Seaside Therapeutics has announced the publication of two papers in Science Translational Medicine, supporting its lead candidate, STX209 (arbaclofen), for the treatment of fragile X syndrome (FXS). The works presented highlight STX209 as a potential disease-modifying drug in preclinical studies, with improvement in social function in a clinical trial of patients with FXS.
“In preclinical results, we demonstrate that STX209 treatment corrects core aspects of FXS pathophysiology in the fragile X mouse model, leading us to conclude that STX209 is a disease-modifying drug with the potential to significantly improve the lives of patients with fragile X,” said Randall Carpenter, MD, President and Chief Executive Officer of Seaside Therapeutics. “In fact, in our Phase 2 clinical trial, we observed statistically significant improvements in social avoidance, a core symptom of fragile X syndrome that is characterized by behaviors such as preference to be alone and being withdrawn or isolated. Social avoidance is also a core symptom of autism spectrum disorders, suggesting STX209 could have a positive effect in this larger patient population. Together, these results support our continued development of STX209, which is currently enrolling patients in a Phase 3 study in fragile X syndrome and recently completed enrollment in a Phase 2b study in autism spectrum disorders.”
“There are currently no FDA approved therapeutics that address the core symptoms of fragile X syndrome, leaving patients and their caregivers with limited treatment options,” said Elizabeth Berry-Kravis, MD, PhD, Professor of Pediatrics, Neurology, and Biochemistry at Rush University Medical Center in Chicago, and the lead author of the paper on the Phase 2 study results. “We are very excited about the clinically meaningful improvements in social impairment observed to date in patients receiving STX209 – marking the first time a drug candidate has positively impacted a specific core symptom of fragile X. With continued success in ongoing clinical trials, I am hopeful that STX209 may be able to transform the treatment paradigm for fragile X syndrome – which would confirm what I have believed all along – that intellectual disability is not, as previously understood, an immutable condition.”
FXS is the most common inherited cause of intellectual disability (mental retardation) and the most prevalent known cause of autism. FXS is caused by the mutation of a single gene known as FMR1. FMR1 codes for a protein called fragile X mental retardation protein (FMRP) that is necessary for normal brain development. Without FMRP, patients exhibit several changes in their brains that underlie the cognitive and behavioral deficits associated with FXS. These changes include: alterations of neuronal morphology and an imbalance between excitatory and inhibitory neurotransmission in the brain. In addition, changes in localized protein synthesis have been observed in mouse models of FXS.
In the paper entitled “Postnatal pharmacological activation of the GABA-B receptor has potential to be disease-modifying in fragile X syndrome,” the researchers tested whether STX209 was effective in reversing the hallmark changes in the brains of mice lacking the Fmr1 gene. In vitro application of STX209 to the hippocampus of mice lacking Fmr1 reduced levels of localized protein synthesis to that of normal mice. Additionally, this treatment reduced a known functional consequence of increased protein synthesis, AMPA receptor internalization, to levels found in normal mice. Furthermore, in vivo administration of STX209 corrected alterations in neuronal morphology specific to Fmr1-deficient mice and FXS patients, but STX209 did not alter neuronal morphology in normal mice and STX209 also reduced protein translation in mice lacking Fmr1, but not in normal mice. Of note, the magnitude of effect observed with STX209 is comparable to that reported for selective mGluR5 antagonists. These results demonstrate that STX209 has the potential to modify the underlying disease of patients with FXS and support the development of STX209 in the clinic.*
The accompanying paper, “Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, Phase 2 trial,” detailed the results previously announced from the Company’s Phase 2 trial. The randomized, double-blind, placebo-controlled Phase 2 study was designed to evaluate the clinical effects of STX209 in 63 subjects, age 6-40 years, with a full mutation of the FMR1 gene. As previously reported, STX209 was well-tolerated and no metabolic side effects were 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. In per-protocol analyses, improvement was seen on the visual analog scale (VAS) ratings of parent-nominated problem behaviors and positive trends were observed on multiple global measures. 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.
Social avoidance is a core symptom of FXS. Post-hoc analysis of ABC-Social Avoidance scale, a newly validated scale for the assessment of FXS, revealed a significant beneficial treatment effect in the full study population (p<0.01). A post-hoc subgroup of 27 subjects with more severe social impairment showed improvements on the Vineland II-Socialization raw score (p=0.03), the ABC-Social Avoidance scale (p=0.04) and on all global measures. The results suggest that STX209 has the potential to improve social function and behavior in patients with FXS.**
STX209 is an oral selective gamma-amino butyric acid type B (GABA-B) receptor agonist. Pathologies observed in certain neurodevelopmental disorders, including autism spectrum disorders and fragile X syndrome are believed to be caused by excessive activation of glutamate receptors and abnormally high ratios of excitatory to inhibitory neurotransmission in the brain. GABA-B receptors play an important role in modulating the release of glutamate and optimizing the ratio of excitatory to inhibitory neurotransmission. STX209 has demonstrated efficacy in preclinical models, suggesting that it may improve function in individuals with autism spectrum disorders and fragile X syndrome. With STX209, Seaside has successfully completed the largest, randomized, blinded, placebo-controlled trial (Phase 2) in patients with fragile X syndrome and an open-label Phase 2a exploratory trial in patients with autism spectrum disorders. Two Phase 3 studies, one in adolescents and adults (ages 12 to 50) and one in children (ages 5 to 11) with fragile X syndrome, are currently enrolling participants. A Phase 2b study in children, adolescents and adults (ages 5 to 21) with autism spectrum disorders recently completed enrollment.
Roche and Seaside Therapeutics recently entered into an alliance under which Roche may exercise options to commercialize Seaside’s arbaclofen (STX209) upon completion of certain clinical development phases in Fragile X Syndrome and Autism Spectrum Disorders, while Seaside will continue to lead the clinical development of these programs.
About Fragile X Syndrome:
Fragile X syndrome is a neurodevelopmental disorder characterized by impaired social function, cognition and speech, as well as attention deficits and low functional independence. It is the most common inherited form of intellectual disability and affects roughly 100,000 individuals in the U.S. It is also the largest known cause of autism. 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, the majority of affected individuals will have significant intellectual disabilities and require life-time care. To date, there are no approved treatments for this disorder. The FDA and EMA have designated fragile X syndrome as an orphan disease.
Study authors included Christina Henderson, Aileen M. Healy, Matthew Shumway, Rebecca S. Hammond, Friso R. Postima, Christopher Brynczka, Roger Rush and Randall L. Carpenter of Seaside Therapeutics; Lasani Wijetunge and Peter C. Kind of the University of Edinburgh; Mika Nakamoto Kinoshita and Stephen T. Warren of Emory University; Alicia Thomas and Richard Paylor of Baylor College of Medicine; Peter W. Vanderklish of The Scripps Research Institute; and Mark F. Bear of the Massachusetts Institute of Technology.
Study authors included Elizabeth M. Berry-Kravis of Rush University Medical Center, Randi J. Hagerman, David R. Hessl, Yi Mu and Danh V. Nguyen of the University of California Davis; Barbara Rathmell, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Paul P. Wang and Randall L. Carpenter of Seaside Therapeutics; Joseph Gonzalez-Heydrich of Children’s Hospital Boston; and Mark F. Bear of the Massachusetts Institute of Technology.
MacDougall Biomedical Communications, Inc.