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

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

Saturday, May 14, 2011: 3:00 PM
Elizabeth Ballroom GH (Manchester Grand Hyatt)
1:15 PM
P. Wang1, C. A. Erickson2, L. Ginsberg3, B. Rathmell4, M. Cherubini5, P. Zarevics6 and B. King7, (1)Seaside Therapeutics, Cambridge, MA, (2)Indiana University School of Medicine, Indianapolis, IN, (3)Red Oak Psychiatry Associates, Houston, TX, (4)Seaside Therapeutics, LLC, Cambridge, MA, United States, (5)Seaside Therapeutics, Inc., Cambridge, MA, United States, (6)Seaside Therapeutics, Cambridge, MA, United States, (7)University of Washington and Seattle Children's Hospital, Seattle, WA, United States
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.

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