For most people, attending a relative's wedding is a happy occasion. But for one Highland Park couple, seeing their son socialize and dance qualified as a once-in-a-lifetime thrill.
"Ethan was just so appropriate ... so engaged in life," said Rebecca Fishman, reflecting on the spring event. "For one glorious moment, we got to be this normal family ... and I just can't let that slip away."
Ethan Fishman, 20, has Fragile X syndrome, a genetic condition closely related to autism. His mother credited his newfound social skills to arbaclofen, an experimental drug he was taking in a clinical trial.
But the study was terminated in May because it failed to reach its goals and resources were limited, according to a statement from Seaside Therapeutics, the company that created the drug. Two months later, with the drug no longer available, the Fishmans, along with other families in the trial, say the benefits they had observed are dwindling.
"It's just been devastating," said Rebecca Fishman, who was attending her 11-year-old child's school concert when the news about ending the study popped up in a text message. "I had to get out of there ... it felt like a death."
The Fishmans' experience sheds light on the emotional roller coaster of all clinical trials, which combine vulnerable and often desperate patients with untested drugs and market forces. Despite all the consent forms and cautionary language, the subjects sometimes perceive the process as a cure, rather than an experiment.
It also illuminates the long odds of bringing new drugs to market. Researchers say the challenges are particularly daunting when the objective of the study is assessing something as complex as behavior, which, unlike the size of a tumor or cholesterol count, is difficult to measure.
Three Illinois families whose children participated in the trial and took arbaclofen told the Tribune they believe the drug reduced their child's anxiety or increased communication. They viewed the drug as the key to unlocking the enigma of Fragile X, which has no cure and affects 1 in 100,000 Americans with symptoms ranging from mild aggression to severe cognitive impairment.
While the drug showed significant benefits in some areas in the 300-patient trial, researchers said, it failed to beat the placebo on the main goal of the study: social withdrawal. That caused Seaside and its partner, Roche, the Swiss pharmaceutical giant, to pull the plug. Seaside and Roche issued statements expressing regret and acknowledging the disappointment by participants.
The drug is unavailable anywhere in the world, leaving the families frustrated and feeling abandoned. Following the announcement, advocates started online petitions, reached out to potential investors and even appealed to the White House, all to no avail.
"I got so much out of those 31/2 years," sighed Holly Usrey-Roos, referring to her son's time in the study. His vocabulary exploded, enabling the 14-year-old to use a complete sentence rather than a single word when he wanted an object. One of those sentences allowed Usrey-Roos to hear Parker say "I love you" for the first time.
The single mother made the four-hour one-way drive each week from her home in Canton in west central Illinois to Rush University Medical Center, the largest of Seaside's 23 research sites.
"You know going in that participating in a trial is a risk," said Usrey-Roos. "But we didn't expect it to end this way."
Melissa Zolecki of Plainfield said she also observed dramatic strides forward, including being able to take her 12-year-old son, Matt, for his regular blood draws without him physically resisting.
"It's just so frustrating to know that there's help out there and not be able to fix it," said Zolecki, whose son started taking arbaclofen in 2010 and finished his last dose in mid-June.
Clinicians frustrated, too
Ethan, Parker and Matt are just a few of the 40 patients followed by Dr. Elizabeth Berry-Kravis, a key investigator for the trial of the drug, also known as STX209. It's a derivative of a drug used to treat muscle stiffness in cerebral palsy and was also thought to quiet some of the "noise" in the brains of patients with Fragile X syndrome, which is caused by a single gene.
After four years, arbaclofen was in the home stretch of new drug development that could lead to Food and Drug Administration approval for marketing — to confirm effectiveness, monitor side effects and collect data. It also required meeting a clearly-stated and specific goal: In this case, arbaclofen's effect on social withdrawal in patients ages 12 to 25.
During the first three months, neither Berry-Kravis nor the volunteers knew who was on the drug or the placebo. Later, all participants had the option of going on arbaclofen.
The drug cleared early safety hurdles and researchers were focused primarily on efficacy, said the pediatric neurologist. Among her participants taking the drug, about one-third had little or no improvement from their previous behaviors, one-third showed some benefits and for the remaining 30-40 percent arbaclofen "could be life-changing," she said.
Measuring the drug's effectiveness can be difficult because children and young adults develop at different rates, and some will mature and show behavioral and cognitive improvements without the help of drugs at all. Moreover, the gains were not always the particular behavior that Seaside was looking for, so it still counts as a failed study, Berry-Kravis said. "But in my heart of hearts, I know the drug works for some patients."
When the statistics were compiled, arbaclofen didn't succeed strongly enough and scientific rigor trumped anecdote.
Like all researchers, Berry-Kravis understands that controlled, well-regulated clinical trials are the only way to protect the public from untested new drugs, some with potentially lethal side effects.
Still, with a disease like Fragile X, pinpointing one single behavior is much more elusive and nuanced than for other drug trials, such as lowering cholesterol. In these instances, Berry-Kravis can't help but wonder if the rules shouldn't be tweaked.
"Maybe the tests for these brain-based disorders need to be designed differently? How do we create new measures that will capture the whole disorder?" she said. "That's really a key issue for all of us in the scientific community."
While the process is frustrating for researchers, it pales compared with the agony it causes for trial participants, said Berry-Kravis, who spent hours on the phone with distraught parents weaning their children off the drug.
Parents across the country pleaded with the researchers, proposing every possible way of getting arbaclofen, such as asking "someone rich" to buy Seaside. But without FDA approval, drugs — even trial leftovers — simply cannot be legally obtained, Berry-Kravis said.
Laurie Zoloth, a professor of medical humanities & bioethics at Northwestern University Feinberg School of Medicine, understands the moral dilemma. She has spent time at the National Institutes of Health in Washington, listening while parents begged to allow a certain gene therapy trial to be approved.
"In all of these situations, we as a society have to make difficult choices and we set in place a system to make the choices as fair and deliberate as possible — and in any such system, individuals will not get all they need," said Zoloth. "But unless everyone operates under the same rules, we will not have a system for research, sharing resources, evaluating drugs or, ultimately, finding stable cures."
Most drug trials fail
While the announcement that arbaclofen was being discontinued hit hard, the fact that the drug fell short is more the rule than the exception, experts said.
At any given time, hundreds of treatments are vying to win the FDA's endorsement through clinical trials. But only 16 percent of the medications that are studied in humans actually get to market, according to Kenneth Kaitin, director of Tufts University's Center for the Study of Drug Development.
For psychiatric and neurological disorders, the odds are even lower at 8 percent.
Pharmaceutical companies weigh many factors before embarking on a trial, and psychiatric and neurological diseases have a double-whammy: Patients usually need to be on the drug for a lifetime, which means studies need to be done to demonstrate that the drug works and is safe over a long period. And the end points are notoriously hard to measure, whether it's Fragile X or Alzheimer's disease, which has not seen the FDA green-light a new treatment in almost a decade.
"These clinical trials tend be longer, larger, more complex and, unfortunately, more likely to fail," Kaitin said. "That's why, even though the market potential is enormous, several major pharmaceutical companies have reduced or totally eliminated their investment to treat these diseases."
Starting all over again means more time lost for patients. For companies, it may not be feasible to channel more money into something that will, in all likelihood, yield little or no return.
Robert Miller, executive director of the National Fragile X Foundation, called the arbaclofen story "gut-wrenching." He acknowledged the controversy, but said this wasn't a case of a heartless corporation putting profits over people. "Apparently, it just didn't hit the endpoint Seaside was looking for."
'Something just clicked'
Since Ethan was diagnosed with Fragile X at age 2, Rebecca and Ira Fishman have tenaciously searched for ways to combat the condition. They have traveled all over the country seeking alternative therapies, trying special diets, surrounding him with mentors.
But no intervention had ever worked like arbaclofen, his mother said. "Right from the beginning, something just clicked. … He was calmer, more socially appropriate. The nerves in his brain were firing like never before," she said.
At that memorable family wedding in May, Rebecca Fishman felt as if she caught lightning in a bottle.
"The five of us were all together, on the dance floor … and that had never happened before," she said. "Instead of being on the outside of life, Ethan wanted to be a part of it."
And now? "We're back to all of us swimming inside the fishbowl, while Ethan is knocking on the outside," said Fishman, who is the cousin of the spouse of a Tribune editorial employee.
For Usrey-Roos, the difference between "before" and "after" can be summed up by a simple trip to the movies.
Before arbaclofen, she'd start out well before show time to coax Parker from the car to the lobby, from the lobby to inside the theater. Once inside, he could enjoy himself, providing she had packed headphones and Twizzlers to help alleviate irritability and sensory overload.
With the drug, though, it was a glitch-free outing, just one of the many gifts she gleaned from the study, she said. "I know what is inside him now. ... I got to see all the thoughts and humor that I knew were going on in his head. What is breaking my heart is that we are going to lose it. We are going to lose it not because it isn't safe or doesn't work. How was I to know that was a possibility?"
For Matt Zolecki, the proof was also in his sociability, his mother said. While on the medication, "he was eager to attend his special education golf class, but now he doesn't want to go at all," said Melissa Zolecki, an emergency room nurse.
Matt has been enrolled in numerous trials, starting when he was barely 2 weeks old. But his mother said she's done with medications.
"As important as research is, we've done our fair share. I can't do this anymore ... not to him, not to us."Copyright © 2015, The Baltimore Sun