The Hunt for an Autism Drug

The Weakley family lives in Dover, Pa., about 30 miles south of Harrisburg. Their two-story house sits on a mostly treeless tract of land, across the road from a big white barn. Seated at the dining table, Beverly Morgart-Weakley is describing the recent changes she's seen in her 21-year-old daughter Jennifer. Once unable to form words, "she keeps saying 'mama', and she's starting to say the beginnings of other words. You'll hear something that almost sounds like a sentence and you can figure out what she's trying to tell you."

Every parent looks forward to these developmental milestones, but Beverly has been waiting two decades. In the early 1990s, Jennifer was diagnosed with autism, and her early childhood was dominated by doctor's visits. Things got worse in her teens. The girl would sometimes bite her own arms in paroxysms of frustration. Many times she grabbed her mother or her younger sister by the neck and squeezed hard. Even the family's collie was bitten.

Beverly was skeptical of medications, but she needed a way to quell her daughter's increasingly violent outbursts. Doctors tried the antipsychotic drug Risperdal, but Jennifer gained weight and grew sluggish. Then they turned to Zyprexa, a schizophrenia medication, but the symptoms persisted. Over the past year the family has had a modest breakthrough with Namenda, an Alzheimer's drug from Forest Laboratories (FRX). Jen's aggression has subsided and her communication skills have improved. "She is still far from normal," says Beverly, looking on as her daughter repeatedly opens and closes the refrigerator, then settles on the floor in the den and methodically removes every item from a filing cabinet. "But she's made progress, and that in itself is a miracle."


Encouraged by even partial success stories like the Weakleys', the drug industry is gearing up for an assault on autism. The timing makes good sense for both scientific and economic reasons. Powerful genetic tools and brain-imaging techniques have given researchers fresh insights about the disorder, often described as a "spectrum" because symptoms vary greatly in nature and severity. In the past year scientists at several small biotech companies have voiced excitement over new drugs in early-stage clinical trials. Last year, industry giant Pfizer (PFE) formed a 14-person autism research group at its Groton (Conn.) laboratories. "The science has evolved to the point where we can now start investing in potential pathways and targets," says Anabella Villalobos, Pfizer's vice-president for neuroscience chemistry.

From a drug-industry standpoint, the demographics of the disease are also compelling. Diagnoses among children jumped 57% from 2002 to 2006, according to the Centers for Disease Control & Prevention in Atlanta. Roughly 1 in 110 8-year-olds in the U.S. is on the autism spectrum. Just as interesting to drugmakers is the fast-growing population of adult autistics who can't be helped by the kind of intensive behavioral therapy that sometimes works on children, because their brains lack the same plasticity. One decade from now there will be seven times as many autistics entering the adult-services sector as there are today. The disorder already costs the U.S. about $35 billion per year for special education, medical care, and assisted living. If the drug industry can devise better treatments, families and society will find a way to pay.

At the federal level, autism is already a priority. Among pediatric disorders, only diabetes, AIDS, and asthma draw more research funding from the National Institutes of Health. Last year, President Barack Obama allocated $60 million of stimulus funds to the autism research pool and earmarked $1 billion for studies extending through 2018. While many medical authorities play down the idea of an autism epidemic, noting that better detection and changes in diagnostic criteria account for part of the rise, most experts believe cases are increasing.

Researchers often express awe at autism's complexity. "Early on we felt that if we could collect large enough samples of families with multiple affected individuals, we would find the autism gene," says Dr. Eric Hollander, a psychiatrist and former director of the Seaver Autism Center for Research & Treatment in New York. "As the sample size got bigger, there were more genes popping up that had minor effects."

Many autism experts are now looking to epigenetics for a possible explanation. This is the branch of genetics that looks at how the environment influences gene expression. Last year, researchers at the University of California Davis's MIND Institute concluded that the state's sevenfold increase in autism cases since 1990 is most likely linked to environmental exposure—to pesticides, viruses, chemicals in household products, or some other agent. One reason they think so: there are cases in which one identical twin is autistic and the other is not; the two have identical genes, so environmental factors must contribute.

Considering how little is known about the underlying biology, it's not surprising the Food & Drug Administration has yet to approve a single medication to treat the core conditions of the disorder. Yet drugmakers are racking up nearly $3.5 billion in annual sales for treatments aimed at managing secondary symptoms—everything from antidepressants for anxiety to anticonvulsants for seizures.

As autistic people grow up, their doctors often add to the drug regimen, meaning an autistic adult may be on three or four different drugs at once, with no solid data on their effectiveness or how they may interact. A 2007 study found that 70% of autistics ages 8 and up received a psychoactive medication in a given year. "The word 'experimentation' sounds scary," says Bryan H. King, director of psychiatry at the Seattle Children's Hospital. "People aren't randomly picking drugs off the shelf and saying, 'Let's try this.' But it starts to look like that when you take two steps back."

As a research target, autism has suffered from companies' reluctance to run large placebo-controlled trials. When such studies were done, the results were mostly disappointing. In June, for example, a large trial of Forest Labs' depression drug Celexa showed no benefit over a placebo. Up to that point, Celexa had been a go-to drug. But greater efforts by large drugmakers change the picture: "Companies are finally starting to take an interest in autism, which is great to see," says King.


While blockbusters may still be far off, researchers are laying foundations for discovery. The new research team at Pfizer, for example, is focusing on genes that may affect synapses in the brain. These are the spaces where two nerve endings meet—a tiny gap neurochemicals must cross in order to transmit information. Many researchers are now framing autism in terms of information processing, says Larry Fitzgerald, a scientist who helped found Pfizer's autism team before departing the company in September. Brain-scan data, for example, suggest autistics may process spoken language more slowly than "neuro-typicals," meaning non-autistics. One theory holds that the brains of autistics are miswired, with too many local neural connections and too little long-distance connectivity. The latter might make it difficult to integrate new information, causing characteristic social impairment, posits Clarence Schutt, a Princeton University chemistry professor who co-founded the National Alliance for Autism Research. On the other hand, enhanced local networks could explain why some autistics are exquisitely tuned to sensory input, and may explain the "savant" capabilities—musical or mathematical genius, for instance—that about 10% of autistic people display.

While Pfizer plumbs the basic biology, tiny Seaside Therapeutics in Cambridge, Mass., is going after a specific target. The company has zeroed in on a rare brain disorder called Fragile X, caused by a mutation on the X chromosome and known to cause a hereditary form of autism. Founded in 2005 by former Massachusetts Institute of Technology neuroscientist Mark F. Bear, Seaside has two drug candidates in clinical trials. Like Jennifer Weakley's drug, Namenda, these compounds zero in on the brain's glutamate system, involved in learning and memory.

"What you need is a company to be successful—to show that the FDA will approve you, and that you can make money—and everybody will jump in," says Seaside CEO Dr. Randy Carpenter. "If [a drug] shows a benefit, we can charge a premium."

Some experimental treatments focus on the social-bonding aspects of the disorder. Oxytocin, which is given to pregnant women to induce labor under the brand name Pitocin, has earned the nickname the "love chemical," because studies in healthy adults have shown that sniffing it results in the formation of strong bonds of trust. Studying the effects of the drug on patients with Asperger's, a syndrome marked by social awkwardness that is on the less severe end of the autism spectrum, psychiatrist Hollander found a reduction in repetitive behaviors and an improved ability to recognize the emotional tone of sentences. Other drugs target the brain's interaction with organs that aren't usually associated with autism, including those of the gastrointestinal tract and the immune system.

One of the most promising treatments in this category is a drug called CM-AT made by a startup called Curemark. Dr. Joan Fallon, the company's founder and CEO, observed that many autistics show a strong preference for foods high in carbohydrates and low in protein. A diagnostic test revealed that some autistic children lack enzymes that digest protein. As a result, these children produce fewer of the essential amino acids that are the building blocks for brain development and neuroreception. Fallon believes this deficiency is linked to the most severe symptoms of autism, and she says an early observational study of CM-AT, an orally ingested powder that delivers protein-digesting protease, showed "significant improvements." Curemark is enrolling patients in phase III clinical trials at 10 to 12 sites—the largest autism trial to date.

Beverly Weakley is counting on Namenda—or some yet-to-be-formulated treatment—to "unlock" Jennifer's potential. She describes how one day, many years ago, she heard Jennifer call out from another room "Mommy, I need you." It was as though a window to her daughter had opened up. She raced to her daughter's side, but by the time she got there, Jen was "gone." Since then, the long silence has been almost unbearable, but Beverly has learned not to dwell on setbacks. She keeps hoping, she says, that the window will reopen.

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