|Dr. James T. McCracken, Joseph Campbell Professor of Child Psychiatry Director, Division of Child and Adolescent Psychiatry, Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA|
Autism, once a mysterious and infrequently recognized disorder, is now on most everyone’s radar. The condition and its origins receive much public and media attention and often are the focus of controversy. There is no singular constellation of symptoms that defines autism; its expression can fall anywhere along an extended spectrum. One autistic child might not speak and have pervasive developmental disorders, while another may be a bright student but socially isolated. In the hope of fast-tracking studies of promising drugs to address the core deficits that underlie autism-spectrum disorders (ASDs), which the Centers of Disease Control and Prevention says affects one-in-68 children in the United States, the National Institute of Mental Health (NIMH) awarded a $9-million grant to UCLA. James T. McCracken, MD (FEL ’87), will lead that effort as a principal investigator, coordinating a national network of researchers at UCLA and other academic centers. Freelance writer Clara Sturak, herself a passionate advocate on behalf of children with autism, spoke with Dr. McCracken for U Magazine.
What led the NIMH to the fast-fail-trials approach to address the issues of autism?
Dr. James T. McCracken: Over the last 10 years, different large pharmaceutical companies have been working to develop new drugs to treat neuropsychiatric disorders, including ASDs. A huge number of those drugs failed in testing, and so much capital was lost, that it’s caused a lot of these big pharmaceutical companies to abandon the business of creating neuro-pharmaceutical drugs. As one might imagine, this created a great deal of alarm within the mental-health field. Without the resources of big drug companies, how can much-needed new and effective drugs be developed? The NIMH recognized the challenge and started “fast-fail” networks.
Why “fast fail” and not “fast success”?
Dr. McCracken: The emphasis on “fast fail” springs from the fact that most experimental drugs are destined to fail. So knowing that outcome as early as possible is crucial to not waste time and money and to inform the science. The major problem encountered in drug development for neuropsychiatric disorders is that too many compounds are failing to show benefits or safety in late-stage clinical trials. The goal of a fast-fail program is to weed out as early as possible those drugs that are less likely to make it through successfully as approvable treatments. We can then focus on those drugs we believe will be successful, which will benefit the entire drug-development process from beginning to end.
Still, with a growing need for effective treatments for ASDs, wouldn’t drug companies consider the cost of neurological-drug development a financial risk worth taking?
Dr. McCracken: It’s not just an issue of money; this kind of work also absorbs a great deal of time. Recent estimates are that it takes 13 years on average to go from the identification of a new potential drug in the laboratory to having it approved and marketed, at a cost of $1.8 billion per each new approved medication. The final costs of drug development include the cost of many more failures, which often occur in the second and third phases of clinical trials. Often, there will be a lot of excitement about a potential new treatment that ultimately disappoints. Simply reducing the late-stage failure rates of drugs in clinical studies from 66 percent to 50 percent — guided by fast-fail trials — could shave 30 percent off the total costs. That would free up money that might double or triple the number of other compounds a company could pursue. This is one place where both medicine and people with these disorders could clearly benefit. Neuropsychiatric disorders — depression, schizophrenia, dementia, autism — are among the top-10 disabling illnesses. So it is clear that the need for effective treatments is huge.
How have advancements in basic science aided your team in finding new approaches to studying compounds?
Dr. McCracken: Our basic-science colleagues are generating enormous information on the likely underlying causes of ASDs. One goal of the fastfail- trial networks is to make strategic choices about what compounds or drugs to test, based on growing basic science. A number of animal models of ASDs have been developed and studied, including several at UCLA. Together with progress in genetics, basic findings have suggested some pathways for possible treatments. By themselves, basic findings are incomplete and fraught with risks of not translating
|“Recent estimates are that it takes 13 years on average to go from the identification of a new potential drug in the laboratory to having it approved and marketed, at a cost of $1.8 billion per each new approved medication.”|
to human beings. But when the basic findings line up in agreement with clinical studies, strong hypotheses emerge to test them as treatments, which is exactly how we came to the choice of our first compound for our fast-fail trial. The other goal of the networks is to take leaps by doing trials differently — using different kinds of measurements. The testing is not only faster, it’s less clinical and more empirical. Of course, we still test on human subjects, but it is more to incorporate empirical data. Instead of using information gained from interviews with, or surveys of, the subjects, we look at biological measurements or changes in brain function that can be seen on brain scans or electroencephalography.
By looking at hard data, you are reducing the built-in subjectivity of participants’ reporting?
Dr. McCracken: Yes, by using more-objective measures, we expect more-accurate and reliable results, though we will continue to survey the subjects. It’s just that we won’t be relying only on traditional clinical reporting.
How do you envision new drug treatments for ASDs differing from what is available at present?
Dr. McCracken: The pharmaceutical approach to autism up until now has not been particularly effective. Existing psychotropic drugs are being used to treat symptoms or behaviors sometimes seen in autism, like outbursts of anger or hyperactivity, but the core deficits associated with autism have not been addressed. The core problems in ASDs are difficulties with effectively communicating or developing language, difficulty relating well to others and intense repetitive behaviors that can border on being allconsuming and can block kids from learning. Some other features do commonly occur. For instance, up to 70 percent of children with ASDs show anxiety symptoms, and many have sensory-processing disorders and/or some degree of intellectual or cognitive difficulties. Cognitive difficulties can range across a whole spectrum — from severely impaired to superior intelligence, but with specific areas of strength and weakness — but the other symptoms emerge from the core deficits. We are focusing on pharmaceuticals to treat those core deficits.
The first compound your team is testing is a gamma-aminobutyric acid (GABA) enhancer. How was it chosen, and why?
|“The goal of a fast-fail program is to weed out as early as possible those drugs that are less likely to make it through successfully as approvable treatments.”|
Dr. McCracken: We’ve chosen to test a drug that accentuates the action of GABA in the brain. GABA and its neurons are found throughout the brain — it is one of the brain’s most-important neurotransmitters, affecting everything from learning and memory to anxiety to inhibiting electrical storms such as seizures. The signaling in the brain by GABA appears to be reduced in ASDs, as studied in multiple ways. In theory, reductions in brain GABA activity could be a key to what underlies the differences in understanding social interactions, the common anxiety seen in ASDs, and the high rate of seizures in many people with ASDs. We hope to see benefits in several areas. The disorder of brain functioning is evident early on in brain development, and it can give rise to a cascade of difficulties, an array of difficulties that come with autism. So, it comes back to the core deficits. This is why we’ve chosen a GABA enhancer as the first of the compounds we plan to put through trials.
|“Existing psychotropic drugs are being used to treat symptoms or behaviors sometimes seen in autism, like outbursts of anger or hyperactivity, but the core deficits associated with autism have not been addressed.”|
Have other compounds been chosen as well?
Dr. McCracken: We are in the process of choosing three or four additional agents to study. In choosing which compounds to study, we have two main sources — repurposed drugs, which may have been marketed as treatment for another condition or that may have been tested and failed at their original intended purpose, and new drugs that are currently in development.
Using the GABA enhancer as an example, how will the project play out over the next three years?
Dr. McCracken: As I said, we have chosen to look at the GABA system and have started a first-phase trial of a GABA enhancer with adults between the ages of 18 and 35 years. When that phase is complete, we will follow up with a child study. In the second, moreimportant part of the trial, we’re hoping to be more precise in yielding a clear-cut yes-or-no answer as to the efficacy of the compound as a potential treatment. Last, we will conduct a larger, phase-three trial. And if we can reduce the phase-three failure rate, that will have lots of impact.
The Centers for Disease Control and Prevention recently released data that show one-in-68 children is now diagnosed with ASDs. How does this news relate to the fast-fail trials?
|“The disorder of brain functioning is evident early on in brain development, and it can give rise to a cascade of difficulties, an array of difficulties that come with autism.”|
Dr. McCracken: The recent increase in rates of ASDs reported from community surveys has caused a general sense of alarm. We know that much of the increase is due to heightened awareness of ASDs and diagnosing less-severe cases, but no one knows if other factors may also be contributing to the increased rates. Since no drug therapy has yet been identified to improve the core deficits of ASDs, an even-greater need exists to accelerate research to find ways to reduce the suffering and disability that accompany these disorders and their associated challenges. We’re looking at drugs not as solutions by themselves, but as a way to make a difference in people’s lives.