Effects of STX209 (arbaclofen) on Social and Communicative Function In ASD: Results of An 8-Week Open-Label Trial

Background:  STX209 (arbaclofen) is an orally-administered GABA-B agonist and is the active isomer of racemic baclofen.  Results of a placebo-controlled Phase 2 trial suggest that it may decrease social withdrawal and improve adaptive social function in Fragile X syndrome.  In addition, there are anecdotal reports in autism spectrum disorders (ASD) of improvement in social, communicative, and anxiety-related symptoms after treatment with racemic baclofen.  The hypothesized mechanisms of action of STX209 include augmentation of inhibitory neurotransmission (excitation:inhibition imbalance theory of autism), and modulation of synaptic plasticity (mGluR theory, via GABA suppression of glutamate release).

Objectives:  To evaluate the safety and efficacy of STX209 in pediatric patients with ASD.

Methods:  An 8-week, open-label trial was conducted at 8 sites in the U.S.A.  Enrollment criteria included a diagnosis of autistic disorder or PDD-NOS, age 6 – 17 years, and an Aberrant Behavior Checklist-Irritability score (ABC-I) > 16.  Concomitant anti-psychotic medications were not allowed, but up to 2 other concurrent psychoactive medications were permitted at stable doses.  A flexible dose titration was employed, with a starting dose of 1 mg BID, titrating every 3-4 days to a maximum of 10 mg TID (or 10 mg BID for subjects below age 12 years).

An extensive battery of outcome measures was administered, including the ABC, CGI-I, CGI-S, Social Responsiveness Scale, CASI-Anxiety scale, CY-BOCS-PDD, Repetitive Behavior Scale, ADHD-IV Rating Scale, Vineland Adaptive Behavior Scales, and the Leiter Brief IQ.  Standard safety assessments were performed.

Results:  32 children (29 male) were enrolled, with 27 meeting DSM-IV criteria for Autistic Disorder, and 5 PDD-NOS.  Their mean age was 12 ± 3 (mean ± SD), and mean IQ was 56 ± 4.  Twenty-five of 32 subjects completed the study, with 2 discontinuing due to adverse events and 5 for other reasons. STX209 was well-tolerated.  There was 1 serious adverse event (increased aggression), which occurred during down-titration of study medication.

In the ITT population, there was significant improvement on the primary endpoint, the ABC-I, from 24.7 ± 8.3 at baseline, to 17.3 ± 10.5 at Week 8 (p<0.001).  Subjects also showed significant improvements on the ABC-Social Withdrawal scale (from 18.1 ± 8.2 to 12.6 ± 9.3, p=0.001), the CGI-I (p<0.05), the CGI-S (p<0.001), and on most of the other outcome measures, including the Communication domain standard score on the Vineland (from 61.4 ± 10.5 to 65.4 ± 9.5, p<0.01).

The most common adverse events were agitation (22%), irritability (22%), fatigue (16%), psychomotor hyperactivity (16%), insomnia (13%) and diarrhea (13%).  Many of these events resolved without dose changes and may reflect spontaneous variability in underlying symptoms.  Clinical laboratory assessments did not show any potential treatment associated abnormalities.

Conclusions:  STX209 showed broad beneficial effects in this open-label study, notably on core symptoms in the social and communication domains. A double-blind, placebo-controlled trial is planned to begin early in 2011.