Seaside Therapeutics Reports Data from Randomized, Placebo-Controlled Phase 2 Study in Fragile X Syndrome
--First data reported in the field from the largest randomized study to date--
--Study of STX209 to advance --
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jul 26, 2010 - Seaside Therapeutics, Inc. announced today data from the largest randomized, placebo-controlled study conducted to date in individuals with fragile X syndrome. In a Phase 2 study of STX209, clinically meaningful improvements on global and specific neurobehavioral outcomes were observed in the general study population. The improvements were statistically significant in pediatric patients with more severe impairments in sociability -- a core symptom of fragile X syndrome. STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist. The results were presented in a podium presentation at the National Fragile X Foundation's 12th International Fragile X Conference in Michigan on Saturday, July 24, 2010 by investigators Elizabeth Berry-Kravis, MD, PhD, Professor of Pediatrics, Neurological Sciences and Biochemistry at Rush University Medical Center in Chicago, Illinois and Randi Hagerman, MD, Medical Director, M.I.N.D. Institute, Professor, Endowed Chair in Fragile X Research, School of Medicine, University of California, Davis, in Sacramento, California. Seaside continues to conduct additional analyses of other outcome measures and biomarker data sets and intends to submit full results for publication.
“A majority of the patients enrolled in the STX209 study are participating in the ongoing open-label extension study and are continuing to benefit from treatment with STX209,” said Dr. Randi Hagerman. “Physicians and parents are reporting increased sociability and communication and decreased outbursts and tantrums. In several cases, patients have been successfully withdrawn from other medications, including mood stabilizers, anti-depressants and, most importantly, anti-psychotics—a significant benefit for patients given the severe side effects associated with this particular class of drug. It is my hope that, with further study, STX209 may be able to play a much needed role in improving the symptoms of fragile X syndrome and help patients and their families achieve an improved quality of life.”
“Seaside Therapeutics conducted one of the most comprehensive studies to date in a neurodevelopmental disorder and achieved our goal of increasing knowledge regarding potential efficacy measures in patients with fragile X syndrome,” said Randall L. Carpenter, MD, President and Chief Executive Officer of Seaside Therapeutics. “The study assessed a broad range of behavioral and cognitive outcomes and, as would be expected in a study of this scope, we observed significant benefit in some key areas but not in others. We believe the depth of data coming from this study will be of tremendous benefit for the field and will inform ongoing discussions with both clinicians and the FDA to confirm the most appropriate outcomes to measure efficacy in individuals with fragile X syndrome. We look forward to initiating late-stage clinical trials of STX209 later this year after discussions with the FDA.”
Per Protocol Population:
In the per protocol population of 54 patients, STX209 consistently showed a positive trend for all global measures, including investigators' assessments of Clinical Global Impressions of Improvement (CGI-I) (p=0.18) and Severity (CGI-S) (p<0.10) and investigator (p<0.10) and caregiver treatment preference (p<0.10). One third of the treatment population was noted as “Much improved” or “Very much improved” on the CGI-I scale, whereas placebo scores were clustered around “No change.” While improvement was noted on the Irritability subscale of the Aberrant Behavior Checklist (ABC-I), the study's primary endpoint, the magnitude was comparable to that observed on placebo and did not achieve statistical significance.
Low Sociability Population:
Social withdrawal is a core symptom of fragile X syndrome. In the STX209 study, 15 pediatric patients presented with more severe impairments in sociability at baseline. In these patients, STX209 treatment was associated with statistically significant improvements on all global measures, including CGI-I (p<0.01), CGI-S (p<0.05), clinician (p<0.01) and parent/caregiver (p<0.01) preference, as well as improvements on two widely-used measures of social function—the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW, p=0.05) and the Vineland Play and Leisure (p<0.10). In the responder analysis, responders were defined as those subjects with a score of “Very much” or “Much improved” on the CGI-I scale and with a 25%+ improvement on the ABC-SW. When applying these rigorous criteria, more than 50% of subjects showed a positive response while taking STX209, versus just 13% on placebo (p=0.05).
STX209 was well tolerated, and there were no metabolic side effects observed. The most common adverse events in subjects receiving STX209 were upper respiratory infections (13%), sedation (8%) and headache (8%), compared to 10%, 2% and 2%, respectively, while receiving placebo. Three patients withdrew due to adverse events, including one serious adverse event on the STX209 arm and two adverse events on placebo. The serious adverse event of worsening irritability and hospitalization occurred during taper of STX209 in a patient who had a positive clinical response while taking the drug.
The STX209 trial was a Phase 2 randomized, double-blind, placebo-controlled, two-period crossover study in 63 patients with fragile X syndrome. The study enrolled 24 patients ages 6-11 years, 22 patients ages 12-17 years and 17 patients ages 18-40 years. The objective of the study was to explore the safety and efficacy of STX209 in patients with fragile X syndrome. A broad range of behavioral and cognitive outcomes were included in the study design to add to the Company's knowledge of potential efficacy measures in patients with fragile X syndrome.
Key inclusion/exclusion criteria included a fragile X full mutation and a minimum severity on the ABC-I scale. Participants were limited to no more than three psychoactive medications, with stable dosing for four weeks prior to entering the study.
Dosing was conducted as a flexible titration, every three days, to the optimal titrated dose (OTD). The starting dose was 1 mg twice a day and was gradually increased up to 10 mg twice a day for subjects ‰¤11 years and up to 10 mg three times a day for subjects ‰¥12 years. OTD was continued for the remainder of the four-week treatment period, with a taper after completion of the four-week period.
Recent discoveries by Mark Bear, PhD, Professor of Neuroscience, M.I.T, Investigator, Howard Hughes Medical Institute, and Seaside's scientific founder, have revealed a molecular pathway, the mGluR5 signaling cascade, that is disrupted in fragile X syndrome. With this knowledge, further research has provided insights for developing novel medications to correct the function of this pathway, which Seaside believes may extend beyond fragile X syndrome into a number of other developmental disorders, including autism.
STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist. STX209 inhibits glutamate signaling in the brain and should, thereby, indirectly inhibit the excessive metabotropic glutamate receptor (mGluR) mediated protein synthesis implicated in fragile X syndrome. Preclinical studies using STX209 and other prototypic GABA agonists have demonstrated efficacy in animal models of fragile X syndrome, suggesting that GABA agonists may provide benefits for individuals with fragile X syndrome.
About Fragile X Syndrome:
Fragile X syndrome is the most common inherited form of mental impairment and the most common known cause of autism. According to the Centers for Disease Control, an estimated one in 4,000 males and one in 6,000 to 8,000 females have fragile X syndrome. Fragile X syndrome is caused by a mutation of a single gene, the Fragile X mental retardation 1 (FMR1) gene, on the X chromosome. The FMR1 gene produces a protein needed for normal brain development. Individuals with fragile X syndrome lack this protein and, as a result, exhibit a number of behavioral and physical symptoms, including mental and developmental impairment, attention deficit and hyperactivity, autistic behaviors, anxiety, seizures and characteristic facial appearance.
About Seaside Therapeutics:
Seaside Therapeutics, Inc. is creating novel drug treatments to correct or improve the course of fragile X syndrome, autism and other neurodevelopmental disorders. The Company is dedicated to translating breakthrough discoveries in neurobiology into therapeutics that improve the lives of patients and their families. For more information please visit www.seasidetherapeutics.com.
Contact: Seaside Therapeutics, Inc.
Daniel E. Geffken, 617-374-9009, ext. 1012
Chief Operating Officer
MacDougall Biomedical Communications
Sarah Cavanaugh, 781-235-3060
Posted: July 2010