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A treatment for autism looked tantalizingly close just five years ago, as the first drug studies launched for the disorder fragile X. Advocates hoped that treatments for the rest of the autism spectrum would soon follow.

Today, that optimism is gone, as drug after promising drug has failed.

Novartis announced last week that two drug trials showed an experimental medication did not improve the conditions of adults and teens with fragile X, a genetic disorder that can lead to intellectual disability, anxiety, speech delay, seizures, and social challenges. Other trials run by Roche and startup Seaside Therapeutics also failed to show benefits.


“The patient community had been sold on the hope that comes with these clinical trials,” said Robert Ring, the outgoing chief scientific officer of Autism Speaks, an advocacy and research group. “I think we can do a lot better job of spelling out the realistic context in which these things are happening.”

Ring, who formerly headed the autism research unit at drug giant Pfizer, said the results may discourage venture capitalists from pursuing drug development in the field. But he said big drug companies will likely stick with it.


It’ll just take a lot longer, and a lot more work, than advocates and scientists had hoped.

“We’re just learning how to conduct clinical trials in this patient community,” he said. “That means we’re going to have some failures up front, but I don’t think it’s diminishing the excitement and interest in wanting to bring other opportunities. Not at all.”

Fragile X is caused by a genetic mutation on the X chromosome. Because males have only one X, they get fragile X more often and usually more severely than females, whose second X chromosome often overrides the mutation.

About 30 percent of boys with fragile X also meet full criteria for autism, according to the FRAXA Research Foundation. There is enough overlap between the two conditions that scientists presume any drug that works in those with fragile X will also help a larger group on the autism spectrum. There are no drugs approved for treating fragile X. The medications available for autism only address symptoms, not its underlying cause.

Mouse studies had suggested that although the fragile X mutation affects brain development, the condition could be reversed later in life. But this new set of trials, published in Science Translational Medicine, failed to show any significant improvement in behavioral symptoms in 139 teens or 175 adults.

There are many reasons the trials may have failed, said Dr. Shafali Jeste, a behavioral child neurologist at the University of California, Los Angeles David Geffen School of Medicine, who cowrote an opinion piece published along with the study.

It may be that the drug tested — called mavoglurant — is not the right drug. It may need to be taken for longer or at a higher dose to show a benefit. Or it may be that its effects on people are not directly comparable to the ones seen in mice, so different study measures are needed, she said.

One major problem with studying both autism and fragile X is that symptoms are subjective. Both conditions are variable and people often have good days and bad days. Parents and caregivers may want to see improvements or be so used to certain behaviors that they don’t notice slight changes.

Jeste, along with a group of researchers across the country, has just launched the federally funded Autism Biomarkers Consortium for Clinical Trials to try to develop more objective measures both for diagnosing autism in young children and for tracking changes. Eventually, that group’s work will benefit drug trials, she said.

She thinks future drugs will need to be tested on young children or infants, rather than teens and adults.

Both fragile X and autism affect the developing brain beginning before birth, so it makes sense that medications would have the most profound benefits if given while the brain is still developing, she said.

Studies so far have focused on older children and adults out of a desire to help people who are suffering, and because of concerns about testing novel drugs with unknown side effects on small children, she said.

Randall Carpenter, who led the Seaside drug trials when he ran that company,  said the negative trials also helped the Food and Drug Administration better understand drug treatments for autism and related conditions, which will make it easier for future drugs to win approval.

“The story of autism science is really reaching an inflection point,” Ring added. “There’s undoubtedly going to be a lot of activity turning that into actual products.”

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