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Some parents upset after trial halted for autism drug

Anders Zorovic’s last visit to the dentist was uneventful. His mother, Becky, did not have to hold him down, screaming and crying. The 11-year-old from Sharon simply sat still as the dentist scraped away at his teeth.

Anders has autism and a closely related genetic condition called fragile X. He has been calmer since taking an experimental treatment known as arbaclofen that his mother credits for his peaceful climb into the dentist’s chair, and the first real family conversations at the dinner table.

But in a development painfully familiar to autism families, the Cambridge company behind arbaclofen, Seaside Therapeutics, discontinued a critical clinical trial of the drug for fragile X, and it will soon no longer be available.


“Everyone’s so disappointed,” said Becky Zorovic. “That’s part of being in a clinical trial. There’s no guarantee going in. It just highlights some of the pitfalls of doing clinical trials on drugs for autism or fragile X.”

Greater Boston is at the forefront of autism research, and the condition itself — estimated to affect 1 in 50 American children — is now receiving major scientific interest. Arbaclofen in particular was received with great expectations by the autism community.

Zorovic and other parents said arbaclofen reduced the level of anxiety and otherwise helped their children. But Seaside said the drug did not show enough progress on the one behavior it had targeted for the trial: the social withdrawal so characteristic of people with fragile X or autism.

People with autism have difficulty with communication and social interactions, and are preoccupied with repetitive behaviors or routines. About 5 percent of those with autism also have fragile X, which is a genetic mutation of the X chromosome; many of them exhibit severe behaviors, such as sudden rages or panic attacks, obsessive or age-inappropriate actions and constant motion.


“This is not an easy disorder, to say the least,” said Katie Clapp, whose 23-year-old son Andy has both fragile X and autism.

Despite greater understanding of autism among the general public, and significant advances in research, the condition and related ones have so far resisted treatment. The only scientifically proven approach remains behavioral therapy — teaching children techniques so they can learn better in school and communicate more easily. But behavioral therapy can take years to work, and it doesn’t benefit everyone.

Arbaclofen would have been the first drug to treat the core symptoms of autism and fragile X. But not only did it not work well enough, Seaside also said the company had “resource limitations” that prevented it from continuing its studies.

Moreover, pharmaceutical giant Roche Holding AG pulled out of a joint effort with Seaside to develop arbaclofen for the broader population of people with autism.

Seaside declined to comment beyond a statement it released to families. In a statement, Roche said that although it won’t participate in further research on arbaclofen with Seaside, it remains committed to several other compounds under development for autism and fragile X, including one from Seaside.

While parents like Clapp, the founder and president of FRAXA Research Foundation, had high hopes for arbaclofen, they have also become toughened to the highs and lows that accompany every new promising avenue of research into autism.

“I wish they’d succeeded,” Clapp said. “It’s a real blow, but there’s a lot more hope.”


A scientific backwater just 20 years ago, autism research now attracts some of the world’s most accomplished scientists, with Boston leading much of that work. The region has a number of top-notch neuroscientists, geneticists, and other specialists devoted to the disorder; the drugs under development by Seaside, for example, were based on landmark research by Mark Bear of the Massachusetts Institute of Technology.

There are also several area venture capitalists backing this research.

While confident they will make inroads against autism, researchers said it is the disorder’s broad range of symptoms, from relatively mild social awkwardness to a total inability to communicate, that make it difficult to treat. Patients don’t start in the same place, so it’s hard to measure improvements that are consistent from one to the next, said Jeremy Veenstra-VanderWeele, an associate professor of psychiatry, pediatrics, and pharmacology at Vanderbilt University in Nashville, who was involved in the arbaclofen trial.

Indeed, scientists aren’t even sure if autism is a single condition, or a range of different conditions. It is also unclear what causes autism, though genetics and environmental factors both play a role, according to a 2011 study by Stanford University.

This complexity makes developing any new drug “heinously complicated,” and particularly difficult for a small company such as Seaside, said Michael Poole, head of neuroscience innovative medicines at AstraZeneca in Cambridge.

Moreover, Poole said, autism is “a new and uncharted field, and new and uncharted fields are constantly beset by challenges.” He has a personal stake in Seaside’s success, he said, as his son has been diagnosed with autism.


Seaside’s work on fragile X derived out of Bear’s research that arbaclofen, and another class of drugs under development called mGluR5 antagonists, helped control the release and transmission of chemicals in the brain. A problem with the flow of these chemicals leads to the symptoms of fragile X, and likely plays a role in autism, too, Bear hypothesized.

Bear did not return a request for comment.

Veenstra-VanderWeele said drug companies have to go by the measures they select for their drug trials — social withdrawal, in this case — even if the medication showed ancillary benefits in patients, as was the case with Anders Zorovic and other patients.

Some parents in the arbaclofen test said the reports requested by Seaside did not offer much opportunity to explain dramatic changes that were outside the target behavior of the trial.

“The changes we’ve seen are not measurable. There is no concrete way to measure his response in a dentist’s office,” said Melissa Zolecki, of Plainfield, Ill., whose 12-year-old son Matthew was, like Anders, apparently calmed by arbaclofen.

Matthew Zolecki had taken arbaclofen for 3½ years, and now Zolecki is anxious about which of his challenging behaviors will return as he comes off the drug.

Anders Zorovic, meanwhile, used to obsess over afternoon fire drills at his school, to the point of refusing to eat before 3 p.m. because he was afraid he’d throw up if the sirens went off. Those are now nonevents.


His mother said the two can now talk out issues — with her explaining situations to reduce his anxiety, and he in turn, articulating what was bothering him. It was almost as if the drug helped him pass beyond the drama most toddlers go through around age 2.

All that made family life much calmer and happier, but again, those qualities were hard to note on the simple checklist provided to the drug company, said Zorovic, who put a career as an endocrinologist on hold to care for her son.

She too is unsure how her son will respond as he is weaned off arbaclofen.

“My hope is those effects will last even without the medicine on board,” Zorovic said.

Seaside, meanwhile, does have a third trial of arbaclofen, for children with fragile X between the ages of 5 and 11, which it promises to complete by the end of the summer. If the drug is shown to be effective in the younger group, Seaside will discuss with the Food and Drug Administration the next steps involved in approval, the company said in a statement.