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FDA Gives Green Light to Studies of Extended-Release Metadoxine in Adults With ADHD

Phase III trial to begin enrollment in first quarter of 2014

The FDA has approved an investigational new drug (IND) application for metadoxine extended release (MDX, Alcobra Ltd.) as a potential treatment for attention-deficit hyperactivity disorder (ADHD). This step will allow the initiation of U.S. clinical trials.

Unlike commonly prescribed ADHD medications, MDX is not a stimulant, and it targets neither dopamine nor norepinephrine.

ADHD is a common and potentially debilitating neuropsychiatric condition. Once believed to affect only children, the disorder is now known to persist into adolescence and adulthood. An estimated 4% to 5% of adults worldwide have ADHD.

While approved stimulant medications have been shown to be effective and safe for the treatment of ADHD, up to 30% to 50% of patients that are prescribed such medications either do not respond to them or do not tolerate them; the utility of stimulants is further hindered by the potential for abuse.

MDX is an extended-release oral formulation of metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate). Metadoxine is an ion-pair salt of pyridoxine (vitamin B6) and 2-pyrrolidone-5-carboxylate. The drug is a selective antagonist of the 5-HT2B receptor, a member of the serotonin receptor family, and does bind to other serotonin receptors.

Moreover, metadoxine does not bind to the characterized targets of existing stimulant and nonstimulant medications (i.e., dopamine and norepinephrine receptors and transporters) and does not affect the concentrations of these neurotransmitters or their metabolites in the brain. Electrophysiological studies have shown that metadoxine causes a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.

MDX was effective and generally well tolerated in two phase II trials in adults with ADHD. The first study, completed in 2011, was a 6-week randomized, double-blind, placebo-controlled, parallel-group, phase IIb trial of MDX 1,400 mg in 120 adults with ADHD. Results from this study were published in the December 2012 issue of the Journal of Clinical Psychiatry and in the July 2013 issue of Postgraduate Medicine.

The efficacy measures in this trial were baseline to end-of-treatment changes in Conners’ Adult ADHD Rating Scale–Investigator Rated (CAARS-INV) Total ADHD Symptoms scores with adult ADHD prompts; the Test of Variables of Attention ADHD scores; and response rates (≥ 25% or ≥ 40% improvement in CAARS-INV Total ADHD Symptoms score).

The authors reported a significant decrease in CAARS-INV Total ADHD Symptoms scores in patients with predominantly inattentive ADHD (ADHD-PI) treated with MDX compared with those given placebo (40% vs. 21%, respectively; P = 0.05). There was also a significant decrease in inattentive scores in patients with ADHD-PI treated with MDX versus placebo (50% vs. 23%, respectively; P = 0.005). Significantly higher response rates at both cutoffs (i.e., 25% and 40% improvement) were seen in the MDX group compared with the placebo group in CAARS-INV Total ADHD Symptoms scores. Moreover, Test of Variables of Attention ADHD scores were significantly decreased in the MDX group compared with the placebo group.

The second study, completed in 2013, was a randomized, double-blind, placebo-controlled, cross-over trial in 36 adult subjects with ADHD-PI. The results from this study were reported in December 2013.

The subjects were randomly assigned to one of three treatment sequences. In each sequence, they received a single administration, approximately 1 week apart and in different orders, of MDX 1,400 mg, MDX 700 mg, and placebo. The study’s primary outcome was the change from baseline in the Test of Variables of Attention (TOVA) ADHD score.

In an intent-to-treat analysis of the primary endpoint, the study demonstrated a statistically significant change from baseline for MDX 1,400 mg compared with both placebo (mean change: 2.0; P = 0.009) and MDX 700 mg (mean change: 1.8; P = 0.032) on the TOVA ADHD score. The study also demonstrated a statistically significant change from baseline for MDX 1,400 mg compared with placebo on the TOVA sub-score of reaction time variability (mean change: 7.9; P = 0.022).

Sources: Alcobra Pharma; March 6, 2014; Alcobra Pharma; December 16, 2013; and Postgraduate Medicine; July 2013.

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