Date: 2015-06-24
Type of information: Results
phase: 2b
Announcement: results
Company: Alcobra (Israel)
Product: metadoxine extended release (MDX)
Action mechanism:
Disease: fragile X syndrome
Therapeutic area: Rare diseases - Genetic diseases
Country: Israel, USA
Trial
details: The Phase IIb Fragile X trial is a multi-center, randomized, placebo-controlled study and is being conducted in 11 clinical sites, primarily in the U.S. It is designed to investigate MDX for 6 weeks compared with placebo in 60 adolescent and adult subjects with Fragile X Syndrome. (NCT02126995)
Latest
news: * On June 24, 2015, Alcobra, an emerging pharmaceutical company focused on the development of new medications to help patients with cognitive disorders, including Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome (FXS), reported that the company's 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). The baseline demographics of the study demonstrated a mean age of 24 years, with approximately 75% 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% 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). Primary Endpoint: 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), favoring 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. Secondary Endpoints: 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. A detailed analysis of the study's efficacy measures will be presented during the conference call and webcast hosted by management later this morning. In the study, MDX was generally well tolerated and no safety concerns were identified. Alcobra plans to discuss these trial results with the FDA before finalizing the design of the next study of MDX in FXS. * On August 19, 2014, Alcobra announced that the first patient has been enrolled in a Phase IIb Fragile X study of Metadoxine Extended Release (MDX). The goal is now to complete patient enrollment and report top-line data in the 4th quarter of 2014. * On April 10, 2014, Alcobra has announced that it has submitted a protocol to the FDA for a Phase IIb clinical trial for its MDX product candidate for the treatment of patients with Fragile X Syndrome. The planned Phase IIb MDX clinical trial will be a multi-center, randomized, placebo-controlled study, conducted primarily in the US. The protocol submission is under an IND and is supported by strong, positive data collected from multiple earlier pre-clinical trials on metadoxine. Results from these studies demonstrated significant improvement in behavioral and cognitive outcomes based on evaluations of memory, learning, and social interaction. Furthermore, in a validated mouse model of Fragile X Syndrome, metadoxine treatment was shown to result in improved levels of certain Fragile X-associated blood and brain biological markers that may have a role in learning and memory, while simultaneously reducing the number of immature brain connections and levels of abnormally increased protein. In December 2013, the FDA granted \"Orphan Drug\" designation to Metadoxine in the treatment of Fragile X Syndrome.
Safety: 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% in MDX, 15.6% in placebo), irritability (10.0% in MDX, 9.4% in placebo), and headache (10.0% in MDX, 3.1% in placebo). A single Serious Adverse Event of Bell's Palsy was recorded in the trial, and occurred in a placebo-treated patient.
