Kum-ba-arbaclofen

I assume quite a few people have already read the various reports about STX209* (most definitely not to be confused with ED-209) otherwise known as arbaclofen with Fragile X syndrome in mind. Hailed as 'The First Drug that Could Ease Social Withdrawal in Autism' according to one news source, the headlines are based on the results of this study by Elizabeth Berry-Kravis and colleagues** complemented by this study by Henderson and colleagues*** published on the same day in the same journal.

OK reverse please.

Seaside Therapeutics, yet another pharmaceutical company with autism or autistic behaviours in their sights, had been working for quite a while now on a new formulation, a derivative of baclofen, itself a derivative of everyone's favourite inhibitory neurotransmitter, GABA - gamma aminobutyric acid (see here for a description) as a possible therapeutic for certain behaviours associated with autism. Baclofen is normally indicated for the treatment of spasticity resulting from conditions like multiple sclerosis and cerebral palsy.

GABA is the yin to glutamate - an excitatory neurotransmitter - the yang. The balancing act between excitatory and inhibitory neurotransmitters has, on more than one occasions, been suggested to be slightly skewed in some cases of autism (and other conditions and states) as glutamate takes centre stage.

So then STX209 is, as its chemical relations are, recognised as an agonist for GABAB receptors which in turn inhibits the release of glutamate (and aspartate). You can perhaps see therefore where the interest lies.

I know quite a lot of the press around STX209 has focused on autism, but to be more accurate, Fragile X syndrome  - which presents with autistic features - is the target patient group based on the trials completed so far. The suggestion being that the primary mutation associated with Fragile X syndrome - FMR1 gene - has some knock-on effects**** including "activation of mGluR5, a metabotropic glutamate receptor". Avid watchers of the autism research landscape might remember mGluR5 as being a target for other pharmaceutics with autism/autistic characteristics in mind, including another interesting compound, GRN-529***** (at least in mice).

So:

• The recent trial of STX209** relied on human participants rather than mice, 63 of them in all, mostly male and all carrying "a full mutation in the FMR1 gene". 
• Randomised, double-blind, placebo-controlled (all the things that science really likes to hear about) was the study design and outcome-wise, the Aberrant Behavior Checklist (ABC) and the Vineland Adaptive Behaviour Scales (VABS) are listed.
• The primary endpoint of the study was a focus on irritability, which actually didn't come up trumps over placebo. 
• Having said that, there were some significant positive effects noted on areas of social avoidance in the treatment group acknowledging that the absolute number of participants in the study was relatively small and actually got even smaller following some post-hoc analysis.
• Importantly also, a few side-effects were noted, particularly in the treatment group including URTIs (13%) and headaches (8%).

I note that Seaside Therapeutics have quite recently agreed some terms over STX209 with pharmaceutical giant Roche which suggests to me that things might potentially get quite big for arbaclofen rather quickly. By saying that, I'm not in anyway endorsing the medicine. Quite a bit more data is required on long-term safety, efficacy and best responder characteristics.

With that in mind, I'll be quite interested to see the results of further trials of STX209 as are apparently planned and/or getting underway including a trial specific to children and young adults diagnosed with an autism spectrum disorders (see here). As to the mechanism of STX209 to GABAB receptors to improving social avoidance... more investigation needed I assume.

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* Hopkins CR. ACS Chemical Neuroscience Molecule Spotlight on STX209 (Arbaclofen). ACS Chem Neurosci. 2011; 2: 381.

** Berry-Kravis EM. et al. Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial. Science Translational Medicine. 2012; 4: 152ra127

*** Henderson C. Reversal of disease-related pathologies in the Fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Science Translational Medicine. 2012; 4: 152ra128

**** Dölen G. et al. Correction of fragile X syndrome in mice. Neuron. 2007: 56: 955-962.

***** Silverman JL. et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Science Translational Medicine. 2012; 4: 131ra51.

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Elizabeth M. Berry-Kravis, David Hessl, Barbara Rathmell, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Yi Mu, Danh V. Nguyen, Joseph Gonzalez-Heydrich, Paul P. Wang, Randall L. Carpenter, Mark F. Bear, & Randi J. Hagerman (2012). Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial Science Translational Medicine DOI: 10.1126/scitranslmed.3004214