-- Improvements in cognitive performance in animal models are consistent with MDX effects in human adults with ADHD –
-- Metadoxine has effects on neurotransmitters associated with attention, learning and memory while avoiding targets of conventional ADHD medications –
-- Pharmacological activity of metadoxine clearly differs from the activity of either of its components administered alone or in combination --
NEW YORK, May 12, 2014 (GLOBE NEWSWIRE) -- Alcobra Ltd. (Nasdaq:ADHD), an emerging biopharmaceutical company focused on the development of new medications to help patients with cognitive disorders, including Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome, today announced the presentation of data supporting a novel mechanism of action for its proprietary drug candidate Metadoxine Extended Release (MDX; MG01CI) at the 69th Annual Scientific Meeting of the Society of Biological Psychiatry (SOBP).1
Based on results from a validated mouse model of Fragile X Syndrome, investigators reported that metadoxine improved measures of cognitive performance in a manner consistent with human clinical studies in adults with ADHD, and was shown to have effects on several key neurotransmitters thought to play a role in learning and memory but not on those thought to be responsible for the activity, side-effects and abuse potential of conventional stimulant medications for ADHD.
"These new data support our working hypothesis about the mechanisms underlying the observed effects of MDX on attention, learning and memory, and its attractive safety profile, in human trials," said Jonathan Rubin, M.D., Chief Medical Officer at Alcobra. "By documenting the activity of metadoxine on GABAergic and glutamatergic neurotransmission, while showing a lack of activity of metadoxine on dopamine and norepinephrine, these data confirm that metadoxine works differently than conventional stimulant and non-stimulant medications used to treat patients with ADHD."
In the study, investigators compared metadoxine, dosed for seven days by intraperitoneal injection or orally, to placebo in wild-type and Fmr1 knockout mice, whose behavior and brain biology mimic the phenotype of Fragile X Syndrome. After dosing, behavioral assessments were performed followed by a variety of biochemical assays.
The Fmr1 knockout mice treated with metadoxine demonstrated improved performance on standardized tasks involving attention, memory, learning, hyperactivity and sociability. This effect was consistent with that seen in studies in human adults with ADHD, in which MDX demonstrated the greatest benefit in subjects with Predominantly Inattentive ADHD (PI-ADHD). Neurochemical evaluations of the treated mice demonstrated that metadoxine normalized Akt and ERK hyperactivity and increased glutathione-S-transferase (GST) activity. Normalization of hyperactivated Akt and ERK by metadoxine suggests a possible mechanism for the use of metadoxine in additional disorders associated with cognitive impairment.
In several separate sets of experiments in vitro, metadoxine was found to increase GABAergic inhibitory neurotransmission, and selectively antagonize the serotonin 5-HT2b receptor. An additional microdialysis study in rats revealed no effects on dopamine or norepinephrine levels. Based on this evidence, the investigators concluded that metadoxine has a mechanism of action characterized by monoamine-independent GABA and glutamate modulation.
A tissue-based GABAB assay also demonstrated that the pharmacologic activity of metadoxine (an ion pair salt of pyridoxine and PCA) clearly differs from the activity of either compound administered alone and from a co-administered 1:1 mixture of pyridoxine and PCA. This novel mechanism of action helps explain how metadoxine may be able to regulate synaptic plasticity and improve cognitive function in Fmr1 knockout mice and suggests therapeutic potential for MDX in human patients with Fragile X Syndrome.
Alcobra has completed two successful double-bind, placebo-controlled Phase IIb trials of MDX in adults with ADHD. In December 2013, the U.S. Food and Drug Administration (FDA) granted "Orphan Drug" designation to metadoxine in the treatment of Fragile X Syndrome. Last week, the FDA cleared the protocol for the Company's planned Phase IIb clinical trial of MDX for the treatment of adolescents and adults with Fragile X Syndrome, which is expected to begin enrolling patients shortly.
About Fragile X Syndrome
Fragile X Syndrome is a genetic condition that causes intellectual disability, behavioral and learning challenges and various physical characteristics. Behavioral characteristics can include ADHD, autism and autistic behaviors, social anxiety, stereotypic movements, poor eye contact, sensory disorders and increased risk for aggression. Fragile X Syndrome is the leading known genetic cause of autism, accounting for about 2-5% of cases. Fragile X Syndrome represents an unmet medical need and a rare disease, as defined by the Orphan Drug Act. According to the U.S. Centers for Disease Control and Prevention (CDC), approximately one in 4,000 males and one in 8,000 females have Fragile X Syndrome. The FDA has not approved any drugs specifically for the treatment of Fragile X Syndrome or its symptoms.
About ADHD
Attention Deficit Hyperactivity Disorder (ADHD) is a common and impairing neuropsychiatric condition. Once believed to only affect children, ADHD is now known to persist into adolescence and adulthood in a sizeable number of cases. Key symptoms of ADHD include inattention, hyperactivity and impulsivity.
According to the CDC, about 9% of children in the U.S. meet criteria for ADHD with similar numbers reported in other countries. Although boys are more commonly diagnosed, ADHD is also common in girls who often go undiagnosed. Approximately 4-5% of adults worldwide are affected with ADHD, yet most adults with ADHD remain undiagnosed and untreated. There is no known cause of ADHD, however studies suggest that genetics may play a role.
About Alcobra Ltd.
Alcobra Ltd. is an emerging biopharmaceutical company primarily focused on the development and commercialization of a proprietary drug candidate, MDX (Metadoxine Extended Release (MG01CI)), to treat cognitive dysfunctions including Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome. MDX has completed multiple Phase II studies to treat Attention Deficit Hyperactivity Disorder. The company was founded in 2008 and is headquartered in Tel Aviv, Israel. For more information please visit the Company's website, www.alcobra-pharma.com, the content of which is not incorporated herein by reference.
Forward Looking Statements - This press release may contain forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995 and other Federal securities laws. Because such statements deal with future events and are based on Alcobra's current expectations, they are subject to various risks and uncertainties and actual results, performance or achievements of Alcobra could differ materially from those described in or implied by the statements in this press release. For example, forward-looking statements include statements regarding our plan to initiate a Phase IIb MDX clinical trial and the potential therapeutic for MDX in human patients with FXS. In addition, historic results of scientific research and clinical and preclinical trials do not guarantee that the conclusions of future research or trials would not suggest different conclusions or that historic results referred to in this press release would be interpreted differently in light of additional research and clinical and preclinical trials results. The forward-looking statements contained or implied in this press release are subject to other risks and uncertainties, including those discussed under the heading "Risk Factors" in Alcobra Ltd.'s Annual Report on Form 20-F filed with the Securities and Exchange Commission ("SEC") on March 28, 2014, and in subsequent filings with the SEC. Except as otherwise required by law, Alcobra disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.
1. SOBP Poster #1364. Rubin J, Daniely Y, Manor I, et al. MG01CI in ADHD and Fragile X Syndrome: A Novel Mechanism of Action.
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