Fragile X clinical trials: this is not the end

A clinical trial testing a therapy for children with fragile X syndrome is closing down, after the sponsoring company announced that the drug, called arbaclofen, was not meeting its goals.

Readers of Emory Health magazine may remember Samuel McKinnon, an arbaclofen study participant who was featured in a 2012 article and video (below).

“We were surprised,” Samuel’s mother Wendy told us Monday. “But we knew going in that there were no guarantees.”

She reports that Samuel has made significant progress in the last couple of years. He likes playing and talking with the family’s new puppy, Biscuit. Samuel’s language skills have Ray Ban outlet blossomed and he will be headed to second grade this fall. But it’s hard to say whether that’s mainly because of the experimental drug or because Samuel has been continuing to grow and work hard in school and in therapy, she says.

A sizable fraction of patients in the study appeared to benefit from the drug, just not the majority of them, says Emory genetics chair Steve Warren.

Warren led the team that found Fmr1, the gene responsible for fragile X syndrome, in 1991. Fragile X syndrome is the most common inherited form of intellectual disability and the most common single-gene cause of autism. Warren says part of the challenge in designing clinical trials for patients with fragile X syndrome is the broad range of disability, along with the complexity of measuring outcomes such as irritability, social withdrawal, and repetitive or aberrant behavior. Arbaclofen was also being investigated for autism.

Even though the news from the arbaclofen trial is disappointing, Warren points out that it’s not the end for mGluR5 inhibitors, a separate class of experimental drugs developed to address the molecular deficiencies caused by fragile X.

Warren’s laboratory and others have been looking at how disabling the Fmr1 gene changes signals in the brain. Researchers have found that overactive signaling from glutamate plays a maglie calcio poco prezzo large part, and that drugs that tamp down signals from one type of glutamate receptor (mGluR5) can reverse some of the molecular changes in brain cells seen in animal models of fragile X.

Arbaclofen, the drug being tested in the trial that is closing, was aimed at the same problem but came from a different direction. Arbaclofen affects different neurotransmitters — it is a GABA-B receptor agonist and is thought to indirectly affect glutamate. The clinical trials testing mGluR5 inhibitors [being conducted by Roche and Novartis] are not as advanced and the results are yet to come.

If the McKinnons find Samuel losing ground after the drug is taken away, one option the family has is to continue with a related drug, baclofen. Baclofen is a muscle relaxant that has been in clinical use for decades, and it actually consists of a mixture of two mirror-image chemicals, one of which is arbaclofen. The abundance of reassuring safety information on baclofen was the reason why the arbaclofen studies were more advanced, compared to those of the mGluR5 inhibitors, which need more testing.

The FRAXA Research Foundation says in a May 16 letter: “The scientific research behind the mGluR5 drugs is as least as strong as the science behind arbaclofen.”

Warren also says that other genetic or epigenetic differences may account for variations in response to arbaclofen or mGluR5 inhibitors, and more studies could look at what makes a patient do better or worse on experimental therapies.

Posted on by Quinn Eastman in Neuro 2 Comments

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Quinn Eastman

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