International Meeting for Autism Research: Arbaclofen for the Treatment of Children and Adults with Fragile X Syndrome: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study

Arbaclofen for the Treatment of Children and Adults with Fragile X Syndrome: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study

Saturday, May 22, 2010: 2:00 PM
Grand Ballroom AB Level 5 (Philadelphia Marriott Downtown)
1:15 PM
E. Berry-Kravis , Pediatrics; Biochemistry; Neurology, Rush University Medical Center, Chicago, IL
M. Cherubini , Seaside Therapeutics, Cambridge, MA
P. Zarevics , Seaside Therapeutics, Cambridge, MA
B. Rathmell , Seaside Therapeutics, Cambridge, MA
P. P. Wang , Seaside Therapeutics, Cambridge, MA
R. Carpenter , Seaside Therapeutics, Cambridge, MA
M. Bear , Department of Brain and Cognitive Sciences, MIT, Cambridge, MA
R. Hagerman , M.I.N.D. Institute, UC Davis, UC Davis, Sacramento, CA
Background: Fragile X syndrome (FXS) is the most common known genetic cause of autism, and about 25% of males with FXS meet full criteria for autism. According to the “mGluR theory” of FXS, absence of the FX gene product (FMRP) results in dysregulation of dendritic protein synthesis and consequent abnormalities of synaptic plasticity. It is hypothesized that other etiologies of autism may also be characterized by “synapsopathies” (disorders of synaptic function).

The rationale for studying arbaclofen (the active entantiomer of racemic baclofen) in FXS and autism is multifold. First, racemic baclofen anecdotally improves behavior in both FXS and autism. Second, racemic baclofen ameliorates abnormal phenotypes in several animal models of FXS, including audiogenic seizures and hyperactivity in the FXS mouse. Third, transcranial magnetic stimulation studies show that racemic baclofen modulates cortical plasticity in healthy control subjects. Lastly, in both human and animal studies, arbaclofen appears better tolerated and more efficacious than racemic baclofen.

Objectives: To assess the efficacy, safety and tolerability of arbaclofen for the treatment of irritability in FXS. The effects of arbaclofen on other behavioral and cognitive measures also were explored.

Methods: A double-blind, placebo-controlled, crossover trial in subjects with FXS, aged 6 to 40, was conducted at 12 sites in the USA ( NCT00788073). Subjects were randomized to receive either placebo or arbaclofen. After 4 weeks treatment, subjects tapered off medication, entered a washout period, and then began treatment with the other blinded medication.

The primary efficacy endpoint was the Irritability subscale of the Aberrant Behavior Checklist. A sample size of n=60 provided 90% power to detect an effect size of 0.6. Study enrollment was restricted to subjects age 12 – 40 until a planned interim safety review by an independent monitor, to examine data from the first 10 study completers, and to consider extending enrollment to age 6.

Results: The interim safety review determined that adverse events were predominantly attributed to pre-existing conditions or viral infections, and none were unanticipated, given the known side effects of baclofen. One subject experienced a serious adverse event, increased irritability, when tapering off study medication (subsequently unblinded and determined to be arbaclofen). Other subjects showed similar deterioration when blinded study medication was titrated downward. On the independent monitor's recommendation, enrollment was then extended to age 6.

The study completed enrollment on 06Nov2009. Of 63 subjects randomized, 55 were male. There were 23 subjects aged 6-11 years, another 23 aged 12-17 years, and 17 aged 18-40 years. Full efficacy and safety results are anticipated in April 2010.

Conclusions: Advances in the neurobiological understanding of FXS and autism are now leading to the development of targeted pharmacotherapeutics for these conditions. Abundant challenges remain in the translation of neurobiology to clinical therapy, but trials of some rationally-justified agents are already underway. Interim results indicate that arbaclofen shows good safety and tolerability in subjects with FX aged 6 to 40 years. Full efficacy and safety results will be presented.

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