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Fragile X Syndrome, a rare disease, is the most common single-gene cause of autism and inherited cause of intellectual disability among boys. Approximately one in 4,000 males and one in 8,000 females have Fragile X Syndrome, according to the US Centers for Disease Control and Prevention (CDC). Not everyone with the mutation will show signs or symptoms of Fragile X Syndrome, and disabilities will range from mild to severe and may include intellectual disability and behavioral characteristics such as stereotypic movements (e.g., hand-flapping), problems with attention and hyperactivity and social anxiety. A majority of individuals with Fragile X Syndrome will have either Autism Spectrum Disorder or autistic symptoms, and will have varying levels of cognitive impairment. The FDA has not approved any drugs specifically for the treatment of Fragile X Syndrome or its symptoms. Because of the lack of an approved treatment for Fragile X Syndrome, there is substantial unmet medical need.
METADOXINE EXTENDED RELEASE (MDX) is an extended-release oral formulation of metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate). Metadoxine displays high affinity to the GABA transporter, while it does not bind to any other monoamine transporters (dopamine, serotonin, or norepinephrine) and does not affect dopamine, norepinephrine, and serotonin levels. Metadoxine is also an inhibitor of the GABA transaminase enzyme, which responsible for the degradation of GABA. Electrophysiological studies showed that Metadoxine caused a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.
Alcobra has completed two animal studies of Fragile X Syndrome. The first study included multiple behavioral assessments of 40 mice, comprising 20 Fragile X knock-out mice and 20 control mice that were treated with Metadoxine or a placebo. The results showed significant improvement in behavioral outcomes, including contextual fear conditioning (a test primarily evaluating memory and learning), social interaction, and Y-maze alternation (a test of learning and perseverance). The second study included behavioral assessments of young and old Fragile X knock-out mice and control mice. This study showed that Metadoxine treatment led to significant improvement in blood and brain biological markers (AKT and ERK), which may have a role in learning and memory. The study also demonstrated a reduction in the amount of immature neurons and abnormally increased protein levels.
The positive outcomes reported in these animal models, together with the cognitive benefits demonstrated in our trials in ADHD, warrant investigation in human clinical trials to evaluate the safety and efficacy of METADOXINE EXTENDED RELEASE for treatment of Fragile X Syndrome. Alcobra has completed a phase II study in adolescents and adults with Fragile X Syndrome. Preliminary results from this study showing a signal of benefit on adaptive behavior in FXS were reported by Alcobra in June 2015.