Alcobra Ltd., an emerging pharmaceutical company engaged in development of treatment for cognitive disorders, including attention deficit hyperactivity disorder (ADHD) and Fragile X syndrome (FXS), reported that its phase 2 clinical trial of MDX (Metadoxine Extended Release) for the treatment of FXS did not meet the primary endpoint of change from baseline to week 6 of the inattentive subscale of the Attention Deficit Hyperactivity Disorder Rating Scale (ADHD RS-IV).

The difference between treatment groups was not statistically significant. However, MDX did achieve statistical significance, in the Intent-to-Treat (ITT) population, on two secondary endpoints, including the Vineland Adaptive Behavior Scale (VABS) Daily Living Skills Domain (p=0.044), and the computerized cognitive Test of Attentional Performance for Children (KiTAP) Distractibility subscale (p=0.017). In the study, MDX was generally well tolerated and no safety concerns were identified.

"The combination of significant improvements in adaptive behavior and cognition, obtained both by caregiver interview, and direct objective patient assessment, suggests a meaningful finding," commented Elizabeth Berry Kravis, MD, PhD, professor of paediatrics, neurological sciences, and biochemistry at Rush University Medical Center, and the principal investigator of the study. "Previous placebo-controlled trials in adolescent and adult patients with Fragile X have failed to demonstrate such an effect even after a longer treatment duration."

There are no approved medications to treat FXS. MDX has received an Orphan Drug designation from the US Food and Drug Administration (FDA) for the treatment of FXS. Alcobra plans to discuss these trial results with the FDA before finalising the design of the next study of MDX in FXS.

"We are encouraged by the positive findings on two clinically relevant secondary measures, most notably daily functional behavior such as managing time and money, and completing domestic chores, as well as the further evidence of the pro-cognitive activity of MDX," stated Dr. Yaron Daniely, president and chief executive officer of Alcobra. "FXS is a difficult disease to treat and study, as demonstrated by the lack of approved treatments. Our findings suggest a clinically meaningful advance for patients and caregivers affected by FXS and we plan to meet with the FDA to determine next steps in advancing our research," added Dr. Daniely.

The purpose of the randomized, double-blind, placebo-controlled, multi-center phase 2 clinical trial was to assess the efficacy and safety of MDX compared to placebo in 62 adolescent and adult patients with FXS, a rare neurogenetic condition and the leading known genetic cause of autism. Efficacy measures included both behavioral and cognitive scales.

The baseline demographics of the study demonstrated a mean age of 24 years, with approximately 75 per cent males, mostly Caucasian. The average IQ score was 57 for subjects taking MDX and 52 for subjects taking placebo, with a wide overall range of 18 to 107. Autism spectrum disorder, as classified by the Autism Diagnostic Observation Schedule (ADOS), was present in over 80 per cent of subjects. A total of 40 subjects were concurrently treated with at least one psychotropic drug. 16 of these subjects were concurrently treated with an approved ADHD drug. In general, treatment groups had similar demographics, although significantly more placebo-treated subjects took concomitant ADHD medications during the study (p=0.03).

The objective of the primary endpoint was to show a reduction in the symptom score on the ADHD RS-IV Inattentive subscale. The difference between the MDX-treated group and placebo was not statistically significant (p=0.21), favouring placebo. Related secondary endpoints such as the total ADHD RS score and CGI were similarly non-significant. The detection of a signal on this scale may have been obscured in this exploratory trial by the concomitant use of approved ADHD and other psychotropic medications by a majority of patients during the study and the imbalanced randomization of these patients, the limitations of the ADHD-RS assessment in a population with highly variable and mostly abnormal intellectual capacity and developmental age, and the potential challenge in discerning changes in inattentive symptoms in this complex neurobehavioral disorder.

Five measures, including two domains of the Vineland Adaptive Behavior Scale (VABS), the Aberrant Behavior Checklist (ABC), the Test of Attentional Performance for Children (KiTAP), and the Repeatable Battery for the Assessment of Neuropsychological Status List Learning test (RBANS-LL) were used as secondary measures in this trial. MDX showed a statistically significant benefit over placebo, in the ITT population, on the VABS Daily Living Skills Domain (p=0.044) and on the computerized KiTAP Distractibility test (p=0.017). The VABS Daily Living Skills assessment is a validated measure of adaptive behavior often used in FXS studies; it includes three subdomains which are assessed through a clinical interview with a caregiver: the personal subdomain; assessing basic functional skills such as eating, drinking, dressing or undressing, and maintaining personal hygiene, the domestic subdomain; assessing primarily household chores the individual can perform such as cooking, cleaning, putting things in place, and keeping themself safe at home, and the community subdomain; assessing the subjects understanding and proper management of time, money, phone use, TV or computer use, travel, work skills and outdoor functions. The KiTAP Distractibility test is a computerized continuous performance test of attention assessing the ability to maintain attention in the presence of distractors. Findings on both the VABS Daily Living Skills Domain and the KiTAP Distractibility test also showed meaningful clinical effect sizes of 0.56 and 0.63 respectively (Cohen's d; standardized difference between two means). The remaining secondary measures did not yield significant findings in the ITT population, although a directional benefit with an effect size of 0.34 was noted on the RBANS-LL, a short-term verbal memory task.

During the trial, MDX was generally well tolerated and no safety concerns were identified. The profile of adverse events in the MDX-treated group was similar to the placebo comparator group. The most common side effects were upper respiratory tract infection (6.7 per cent in MDX, 15.6 per cent in placebo), irritability (10.0 per cent in MDX, 9.4 per cent in placebo), and headache (10.0 per cent in MDX, 3.1 per cent in placebo). A single Serious Adverse Event of Bell's Palsy was recorded in the trial, and occurred in a placebo-treated patient.

Fragile X syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning challenges. Behavioral characteristics can include ADHD, autism and autistic behaviors, social anxiety, stereotypic movements, poor eye contact, sensory disorders and increased risk for aggression. FXS is the leading known genetic cause of autism, accounting for about 2-6 per cent of cases. FXS represents an unmet medical need and a rare disease, as defined by the Orphan Drug Act. According to the National Institutes of Health (NIH), approximately one in 4,000 males and one in 8,000 females have FXS. Approximately 50,000 Americans are affected by FXS. The FDA has not approved any drugs specifically for the treatment of FXS or its symptoms.

MDX is a proprietary investigational new drug candidate being developed by Alcobra for the potential treatment of ADHD and Fragile X syndrome. MDX is not a stimulant and acts as a monoamine-independent modulator of GABA (gamma-aminobutyric acid) transmission. This novel mechanism of action does not directly affect dopamine or norepinephrine. In studies to date, metadoxine has shown no potential for abuse or addiction. MDX is currently in phase 3 development for adults with ADHD and phase 2 development for paediatric ADHD. A phase 2 study of MDX in adolescents and adults with FXS was completed and results were reported in Q2 2015.