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Positive Phase III Results Reported for Extended-Release Metadoxine in Adults With ADHD

Treatment improves both predominately inattentive and combined-type subtypes

Positive data have been reported from a phase III study of metadoxine extended release (MDX, Alcobra Pharma) in adults with attention-deficit hyperactivity disorder (ADHD).

In a modified intent-to-treat (mITT) population (N = 293), MDX demonstrated a statistically significant (P

The mITT population was derived by a post hoc exclusion of four subjects with extreme placebo responses. Before the exclusion of these subjects, the ITT analysis yielded a positive trend (n = 297; P = 0.15).

The randomized, placebo-controlled study was conducted in the U.S. and Israel. Approximately 70% of the patients were enrolled in the U.S., and the patients were nearly evenly divided between men and women. The patients were randomly assigned to receive either 1,400 mg of MDX or placebo over 6 weeks. The trial’s primary endpoint was the CAARS-INV.

In the mITT analysis, a mean change on the CAARS-INV from baseline to the final visit of 11.6 was observed in the MDX group compared with a mean change of 8.7 in the placebo group (P P

The numbers of patients reporting adverse events (AEs) were similar between the MDX and placebo groups, with no drug-related serious AEs reported. The most common AEs were headache (15.1% in MDX group vs. 12.3% in placebo group), nausea (8.6% vs. 6.2%), and fatigue (7.2% vs. 8.2%). Additional clinical studies of MDX in adolescents with ADHD, as well as in adolescents and adults with fragile X syndrome, are currently enrolling patients.

MDX is an extended-release oral formulation of metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate). The drug is an ion-pair salt of pyridoxine (vitamin B6) and 2-pyrrolidone-5-carboxylate (PCA, also known as L-PGA). Metadoxine is a selective antagonist of the 5-hydroxytryptamine receptor 2B (5-HT2B), also known as serotonin receptor 2B, and does not show any binding to other serotonin receptors. It does not bind the characterized targets of existing stimulant and non-stimulant medications (i.e., dopamine and norepinephrine receptors and transporters) and does not affect the concentration of these neurotransmitters or their metabolites in the brain.

In electrophysiologic studies, 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.

Sources: Alcobra Pharma; October 6, 2014; and Metadoxine; 2014.

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