Pam Harrison

May 09, 2013

DONOSTIA / SAN SEBASTIÁN, Spain — A post hoc analysis of a phase 2 randomized controlled trial with an experimental agent demonstrated an "unprecedented" treatment effect in reducing symptom severity in some patients with autism spectrum disorder (ASD).

The 12-week randomized controlled trial of STX209 (arbaclofen), an experimental agent that acts upstream from mGluR5 receptor signaling and is thought to augment inhibitory neurotransmission, showed potential for "clinically meaningful improvements in social function," according to investigators led by Jeremy Veenstra-VanderWeele, MD, associate professor of psychiatry, pediatrics and pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.

"There is a long-standing hypothesis that there is an imbalance between excitatory and inhibitory neurotransmission in autism," Dr. Veenstra-VanderWeele said in a press conference.

"And if arbaclofen acts as an agonist in the GABA [γ-aminobutyric acid] system like we think it does, it may rectify that imbalance in some patients."

The study was presented here during the 12th Annual International Meeting for Autism Research (IMFAR).

The phase 2 study included 150 patients between 5 and 21 years of age, all with ASD and most with classic autistic disorder, said Dr. VanderWeele.

A total of 130 participants completed the study; 8 patients discontinued STX209 due to adverse events (AEs), and 2 received placebo. The primary endpoint was change in the Aberrant Behavior Checklist Social Withdrawal and Lethargy (ABC-LSW) subscale.

"There was no difference between subjects on active medication and those on placebo on that particular subscale," said Dr. VanderWeele.

However, one of the key secondary outcomes was Clinical Global Impression–Severity (CGI-S) score, he added. And on this secondary outcomes scale, some patients treated with STX209 did show a "clinically relevant change" compared with those receiving placebo.

On all other secondary endpoints, including results on the Vineland Adaptive Behavior (VAB) socialization scale, results also favored STX209 numerically but did not reach statistical significance.

Table. Change From Baseline

  STX209 Recipients Placebo Recipients (Control)
ABC-LSW subscale -5.4 -6.0 (P = .518)
CGI-S -0.6 -0.2 (P = .006)
VAB socialization score 3.8 2.1 (P = .362)


A post hoc analysis was also conducted among 96 participants whose VAB scale had been completed by the same clinician and caregiver. Results showed that those who received STX209 showed greater improvement in the VAB scale, at 7.2 compared with 1.8 (P = .006).

"This is a scale that a lot of us investigators didn't think could move over this period of time, so this is a potentially very exciting, novel outcome," said Dr. VanderWeele. "And from my perspective, this would really be an unprecedented treatment effect for any medication."

However, he emphasized that as a post hoc analysis, the findings clearly require replication.

The study was based on work initially carried out in fruit flies. Investigators then proceeded to work in mice and subsequently with patients with fragile X syndrome.

"Fragile X syndrome is the most common known inherited cause of ASD and is caused by a particular gene disruption that frequently includes autism as part of its expression," said Dr. VanderWeele.

In fact, approximately 60% of patients with fragile X syndrome have autism as part of their clinical presentation.

"If we can understand the cause of fragile X, some patients with ASD could have similar underlying changes in the brain and could benefit from the same medication," he speculated.

STX209 is currently available only for research purposes.

Improved Social Functioning

Asked by Medscape Medical News to comment on the study, Evdokia Anagnostou, MD, Autism Research Centre, Toronto, Ontario, Canada, noted that the study, although not definitive, suggests that there is potential for STX209 to be used as a treatment for social deficits associated with ASD.

"An excitation to inhibition imbalance has been proposed as a potential set of common mechanisms in the pathophysiology of ASD, and as a GABA agonist, arbaclofen may be targeting such an imbalance," she said.

Dr. Anagnostou emphasized that the study was not able to reach significant results in the primary outcome.

"Still, both pilot studies to date and this study show a signal in measures of social function. Although we still need to understand which aspects of social function are more likely to respond, the study suggests that this is a promising agent and a promising mechanism to target for the treatment of core deficits in ASD."

This study was funded by Seaside Therapeutics. Dr. VanderWeele has received research funding from Seaside Therapeutics among other pharmaceutical companies.

12th Annual International Meeting for Autism Research (IMFAR). Abstract 102.001. Presented May 2, 2013.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.