For a few weeks last year, Michael Tranfaglia and Katie Clapp saw a remarkable change in their son, Andy, who'd been left autistic and intellectually disabled by fragile X syndrome. Andy, who is 25, became more social, more talkative and happier. "He was just doing incredibly well," his father says.
The improvements came while Andy was taking an experimental drug — a drug made possible by the efforts of his parents. And at the time, it appeared this drug might become the first effective treatment for fragile X, a rare genetic syndrome that affects brain development and can lead to intellectual and social disabilities. The reality would turn out to be more complicated.
The story of this drug begins in 1994, when Clapp, a computer scientist, and Tranfaglia, a psychiatrist, helped launch the FRAXA Research Foundation. Their goal was simple: find a way to help Andy and other people with fragile X.
The couple didn't know much about running a foundation. But they made some smart decisions. One of these was that FRAXA should support a researcher at MIT named Mark Bear, who made a big discovery. He found evidence that fragile X disrupts an important pathway in the brain called mGluR5.
Bear also realized that two big drug companies, Novartis and Roche, were already working on drugs for depression and addiction that might help repair this pathway. So Tranfaglia and Clapp began lobbying those companies to try the experimental drugs on people with fragile X.
Part of the sales pitch was that any drug that could reduce autism symptoms in people with fragile X might help millions of other people with autism. "And after a while, it worked," Tranfaglia says. "We finally got their attention, and they were convinced that a drug trial using some of these compounds was worth doing."
That was a huge step because drug trials typically cost millions of dollars. An even bigger step was getting Andy into one of these drug trials.
At first it wasn't possible because the trials were taking place in cities a long way from the family's home in West Newbury, Mass. But after several years, Novartis began testing its drug near Boston and Andy was included in the trial. "I do believe he was the last patient enrolled," Clapp says.
Andy began taking pills. At the time, no one knew whether they were sugar pills or the drug. But both parents saw a change in their son. He wasn't cured, but he was less rigid and more talkative.
For years, Clapp and her son had shared a joke. She would say, "I like that house." Then Andy would say, "Nah, I don't like it." One day during the drug trial, Clapp told Andy about a house she liked. "And this time, he says, 'Yes, I like it too. It has red shutters,' " she says. "He responded to me like any person would."
The couple would find out later that Andy had been receiving the drug, not a placebo. It looked like their 20-year search for a treatment was over. Then Novartis held a meeting to announce the results of its drug trial.
"We went into that meeting fully expecting great results because our son was just doing incredibly well," Tranfaglia says. "I thought, there's no way this doesn't work. This is amazing. And they presented these results, and the numbers were just unbelievably bad."
The drug may have been helping Andy. But overall, it didn't seem to work. "It was truly devastating," Clapp says. Then the couple learned that a second drug, the one from Roche, also failed in a large fragile X trial.
"The failures in these trials led us to question everything," Tranfaglia says. The couple wondered whether they had just seen what they wanted to see in their son's behavior. They even wondered whether it made sense for FRAXA to continue funding basic research in hopes of finding a drug for fragile X.
In the end, the couple decided their approach was sound and that the drug really had helped their son. As a scientist, Tranfaglia knew that was possible. "Most clinical trials have some people who do really well even when the overall result is not necessarily great," he says.
But the drug Andy took is no longer available, even to researchers. And the future of the drug made by Roche is unclear.
The results were a huge disappointment, Clapp says, but not a failure. "To actually see an Andy I never, ever thought I would ever see, that was a success," she says.
Another success is FRAXA itself. The foundation now involves thousands of parents and hundreds of scientists. It has funded more than $24 million in research on fragile X.
And that research isn't going to stop, Clapp says. "We can't give up, because we have Andy."
DAVID GREENE, HOST:
Today in Your Health, a sequel - six years ago we brought you the story of two parents searching for a drug that could help their son, Andy. Andy was born with fragile X, a genetic syndrome that left him autistic and intellectually disabled. Here's Andy's mother, Katie Clapp, talking about what she and her husband hoped to achieve for their son, who was then 19.
KATIE CLAPP: We're not expecting a miracle or to make up for his 19 years of development, but if we can watch improvement happen, that's a dream.
GREENE: Andy is now 25 years old and a lot has happened in his life. Last year, he began taking an experimental drug - a drug made possible by the efforts of his parents. This fall NPR's Jon Hamilton visited the family's home in West Newbury, Massachusetts, and he brings back a story of success, disappointment, doubt and hope.
JON HAMILTON, BYLINE: Andy Tranfaglia has just returned from the farm where he spends most of the day. Now he wants mango juice.
ANDY TRANFAGLIA: Make the juice.
CLAPP: Andy, can you pour it in your cup please?
ANDY TRANFAGLIA: Oh, just get out.
CLAPP: OK, you got to stop.
ANDY TRANFAGLIA: Stop.
HAMILTON: When I first met Andy in 2008, he didn't say much. Now he can string together sentences with three or four words. He's also more social. In other words, Andy is doing somewhat better, but his mother, Katie Clapp, says there was a period last year when Andy seemed to get much better.
CLAPP: For a short time we did see great improvements in Andy, in his behavior, in the way he spoke.
HAMILTON: Katie says the improvements came while her son was taking an experimental drug. That drug was identified after many years of work by a research foundation called FRAXA.
CLAPP: We started FRAXA in 1994.
HAMILTON: Katie Clapp and her husband, Mike Tranfaglia, didn't know much about running a foundation. He's a psychiatrist, she's a computer scientist. And they had no idea their foundation would go on to involve thousands of parents and fund more than $24 million in research on fragile X, but from the start, the couple made smart decisions.
One of these was that FRAXA should support a researcher at MIT named Mark Bear, who eventually made a big discovery. He found evidence that fragile X disrupts an important pathway in the brain. Mike Tranfaglia says Bear also realized that drug companies were already working on so-called new molecules that might help repair this pathway.
MIKE TRANFAGLIA: The first time that Mark Bear told us about his breakthrough finding, he mentioned a kind of prototype molecule and it was called MPEP.
HAMILTON: And drugs based on MPEP were being tested by two major pharmaceutical companies, Novartis and Roche. The companies hoped their drugs would prove useful for treating depression or addiction, but Mike and Katie began lobbying the companies to try their drugs on people with fragile X. Mike Tranfaglia pointed out that any drug able to reduce the autism in people with fragile X might help millions of other people with autism.
MIKE TRANFAGLIA: And after a while it worked. We finally got their attention and they were convinced that a drug trial using some of these compounds was worth doing.
HAMILTON: Katie says that was a huge step.
CLAPP: It was just extraordinary to see this happen, to see major commitment from drum companies and excitement.
HAMILTON: An even bigger step was getting their son into one of the drug trials. At first it wasn't possible because they were taking place in cities a long way off.
CLAPP: These trials that we worked so hard to get started, finally - finally after several years - opened up near us in Boston. So we were able to enroll Andy in the Novartis trial. And I do believe he was the last patient enrolled.
HAMILTON: Andy began taking pills. At the time no one knew whether they were sugar pills or the drug, but both Katie and Mike saw a change in their son. He wasn't cured, but he was less rigid and more talkative. Katie says for years she and Andy had shared a joke - she would say I like that house. Then Andy would say no, I don't like it. Then one day during the drug trial Katie mentioned a house she liked.
CLAPP: And this time he says yes, I like it too. It has red shutters. And he said it immediately. There was no delay. There was no fuzzy, blurry noise. He responded to me like any person would.
HAMILTON: Mike and Katie would find out later that Andy had been receiving the drug, not a placebo. So after nearly 20 years, it looked like the couple's dream had come true. Mike Tranfaglia says before long Novartis held a meeting to announce the results of its drug trial.
MIKE TRANFAGLIA: And so we went into that meeting fully expecting great results because at the time our son had been on the full dose of the Novartis drug for about a month and he was just doing incredibly well. And I thought, well, there's no way this doesn't work. This is amazing. And they presented these results and the numbers were just unbelievably bad.
HAMILTON: The drug may have been helping Andy, but overall it didn't seem to work.
CLAPP: It was truly devastating. It did take maybe six or nine months for me to really get over it emotionally, let's say.
HAMILTON: It didn't help that a second drug, the one from Roche, also failed in a large fragile X trial. As for the improvement in Andy, Mike and Katie say they wondered whether they had just seen what they wanted to see. They also wondered whether the drug had failed because it's effect decreased over time, something they noticed with Andy.
MIKE TRANFAGLIA: The failures in these trials, obviously, led us to question everything and one of the things it led us to question was the basic method we were using.
HAMILTON: The method of funding basic scientific research in the hope that it would lead to a treatment. In the end, they decided their approach was sound and that the drug really had helped their son. Mike says, as a scientist, he knew that was possible.
MIKE TRANFAGLIA: Most clinical trials have some people who do really well, even when the overall result is not necessarily great. And for those folks it's really hard to have that drug go away.
HAMILTON: The Novartis drug Andy took will probably never be marketed for any disease. The other drug, the one made by Roche, may eventually be used to treat depression. Katie Clapp says the results are a huge disappointment, but not a failure.
CLAPP: To actually see an Andy I never, ever thought I would ever see - to talk to Andy and have him talk back was incredible. And that was a success because it shows me it's there.
HAMILTON: And Katie says she and her husband will keep searching for a drug to treat fragile X.
CLAPP: We can't give up because we have Andy.
HAMILTON: Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.