Improvement of Daily Living Skills in Adolescents and Adults with Fragile X Syndrome Following MDX (Metadoxine Extended Release) Administration

Background:  Fragile X Syndrome (FXS) is a rare genetic disorder characterized by Intellectual Disability and/or Learning Disability in association with a constellation of neuro-behavioral problems, including Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), anxiety, and repetitive behaviors. Metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate) is an ion-pair salt of pyridoxine (vitamin B6) and 2-pyrrolidone-5-carboxylate (PCA, also known as L-PGA) that has been used outside of the US in an immediate-release form for more than 30 years to treat acute alcohol intoxication, alcohol withdrawal syndrome, and chronic alcoholic liver disease.  Metadoxine extended release (MDX) is a dual-release formulation of metadoxine, demonstrated to be a modulator of GABAergic transmission with a monoamine-independent mechanism of action, and which reverses phenotypes in the mouse model of FXS. In a phase 2, 6-week, randomized, multi-center, double-blind, parallel, flexed- and fixed-dose trial of MDX compared with placebo in adolescents and adults with FXS, the ADHD-RS IV, the primary outcome failed to show improvement, while the Vineland II Daily Living Scale (DLS), a secondary outcome, was significantly improved on MDX versus placebo.

Objectives:  To fully characterize the effects of MDX on the Vineland-II DLS in FXS.

Methods:  Subjects enrolled in the study were males and females with molecular diagnosis of FXS, (≥200 CGG repeats, in FMR1) 14 to 55 years, with a score ≥12 on the inattentive subscale of the ADHD RS-IV. Improvements in the group assigned to MDX, in comparison with the placebo group, with a secondary efficacy assessment, the Vineland Adaptive Behavior Scale, Expanded Interview Form, Second Edition (Vineland-II) DLS were characterized in detail by using item analysis and correlating results with other outcomes.

Results:  62 subjects were randomized (MDX 30; placebo 32). The primary analysis, the MMRM LS mean change from baseline to week6/early termination in the ITT population was significant on the DLS domain standard score (p=0.04) and the community subdomain v-scale score (p=0.004), and was not significant for the personal and domestic subdomain v-scale scores.  These results were strengthened when the ITT population was limited in a post-hoc analysis to subjects with normalized IQ from 40-85 and ages 14-40. 

Analysis of individual items in the DLS domain demonstrated significant effects (p<0.05) for several questions such as:  seeks medical help in emergencies, plans and/or organized daily work, and carries out multi-step tasks. For most of these items, the MDX placebo difference in the mean change from baseline to week 6/ET was 0.5 to 1, demonstrating a categorical improvement. Items from objective secondary measures in the trial directly assessing the subject (KiTAP Distractibility and Go/No-Go computerized tests, and RBANS-List Learning), produced supportive correlations (r>0.25, p<0.05) with improvements on the DLS domain.

Conclusions:  MDX demonstrated a statistically significant effect on the Vineland-II DLS domain in FXS.  Item analyses suggested clinically meaningful changes in areas related to daily living skills, and correlations with other objective outcomes strengthened the effect.