An experimental drug showed promising results in treating the key symptom of social withdrawal in people with Fragile X syndrome, the most common known inherited cause of autism with intellectual disability, according to a recent clinical trial.
The drug, known as arbaclofen or STX209, is a derivative of the FDA-approved drug, baclofen, which is primarily used to treat muscle spasticity in conditions like cerebral palsy and is being studied as a treatment for alcoholism and other addictions.
The new study, published in Science Translational Medicine, hints that arbaclofen could be the first drug to treat symptoms of Fragile X and other autism spectrum disorders, and even other conditions involving social avoidance. “This is an important trial,” says Eric Hollander, director of the autism and obsessive compulsive spectrum disorder program at Montefiore/Albert Einstein School of Medicine in New York, who was not associated with the study. It should be “of interest to the entire field of neurodevelopmental disorders,” he says.
Fragile X syndrome is caused by a defect in the FMR1 gene, located on the X chromosome. It is the most common inherited cause of intellectual disability, particularly in boys, who are harder hit because they have only one X chromosome. In addition to intellectual disability, it causes autistic symptoms like avoidance of eye contact, repetitive behavior and speech and language delays.
In previous studies of mice that are missing the FMR1 gene and show autistic symptoms like repetitive behavior and social avoidance, arbaclofen has been able to treat these problems. The drug works by acting on the brain’s GABA-B receptors and decreasing elevated activity of a neurotransmitter called glutamate; it is the absence of or problems with the FMR1 gene that causes excess glutamate in Fragile X.
In studies of mice and flies, administering arbaclofen as late as adulthood was sufficient to reverse social deficits. That finding is significant, since problems with FMR1 are likely to alter the development of the brain from birth. Whether the same effect would be found in humans is unknown, however, especially given that we undergo a longer period of brain development than do mice or flies.
“It’s not a cure-all,” says lead author Dr. Elizabeth Berry-Kravis of Rush University Medical Center in Chicago, the lead author of the study. “But this is first example of a moderately large clinical trial that took a drug that was developed on the basis of research in mice and fly models of Fragile X, and theoretically corrects the deficit at the neuronal level.”
The double-blinded six-week-long trial, which included 63 people with Fragile X ranging in age from 6 to 39, compared the effects of arbaclofen to placebo; it was originally designed to determine whether the experimental drug would reduced irritability. It was no more effective than placebo at doing that, but it did result in overall improvements in problem behaviors and social avoidance, according to the parents and caregivers of the patients.
Regarding the failure to find an effect on irritability, Berry-Kravis says she and her colleagues chose to study that measure only because it has been used to test other medications approved for autistic symptoms, not because they thought it would be the symptom the drug would fight best. “What symptoms would get better in the first month is impossible to predict,” she says, noting that the trial did show that the drug is safe.
The drug could also work for people with all types of autism. Many autistic people report suffering from sensory overload, which makes social interaction especially difficult to tolerate. This may be due to the glut of glutamate in the brain, a balance that arbaclofen can change. People with autism “would like to socialize, but they can’t make themselves do it because it’s so overwhelming,” says Berry-Kravis. “Arbaclofen lowers that over-responsiveness to the social environment so that they can now tolerate going into it.”
Interestingly, baclofen, the chemically related form of arbaclofen that is government approved, also shows promise in treating conditions — such as alcoholism and other addictions — in which people find socializing overwhelming, but use drugs rather than avoidance to cope.
The new research supports a treatment approach to neurological and psychiatric disorders that focuses on symptoms rather than on diagnoses. “[It] suggests that symptom domains such as social avoidance may cut across different diagnostic entities, and be helpful in drug development efforts,” says Hollander.
Berry-Kravis and other researchers are now engaged in additional trials aimed at ultimately seeking FDA approval for the drug. The current study was funded by the manufacturer of arbaclofen, Seaside Therapeutics.