, just at the beginning of this

autism epidemic, the IDEA is, and always has been, seriously under-funded.

How are we going to pay for what lies ahead? How do we get services to so

many children who equally deserve it? These matters are presented along

with the need for finding means of helping families with autism with the

costs of having an autistic family member.

The research being promoted for finding the cure or treatments for

autism does not address today’s population with autism. Almost all current

research is directed towards genetic causes and diagnostic markers. This is

needed research. But there also needs to be a full-fledged research

campaign to look for the environment sources of autism. What is the role of

vaccines, or mercury poisoning, or diet? It is incredible that this is not

happening.

Politics are the way the research and treatment agendas get changed

and set. The rebuilding ASA can provide a key role in the political

leadership needed for these changes. Local ASA chapters are going to grow

in response to the epidemic. The internet can be an effective way for local

autism organizations to strengthen their networking. Finally, a closer

examination of the internet and the opportunities it offers for both

individual families and autism organizations is undertaken.

Lenny Schafer is the founder and editor of the five-year-old

internet-published FEAT Daily Newsletter. He is a former vice president and

current board member of Families for Early Autism Treatment in Sacramento,

CA. He is a single parent raising an autistic 12-year-old adopted son.

Prior to his son’s diagnosis of autism, he owned and managed a digital image

processing company in San Francisco. He left his business to take care of

his son full time. Earlier he was the co-owner and editor of a weekly

newspaper in Detroit for five years.

Please Plan to attend the entire ASA Conference 2001, “Millennium of

Hope” in San Diego the July 18 to July 22

Other top speakers at the Conference will include presentations in each of

the following five tracks:

. Communication

. Education

. Family and Community

. Medicine and Research

. Adulthood and Independence

As the largest national conference on autism this year's event will

provide the most current information available in the autism field.

For registration, exhibiting, advertising, or sponsoring, contact ASA

Conference 2001 at:

http://www.autism-society.org/conference/index.html

* * *

Reader’s Posts

Parents of a Monmouth County 24 year old male with Asperger Syndrome, (and

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Unlocking Autism has available vehicle license plates to promote autism

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Speech & Language Pathologists desperately needed in the Eureka/Arcata

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In an effort to make our area resource manual more comprehensive and

useful, I would like to hear from anyone in the Baltimore, MD -

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