Opinion Conversations on the science of autism research.

Mouse studies support second chance for fragile X drug

by  /  28 April 2015

Alexis Demetriades

Three years ago, arbaclofen was the most promising drug for the autism-linked disorder fragile X syndrome. But after two cancelled clinical trials, it fell victim to the vagaries of the drug development pipeline. Two new studies in mice hint that this early end to its story may have been premature.

One study, published 28 March in the International Journal of Neuropsychopharmacology, showed that arbaclofen corrects abnormalities in the fragile X brain. It revealed that the drug dampens protein synthesis, which runs amok in fragile X syndrome.

The study also found that neurons in mice may ramp up production of certain proteins to compensate for the drug’s effects. This adaptation may help to explain why arbaclofen failed to significantly improve social skills in adolescents and adults with fragile X syndrome.

Another study, published last month in Neuropsychopharmacology, determined that arbaclofen eases social deficits as well as obsessive and repetitive behaviors in mice with features of autism.

Together, the findings from these studies suggest that the drug can achieve real benefit in easing the symptoms of fragile X syndrome and, perhaps, autism.

Arbaclofen stimulates inhibitory receptors known as GABA-B, an action that ultimately dampens brain activity. Mice that model fragile X syndrome have fewer GABA-B receptors. A 2012 study showed that stimulating the activity of the receptors with arbaclofen helps correct neuronal signaling in the mice and alleviates their repetitive behaviors.

These findings prompted a clinical trial that same year by Seaside Therapeutics, a Massachusetts-based biotechnology firm, in which the drug improved social behavior in children and adults with fragile X syndrome.

Encouraged by this outcome, Seaside extended its trial in people with fragile X syndrome and launched another one in children with autism.

In both trials, there were anecdotal reports that children improved in their ability to communicate and carry out daily tasks. However, the trials were designed primarily to measure social behavior, which did not improve enough to pass the requirements for drug approval. Seaside halted the trials and subsequently went under.

Since then, the Simons Foundation Autism Research Initiative — funded by the Simons Foundation, SFARI.org’s parent organization — has purchased the rights to arbaclofen and plans to revive trials in people with autism to verify the reported benefits. But there’s no question that the field lost valuable time.

The saga serves as a lesson on the importance of carefully designing clinical trials to capture all of a drug’s positive effects. The latest studies in animals are proof that there’s more to arbaclofen’s effects on the brain than the aborted trials had the time to find.

6 responses to “Mouse studies support second chance for fragile X drug”

  1. Parents Know says:

    Seaside received letters from parents begging them to not scrub the drug. My son is doing so well, kind of letters. Please don’t take this away from us, kind of letters. There is the link to the Seaside petition above, and it really makes you cry.

  2. Parents Know says:

    I think you will have a lot of parents’ gratitude for reviving this and giving them access to it again.

  3. Paul Wang, Autism Speaks says:

    As a former employee of Seaside Therapeutics, I can say that we heard many pleas from families like Parents Know’s, and we were very sorry that we could not continue the development of arbaclofen. While the clinical trials of arbaclofen were negative from the strict regulatory perspective, their results are considered intriguing by a large majority of scientists who are familiar with them. As this SFARI.org article notes, Seaside ran out of money and is no longer in business. We are grateful that the Simons Foundation purchased the rights to arbaclofen and plans to revive studies of the drug, as mentioned above.

    My comments are personal comments, and do not necessarily reflect the position of Autism Speaks.

  4. Aditi Bhattacharya says:

    It always comes back to trial design and the conclusions drawn from it. Paul himself has on many occasions presented the Seaside trail data, and it was clear that there were effects- they just did not conform to the rigid guidelines set up for trail evaluations, which are usually a priori. We need more follow up studies like these for other compounds that supposedly did not ‘work’.

  5. John Ferrara says:

    My son was part of the autism clinical trial for arbaclofen. His autism is considered moderate. The arbaclofen worked very well with him. When the trial was discontinued, we were quiet upset. However, his Dr. prescribed him baclofen. He gave it a 50-50 chance of working. My son has been taking the medicine ever since & it has performed very well. He’s in mainstream 3rd grade instead of the special needs class.

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