Results:
>>Repligen Reports Positive Initial Results of Secretin Phase 2 Clinical Trial
Multi-dose Therapy Produces Statistically Significant Improvement in Symptoms of Autism Using Parental Clinical Global Impression Scale
NEEDHAM, Mass., April 4 /PRNewswire/ -- Repligen Corporation (Nasdaq: RGEN - news) announced today initial results from a Phase 2 clinical trial of human synthetic secretin in young children with autism. The double-blind, randomized, placebo-controlled trial evaluated the safety and efficacy of three administrations of secretin or a placebo at three week intervals in autistic children. An initial analysis indicates that secretin produced a statistically significant improvement in autism symptoms as measured with a parental Clinical Global Impression Scale (p = 0.02).
The trial enrolled 136 children 3 to 6 years of age at five U.S. clinical centers. The diagnosis of autism was confirmed in all patients with the Autism Diagnostic Interview. The children who participated in the clinical trial had moderate to severe symptoms of autism and reported gastrointestinal symptoms. There were 66 evaluable patients in the secretin group and 60 in the placebo group.
Two types of observations were used to assess changes in the symptoms of autism: evaluations of symptom changes over an eight week treatment period by a parent and evaluations prior to the first dose and approximately two weeks after the third dose based on direct observation of the patient during a 60 minute clinical visit by a psychologist (``rater'').
A principle parent-based evaluation was the Clinical Global Impression Scale (CGI), an assessment of a patient's behavioral changes from baseline. A CGI is based on a 7 point scale in which 1 = ``very much improved'' and 7 = ``very much worse''. The parental CGI showed a statistically significant improvement in the secretin-treated group versus the placebo-treated group (p = 0.02). In a responder analysis, a total of 12 patients (18%) were rated as 1= ``very much improved'' in the secretin group versus 3 (5%) in the placebo group, a difference which is statistically significant (p = 0.02). There were a total of 44 patients rated as either ``very much'' or ``much'' improved (CGI = 1 or 2). Of this group, 28 were secretin-treated and 16 received placebo (p = 0.09).
A principle rater-based evaluation and the primary endpoint for the trial was the Childhood Autism Rating Scale (CARS). CARS score changes in the secretin-treated group were not significantly different compared to the placebo group. In a further analysis, clinical responders were defined as patients with a CARS score decrease of 10 or more points. There were 12 responders (18%) in the secretin-treated group versus 5 responders (8%) in the placebo group (p = 0.12). Analysis of the change in CARS scores showed a large variation from baseline to week eight which was independent of drug treatment. This suggests that many patients had significant day-to-day variations in symptoms which were randomly captured by this measurement tool.
``This study demonstrates that three doses of secretin produces a statistically significant clinical response in a subset of autistic children,'' stated Walter C. Herlihy, President and CEO of Repligen. ``Our study also indicates that in this patient population parental observations over eight weeks were more sensitive to change than observations based on a clinical visit.''
The safety of secretin was also evaluated. There were no ``serious adverse events'' in either the secretin or placebo-treated groups. Since there have been anecdotal reports of hyperactivity, sleep disruption, and increased irritability or aggressiveness following secretin treatment in patients outside of this study, these symptoms were specifically assessed in the initial data analysis. These four symptoms were observed in a total of 19 patients including 9 of the secretin-treated patients (14%) and 10 of the placebo-treated patients (17%). No patient showed an immune (antibody) response to secretin four weeks after the third dose. Additional analyses of blood chemistries are currently in progress.
Clinical and Biological Correlations with Secretin Response
There was no bias in response to secretin attributable to patient sex, severity of autism symptoms at baseline or the severity or nature of the patients' gastrointestinal symptoms at baseline. There was a trend to higher response rates in younger patients which did not reach statistical significance (p = 0.06).
Multiple blood, urine and stool samples were collected from each patient for analysis of parameters that may be associated with an individual's response to secretin. Initial analysis of these samples has indicated that there is a biological marker which defines a set of patients for whom the effect of secretin or placebo treatment was highly variable. The 37 patients with this marker were removed from the patient population and the remaining 89 patients were analyzed as a subgroup (46 secretin-treated patients and 43 placebo patients). The statistical significance for the parental CGI changed from p = 0.02 for the entire patient population to p < 0.001 for this 89 patient subgroup.
In a further analysis, secretin responders were defined as patients rated as ``very much improved'' and ``much improved'' (CGI = 1 or 2). In the entire patient population there were 28 responders (42%) in the secretin-treated group versus 16 responders (27%) in the placebo group (p = 0.09). By contrast, in the 89 patient subgroup there were 24 responders (52%) in the secretin-treated group versus 9 responders (21%) in the placebo group (p = 0.005). These data will be published following complete analysis of the predictive value of this marker as a patient exclusion criteria and an assessment of its patentability. We intend to carry out additional analyses of the biological samples obtained in this trial to evaluate additional biological markers which may correlate with the clinical response to secretin.
Assessment of the Symptoms of Autism
The Clinical Global Impression is a tool commonly used to assess patient improvements in trials in which the targeted symptom is a behavior or cognition, e.g. depression, obsessive compulsive disorder and Alzheimer's disease. The scale assigns a change of 1 for ``very much improved'', 2 for ``much improved'', 3 for ``minimally improved'', 4 for ``no change'' up to 7 for ``very much worse''. CGI assessments by raters and patients have been used for the approval of numerous drugs including Aricept® and Cognex®.
The CARS is a standardized instrument for the diagnosis of autism. The administration of CARS consists of an observation of a patient for 30 - 90 minutes. The child is then evaluated on 15 specific symptoms of autism. The scores range from 15 (no symptoms) to 60 (severe autism). Based on literature reports, a CARS score of greater than or equal to 30 is required for a clinical diagnosis of autism and a score above 36 indicates severe autism symptomatology.
Clinical Trial Design and Execution
Each patient was evaluated in two visits prior to dosing during which the diagnosis of autism was established with the Autism Diagnostic Interview (ADI-R), the accepted standard for autism. All patients also were initially evaluated with the Autism Diagnostic Observation Schedule (ADOS), the Childhood Autism Rating Scale (CARS), the Gilliam Autism Rating Scale (GARS), and a variety of other standardized instruments to assess socialization, language, daily living skills and intelligence.
The trial enrolled 136 patients of whom 10 withdrew for a variety of reasons. There were no drop-outs due to adverse events and the drop-out rates were not significantly different between the secretin-treated and placebo groups. The average age of participants in the clinical trial was 4.8 and 86% of the patients were boys, a percentage similar to that found in the population of autism. No statistically significant differences in sex, severity of autism or gastrointestinal symptoms existed between the secretin-treated and placebo groups. The average age of the secretin-treated group was 7 months older than the placebo group (p < 0.01).
The clinical trial sites were: the Southwest Autism Research Center/Phoenix Children's Hospital (Phoenix, AZ), the Rochester Institute for Digestive Diseases and Sciences (Rochester, N.Y.), the University of Maryland Medical Center (Baltimore, MD), the Mayo Clinic (Rochester, MN) and the MIND Institute/University of California, Davis (Sacramento, CA).
``We believe that this is the largest and most comprehensive clinical trial carried out to date in autism and the only clinical trial to correlate multiple biological measurements with the symptoms of autism,'' stated Walter C. Herlihy, President and CEO of Repligen. ``The clinical and biological data obtained in this trial will enable us to plan and execute additional clinical trials in this patient population with far greater precision than previously possible.''
Repligen and its clinical collaborators expect to present detailed results from the Phase 2 trial at future scientific meetings and to submit the results for publication in a peer-reviewed journal. The company expects to complete additional analysis of the Phase 2 data as quickly as possible and to discuss the future development program with the FDA.<<
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Cheers, Tuck |
