Taylor Stevenson’s family never left him out of
conversations, but they never expected him to participate, either. His
contributions, if he made any, were a few random words—gibberish or a Big Bird
quote.
So when Taylor started speaking his mind in his squeaky,
sing-songy voice, his mother, Debbie Stevenson, was stunned. “It was such a
huge shock,” Stevenson says. She cried tears of joy. This was in late 2012,
when Taylor was 16. Over the next year, his once-cursory answers spun into
three- to five-word sentences. Phrases such as “I’m okay, thank you” became
part of his repertoire.
Taylor has fragile X syndrome, a genetic condition that
causes lifelong intellectual disability. One in three people with the syndrome
also have autism. Taylor is not one of them, but he does have some autism-like
features, such as difficulties with language. At first, Stevenson wasn’t sure
what was triggering her son’s changing behavior. Perhaps Taylor’s new high
school had sparked the improvement, or perhaps the countless hours of intensive
therapy he had endured were finally paying off.
Stevenson began to suspect that a new drug Taylor was taking
was responsible. A few months earlier, Taylor had enrolled in a clinical trial
exploring the effects of an experimental drug called mavoglurant, manufactured
by the pharmaceutical giant Novartis, for people with fragile X syndrome.
Stevenson had heard about the trial through her volunteer fundraising work with
the nonprofit FRAXA Research Foundation, a fragile X research and advocacy
organization. Because there are no approved drugs to treat fragile X, she
eagerly signed Taylor up.
Taylor enrolled in the 12-week trial in September 2012 and
began taking either mavoglurant or an inactive placebo twice a day. (Neither
the Stevensons nor the researchers knew which drug Taylor was taking.) The
family flew from their New York City home down to Atlanta, Georgia, once a
month for questionnaires and behavioral testing at Emory University, one of the
trial’s 38 sites.
Within a few months, Stevenson noticed a slight shift in
Taylor’s behavior. He started asking her for help when he needed it, and his
anxiety diminished. These improvements persisted even after he switched to the
second, long-term phase, during which he and the other participants took
mavoglurant for more than a year. Stevenson became convinced that Taylor’s
improvement really was due to the drug.
To Stevenson’s surprise, however, rumors that the trial
wasn’t going well began to spread through FRAXA circles in February 2014. When
the family showed up at Emory for another testing session a few months later,
the researchers told them Novartis was suspending the trial. “I was beyond
shocked,” Stevenson says. “I thought that even if only 25 percent of the population
has seen what I’ve seen, of course they’ll approve it—because we have nothing
else.”
When Taylor’s supply of the drug ran out, his strides
forward reversed. Within a few months, his sentences diminished to single
words, and now he mostly ignores questions, as he did before the trial.
Stevenson, who took Taylor’s regression the hardest, wished
the study had been able to capture Taylor’s progress. But it would become clear
to her that the trial had been poised to fail even before it got off the ground.
Deeper issues—the wrong design and inadequate tests—crippled the study from the
start…
“I was pretty horrified,” Stevenson says. “Do we have a drug
that is getting slammed because we didn’t measure this properly?”
As it turns out, this trial’s misfire wasn’t an isolated
incident. The same problems have dogged major trials exploring three of the
most promising drugs for fragile X, including ventures launched within the past
decade by Roche and the now-defunct Seaside Therapeutics. Stunted by flawed
designs, each of the trials flopped, and by late 2014 all three drugs had been
yanked from the research pipeline. To date, no drugs are approved to treat
fragile X syndrome.
In the case of autism, too, few drugs have proven effective
in trials, and several have failed due to poor design. Just two drugs,
risperidone and aripiprazole, are approved by the U.S. Food and Drug
Administration (FDA) for autism and are intended to relieve irritability. A few
others treat attention deficit hyperactivity disorder and epilepsy, which often
accompany autism. But none have passed muster for treating the condition’s core
social impairments or repetitive behaviors…
The researchers thought that blocking a protein called
mGluR5, which counters the normal role of FMRP, might restore the balance of
synaptic proteins in people with fragile X syndrome. To their delight, the idea
worked—in mice. A string of studies showed that in mouse models of fragile X,
mGluR5 blockers normalize synapse function and improve learning. More than 30
papers thus far have shown the benefits of mGluR5 blockers in animal models,
says Elizabeth Berry-Kravis, professor of pediatrics, neurological sciences,
and biochemistry at Rush University in Chicago. “That’s one of the biggest
bodies of basic-science evidence for a mechanism ever amassed.”
Emboldened by this bulk of evidence, several drug companies
launched clinical trials in people with fragile X syndrome. In 2009, a
12-person trial sponsored by Neuropharm Ltd., a U.K.-based company now owned by
Autism Therapeutics, found that an mGluR5 blocker called fenobam eases
oversensitivity to sounds, a common feature in people with fragile X. That same
year, Novartis’ mavoglurant showed early promise for treating hyperactivity,
social difficulties and repetitive behavior in seven people with fragile X who
lack FMRP. And an early Roche-sponsored trial, which also began in 2009, found
that the drug basimglurant, another mGluR5 blocker, seemed to alleviate
anxiety.
However, as Novartis and Roche prepared to launch much
larger trials to test these drugs further, Berry-Kravis, who ran studies at
Rush for both companies, grew concerned. The drugs target connections between
neurons, which have the most capacity for change during early brain
development, so they should work best in children. But both proposed trials
were focused on adults and adolescents, which is the typical first step for
large clinical trials. If these trials failed to show a benefit, the chances
that the companies would launch studies in children were slim, Berry-Kravis
says. (The companies ran early studies to test the drugs’ safety in children
but didn’t include children in larger trials.)…
The researchers voiced their concerns about the trials’
design to Novartis and Roche, but the companies wouldn’t budge. Beginning in
2010, hundreds of adults and teens, including Taylor, enrolled in the trials.
During each study session, the participants’ parents completed the ABC and
several other questionnaires, gauging traits such as social impairment and
anxiety. But none of the measures seemed to capture Taylor’s extraordinary
progress. Stevenson was concerned. “All those amazing things I had just seen in
the last month and then I’d told the clinicians about at Emory, none of it
translated to what I was putting down on this piece of paper,” Stevenson says.
The failure of these trials, with their repetition of
earlier mistakes, is a source of enormous frustration for scientists. “It’s
very possible that we could have drugs that work really well on development,
and we’ve missed them because of the way we develop drugs,” Berry-Kravis says…
Learning from the long string of failures, autism
researchers are collaborating with drug companies and federal agencies to
revamp the way clinical trials are conducted.
One team of researchers spanning multiple centers has
embarked on a $28 million initiative to put autism measures and biomarkers
through rigorous testing…
Taylor still uses words sparingly and fixates on unusual
things, such as the compact discs that go into his beloved portable DVD player.
But he likes being around other people and making them laugh with a funny look
or a non sequitur. He lives at a residential school for people with
disabilities on farmland a couple of hours away from his family’s home in New
York City. In November, he moved into the adult house at the school, and
Stevenson drove up to help him get settled. “It’s huge, because this is where
he could really stay for the rest of his life,” she says.
Given all of his difficulties, Taylor may need a whole
cocktail of drugs, Stevenson says, and so may many others like him. The trick
will be getting enough drugs on the market to try out different combinations.
In the meantime, she is open to anything that might help her son navigate his
world, like his new adult program. Everyday skills, such as brushing his teeth
and cooking himself dinner, are still challenging for Taylor. Learning little
things like this, she says, would dramatically change his life.
Courtesy of Doximity
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