Repligen Corp. is forging ahead with two Phase III trials of secretin in the treatment of autism in children, based on feedback it received from the FDA after Phase II trials on the hormone last year failed to meet their primary endpoints.
“We initiated our first site [Thursday], so it is under way now,” said Walter Herlihy, president and CEO of Needham, Mass.-based Repligen.
Two clinical trials are planned simultaneously, each having 175 children from ages 2 years, 8 months to 4 years, 11 months, all of whom have moderate to severe symptoms of autism. The trials will be conducted at 15 to 20 medical centers in the United States and are identical except that one group is exclusively for children who exhibit gastrointestinal symptoms. The other group will not be screened for gastrointestinal symptoms.
The trial already under way is expected to have results by the end of the first quarter 2003, with the second trial results following three to six months later, Herlihy said. The company said that if the trials are successful, the results would serve as the basis for a new drug application, although Herlihy would not speculate as to when that might happen.
“As we get closer [to the results], we’ll offer more guidance,” Herlihy said.
Each patient will receive six injections of secretin or placebo over 18 weeks and then be evaluated against baseline measurements for improvement in symptoms of autism. The primary endpoints are improvements in reciprocal social interaction as measured by the Autism Diagnostic Observation Schedule (ADOS) and the Clinical Global Impression of Change. Secondary endpoints are improvements in language and behavior.
Repligen also said that it completed additional analysis of the data from its Phase II trial, which evaluated three administrations of secretin or placebo in 126 patients from age 3 to age 6 years, 11 months with moderate to severe symptoms of autism and gastrointestinal disorders.
Initial results reported by the company in April 2001 showed that it failed to meet its primary endpoint, which was an improvement in symptoms as measured by a psychologist’s evaluation using the Childhood Autism Rating Scale. However, the trial did indicate the treatment produced statistically significant improvement in symptoms according to parents, who measured changes in symptoms over an eight-week period. (See BioWorld Today, April 5, 2001.)
More recent data included an analysis of the effect of age on the response to secretin, which is produced by a part of the digestive system called the duodenum, which acts upon the pancreas to assist in digestion. Repligen said that all patients demonstrated a trend toward improvement in social interaction based on ADOS, but this was due to a significant response to treatment in 3- and 4-year-old patients (p<0.20, n=57). Within this group, there also was a correlation of the response as age decreased, which is why the Phase III trial is designed for younger children.
“The Phase II trial was designed to determine where you get the most therapeutic effect of the drug and what symptoms it might affect, such as communication, interaction and behavior,” Herlihy said. “There’s no reason to think that a drug will affect all of them.”
Based on the Phase II trial, social interaction was the behavior most reliably impacted, he said.
“We’re now going to replicate that in the Phase III trial,” Herlihy said.
The U.S. Department of Health and Human Services estimated in a study released late last year that one in 500 children could have autism, which is characterized by difficulties in social interaction, communication and imaginative play.
Repligen’s current Phase III trial program, if successful, would target about 36,600 kids, Herlihy said.
Herlihy pointed out, however, that there are other forms of autism, including those with pervasive development disorder of which there are approximately an equal number of children for whom secretin could possibly be effective. He said Repligen may consider a Phase IV study on this group, depending on the results of the Phase III program.
Repligen had difficulty with its secretin program before the disappointing results of the Phase II trial last April, when its stock fell 30 percent to close at $1.84.
In 1999, Repligen’s stock fell 32 percent, closing at $3, when the New England Journal of Medicine published findings from a study on secretin in autism that was sponsored by the National Institutes of Health National Institute of Child Health and Human Development. The 56-patient study found a single dose of secretin failed to benefit children with autism. (See BioWorld Today, Dec. 9, 1999.)
Repligen’s stock (NASDAQ:RGEN) gained 5 cents Friday to close at $3.05.