Fran Lowry

June 22, 2011

June 22, 2011 (Boca Raton, Florida) — The investigational GABA-B agonist arbaclofen improved irritability and agitation in children with autism spectrum disorder (ASD), new research suggests.

A phase 2, randomized, crossover trial of arbaclofen vs placebo in fragile X syndrome showed improved ratings of social behavior when children were taking arbaclofen, said lead investigator Jeremy Veenstra-VanderWeele, MD, from Vanderbilt University, Nashville, Tennessee.

These promising results prompted the current study, he told Medscape Medical News.

"Fragile X is the most common known inherited cause of autism, but it only accounts for about 5% of kids. In this study, we wanted to see if arbaclofen would be well tolerated and what improvements we might see in children and adolescents with idiopathic autism spectrum disorder," Dr. Veenstra-VanderWeele said.

The findings were presented here at the New Clinical Drug Evaluation Unit 51st Annual Meeting, sponsored by the American Society of Clinical Psychopharmacology.

Significant Improvement

The 8-week, open-label, flexible-dose trial was performed at 8 sites throughout the United States and included 25 children ages 6 to 17 years. All participants had a diagnosis of ASD according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria and the Autism Diagnostic Interview and had an Aberrant Behavior Checklist irritability (ABC-I) score greater than 16.

The children were allowed to be taking up to 2 concurrent psychoactive medications, with the exception of antipsychotics.

The investigators found that, overall, arbaclofen was well tolerated. Two children discontinued use of the drug because of increased agitation or aggression, and 5 dropped out for other reasons. There was 1 serious adverse event in the form of increased aggression, which occurred during planned taper of arbaclofen.

In the intent-to-treat population, the study found a significant improvement on both parent-rated scales and physician-rated scales, Dr. Veenstra-VanderWeele said.

The ABC-I score went from a mean ± SD of 24.7 ± 8.3 at the start of the study to 17.3 ± 10.5 at 8 weeks, and the Social Withdrawal subscale score went from a mean ± SD of 18.1 ± 8.2 to 12.6 ± 9.3.

In all, 20 children were rated "much improved" or "very much improved" on the Clinical Global Impression for Improvement scale.

Reason for Optimism

"I think there is reason to be optimistic, but I think it's also important to not overinterpret an open-label study," Dr. Veenstra-VanderWeele cautioned.

"We did see some participants who showed what looked to us to be pretty dramatic improvements, who seemed more engaged, more talkative, who seemed calmer, but at the same time, until we are able to contrast arbaclofen with placebo, we just don’t know what the specific responses are, and we really can’t say how big the treatment effect might be," he said.

He stressed that the real message from this work is that it motivates further study.

"In this small trial, arbaclofen showed good tolerability and beneficial effects on the core and associated symptoms of autism spectrum disorder. A double-blind, placebo-controlled, phase 2 trial in ASD is planned," he said.

Asked by Medscape Medical News to comment on the findings, Heather Cody Hazlett, MD, from the University of North Carolina at Chapel Hill, said she was intrigued by the research.

"I am familiar with drug trials in the fragile X population with arbaclofen, but I was not aware of any studies using this in an autism population, so this is an exciting new avenue," Dr. Hazlett said.

"This is a strong team of investigators, and as far as I know, this study presented at the conference is the first report looking at arbaclofen in autism. Given the promising results shown with fragile X patients, it seems logical to investigate whether there might be some treatment benefits in autism since the disorders share many behavioral features. I look forward to seeing their double-blind study, which should provide more conclusive data."

The study was sponsored by Seaside Therapeutics. Dr. Veenstra-VanderWeele reports financial relationships with Novartis, Roche Pharmaceuticals, and Seaside Therapeutics. Dr. Hazlett has disclosed no relevant financial relationships.

New Clinical Drug Evaluation Unit (NCDEU) 51st Annual Meeting: Abstract 43. Presented June 15, 2011.

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