Treatment of Fragile X Syndrome with STX209 (arbaclofen): Open-Label Extension Experience

Background:  Fragile X syndrome (FXS) is the most common known cause of autism, and the most common genetic cause of intellectual disability.  Animal models of FXS show that it is characterized by an elevated ratio of excitatory:inhibitory neurotransmission, and by abnormal synaptic plasticity, which results from excessive signaling in the mGluR pathway.   STX209 (arbaclofen) is a GABA-B agonist that augments inhibitory neurotransmission, and that rescues many abnormal phenotypes in FXS animal models.  In a randomized, controlled study of 63 children and young adults with FXS, post-hoc analysis showed that STX209 was associated with significant improvement on the Aberrant Behavior Checklist (ABC) – Social Avoidance scale, which has been specifically validated in the FXS population (Sansone et al., 2011).   Other post-hoc analyses showed improvements on the Socialization domain of the Vineland Adaptive Behavior Scales (VABS) among subjects with more severe social impairment at baseline.  Anecdotally, many subjects were reported to be more communicative as well.

Objectives:  To examine the long-term safety and tolerability of orally-administered STX209 in patients with FXS.  A secondary objective was to examine the open-label effects of STX209 on adaptive function in patients with FXS.

Methods:  Subjects who completed the randomized, controlled study, and who met other inclusion/exclusion criteria, were invited to enroll in a 12-month, open-label extension study of STX209.  The dose of STX209 was titrated upwards flexibly over the first 4 weeks.  Clinicians could continue to adjust drug dosage throughout the remainder of the study, according to their best judgment.  Up to 3 concomitant psychoactive medications were permitted.  Follow-up visits were conducted at Weeks 4, 10, 20, 30, 40 and 52, with safety assessments and the ABC scale.  The VABS and the Stanford-Binet IQ test were administered during the placebo-controlled trial, and then at Week 52 of the extension study.

Results:  45 subjects (6 female, 39 male; age range 6 – 31 years) enrolled in this open-label study, out of 46 who met eligibility criteria.  34 subjects (76%) remained in the study at Week 52.  There were no serious adverse events.  Data from the study are currently being compiled and analyzed.  Available data from 15 subjects showed a change in the standard score on the VABS-Communication domain from 56.9 ± 13.2 (mean ± standard deviation) to 62.3 ± 12.4 at Week 52.  The VABS-Composite score showed a smaller change, from 59.4 ± 9.2 to 61.7 ± 10.0.  By contrast, Fisch et al. (1996) reported that VABS composite scores decreased in 22 out of 24 children and adolescents with FXS who were followed over a 2 year period.

Conclusions:  Full data on subject disposition, safety, tolerability, and efficacy will be presented.