Drug Shows Promise in Fragile X and Possibly Autism

Megan Brooks

September 21, 2012

September 21, 2012 — The investigational γ-aminobutyric acid type B (GABA-B) agonist STX209 (arbaclofen, Seaside Therapeutics) may improve social function and behavior in patients with fragile X syndrome (FXS).

In a randomized, controlled phase 2 study of children and adults with FXS, investigators from Rush University Medical Center in Chicago found that treatment with arbaclofen was well tolerated and improved social avoidance and problem behaviors.

FXS is caused by the presence of expanded CGG triplets in the FMR1 gene on the X chromosome. It is the most common known inherited cause of autism and of intellectual disability, and social impairment is a core feature.

"The hypothesis is that the excess response to stimuli in the fragile X brain is mediated by a defect in inhibition, and that the excessive signaling through the mGluR5 [metabotropic glutamate receptor 5] receptor that occurs due to lack of the block on downstream dendritic translation when FMRP [fragile X mental retardation protein] is absent contributes to the inhibitory defect," first author Elizabeth M. Berry-Kravis, MD, PhD, told Medscape Medical News.

Dr. Elizabeth Berry-Kravis

"The arbaclofen reduces glutamate release, dampening the hypersignaling. Perhaps when the excess signaling is controlled, inputs from the environment become less activating and overwhelming, and the patients can tolerate normal social and environmental stimuli better, leading to a reduction in social withdrawal/avoidance," Dr. Berry-Kravis added.

The study was published online September 19 in Science Translational Medicine.

No Effect on Irritability

Studies in mice genetically engineered to exhibit features of FXS have suggested that the related behavioral problems result from deficiencies in the GABA neurotransmitter. Decreased GABA has been observed in a mouse model of FXS in many areas of the brain, including the hippocampus, and is thought to be a basis of the social anxiety and avoidance characteristic of FXS patients.

The current study tested the effects of arbaclofen on neurobehavioral function in a 6-week double-blind, placebo-controlled crossover study involving 63 FXS patients aged 6 to 39 years from 12 sites in the United States. Patients received placebo or arbaclofen and then crossed over to the other treatment.

Arbaclofen was given at the optimum tolerated dose — 10 mg twice daily in children aged 6 to 11 years and 10 mg thrice daily in patients aged 12 to 40 years. Patients were evaluated at 2- and 4-week intervals after beginning treatment.

Fifty-six (89%) participants completed the entire study. There were no withdrawals related to drug tolerability. The researchers note that arbaclofen was generally well tolerated, with an 8% incidence of sedation and headache as the most common side effects.

They failed to see any treatment effect of arbaclofen on the irritability subscale of the Aberrant Behavior Checklist (ABC) behavior rating scale — the primary outcome measure.

However, they did see improvement on the prespecified analysis of visual analog scale (VAS)-rated problem behaviors, and multiple global assessments of neurobehavioral function showed trends in favor of arbaclofen.

Supports GABA Hypothesis

In particular, post hoc analysis with the ABC–Social Avoidance scale, a newly validated scale for FXS, showed a significant beneficial treatment effect in the intent-to-treat population (P = .01). This was particularly evident in a subgroup of 27 participants with more severe social impairment.

"Our post hoc analyses were designed to identify the nature of the possible beneficial drug effects that contributed to the trend for global functional improvement but would not be accounted for by a change in irritability and aggression as measured by the ABC-I [Aberrant Behavior Checklist–Irritibility]," the authors write.

Dr. Berry-Kravis said the reason arbaclofen seems to help social function/behavior, but not irritability, is not clear.

"Irritability was only chosen because Risperdal [risperidone] and Abilify [aripiprazole] had been approved for autism on the basis of improvement in this subscale. Going into the study, we did not really know what would get better because the drug targeted a brain mechanism and improved phenotypes in animal models of FXS, so we had to pick something empirically. It turned out that social withdrawal/avoidance were the things that improved the most — in the most avoidant patients."

Overall, the researchers note that the results "are consistent with the hypothesis that social impairments in FXS may be related to GABA deficiencies or exaggerated glutamatergic signaling."

Targeted Approach

An Editor's Summary published with the paper notes that arbaclofen is a "targeted approach, which may help restore the balance between excitatory and inhibitory neurotransmission [and] has promise for improving social function in FXS."

Dr. Berry-Kravis said that arbaclofen is now in two phase 3 placebo-controlled studies for FXS, and a placebo-controlled study in autism has recently finished.

"It is hoped that these studies will demonstrate the same positive effects and will lead to US Food and Drug Administration approval for social avoidance in fragile X and autism," she said. There currently are no FDA-approved treatments for FXS.

Arbaclofen is also being studied in autism spectrum disorder (ASD). As previously reported by Medscape Medical News, a phase 2 study found that the drug improved irritability and agitation in children with ASD. Jeremy Veenstra-VanderWeele, MD, from Vanderbilt University, Nashville, Tennessee, led the ASD study, and Vanderbilt was one of the sites involved in the FXS study that was just published. He is not an author on the current paper.

Dr. Veenstra-VanderWeele told Medscape Medical News: "The potential for a medication to benefit social avoidance symptoms in fragile X syndrome is very exciting. These symptoms are often very troubling for children and their families. Social avoidance can interfere with school function and with establishing relationships with peers."

He emphasized that "replication is necessary before we can conclude that these promising findings are robust. I am hopeful that the ongoing trials of arbaclofen in fragile X syndrome will bear out these intriguing findings. It would be even more exciting if these results extend beyond fragile X syndrome to the larger group of children with autism spectrum disorders who struggle with social avoidance," Dr. Veenstra-VanderWeele said.

The study was sponsored by Seaside Therapeutics Inc. Several of the study authors have financial relationships with the company or are employees of the company. A complete list of author disclosures is listed with the original article. Dr. Veenstra-VanderWeele has received research funding from the company.

Sci Transl Med. Published online September 19, 2012. Abstract