Pfizer forms unit to research autism

From The Day in Connecticut:

GROTON, Conn. --Diane Stephenson of Groton has three tangible reasons for wanting to know as much as possible about autism.

Stephenson, associate research fellow at Pfizer Inc.'s Groton laboratories who helped start an autism research unit there earlier this year, has two nephews and a niece with the neurological disorder, which is often accompanied by language difficulties, behavioral problems, sleep interruptions, poor eye contact and low social skills.

Her sister's son Thomas, 23, has never spoken a word. And two of her brother's children, Clarise, 5, and Craig, 2, also have been diagnosed with autism.

Autism is believed to be caused by a combination of environmental and genetic factors, but there is little doubt the disorder tends to run in families. Stephenson said couples who have one autistic child are 30 times more likely than others to have a second with the same disorder.

"Everyone wants a cure," said Stephenson, who has worked at the Groton labs for six years. "I felt there was something I could do."

So Stephenson, along with Pfizer colleague Howie Mayer, who has two children with autism, worked behind the scenes for a year with the idea of forming a separate research unit focusing on autism. They later added another colleague, Larry Fitzgerald, as the group put the finishing touches on its proposal, contacting key experts outside Pfizer who had a grasp on the latest breakthroughs in autism research.

Stephenson said science in the past year has started making significant headway in genetic research geared toward autism. While two years ago might have been too soon to start an autism unit, she and her colleagues believed they had enough science on their side to make the case late last year, she said.

Still, "Most everyone told us we were crazy," Stephenson recalled, especially since Pfizer has been in a downsizing mode lately.

But senior management quickly embraced the idea and launched the autism unit in January with 15 scientists. Fitzgerald became the first head of the unit but departed a few weeks ago while Mayer also has moved on, now working for one of Pfizer's new business units. This left Stephenson as the lone remaining founder of the group still working on-site.

Affects 1 in 100 children

"I think it's a great advance that the pharmaceutical industry is ... looking at how to address the issues related to autism," said Lee Grossman, president and chief executive of the Autism Society of America, in a phone interview. "We believe other companies will start following Pfizer's lead."

Grossman said Pfizer is the only company he's aware of that has taken the initiative to start a research unit devoted strictly to autism, a disorder that now affects 1 in 100 children, according to a new statistical analysis released just last week. Autism was previously thought to affect 1 in 150 children; a dozen years ago, the incidence was put at 1 in 500.

Currently, only one medication -- Johnson & Johnson's antipsychotic drug Risperidone -- has been cleared by the Food and Drug Administration for use in autistic children. But autism advocacy groups are looking eagerly at Pfizer's new model in the hopes that it can develop novel medicines to help alleviate autism symptoms -- or, perhaps more important, delve into a number of its already established drugs that target neural pathways affecting autistic patients.

"Presumably, some drugs already developed could be helpful," said Dr. Michael Tranfaglia, medical director and chief scientific officer of the FRAXA Research Foundation, a Newburyport, Mass.-based organization that funds research and does advocacy work for people with a form of autism known as Fragile X.

Tranfaglia said major pharmaceutical firms like New York-based Pfizer used to spend most of their time chasing the biggest blockbusters but are now gradually coming to realize they may have a treasure trove of older drugs that could target smaller populations, such as those with Fragile X. Fragile X is a rare form of autism in which one key gene shuts down, failing to produce an important protein, leading to learning problems and anxiety, among other symptoms.

Anabella Villalobos of East Lyme, the head of the neuroscience research unit at the Groton labs, said Fragile X gives scientists at Pfizer a relatively easy early target to investigate, since only one gene is involved. Most of the autism disorders -- called a spectrum because they are so wide-ranging -- involve multiple genes.

"This is all a work in progress," said Villalobos, who is overseeing the autism unit on an interim basis.

Addressing symptoms

Villalobos said the long-range goal will be to prevent autism, but Pfizer plans to address short-term solutions at first. Researchers will begin by targeting symptoms that appear to cross the spectrum of autism disorders, including anxiety, agitation, sleep disorders, social deficits, language disabilities and repetitive behaviors. The idea will be to identify medications that seem to address symptoms among all or most people with autism.

A longer-range goal, she said, will be to understand the neurobiology behind the disorder so that the core symptoms can be treated. This requires the use of animal models to test medications before they are tried on humans in clinical trials.

"What is not clear is if we find medicines for the treatment of Fragile X, will it apply to the broader spectrum?" Villalobos said. "It's not one disease; it's multiple diseases."

One difficulty in developing treatments against autism is that testing on children is so problematic because of dosage and safety concerns, according to scientists. Because of this, Pfizer researchers say, initial testing most likely will be on adults with autistic disorders.

Helping Pfizer in the research process, scientists say, is the fact that several markers of autism recently have been identified. One of these telltale signs of autism is eye-tracking. While normal children tend to focus on the eyes of a face, autistic children usually look away toward the mouth. By having a baseline for how autistic children's eye tracking works, scientists can check to see if certain drugs have an effect on this behavior.

In the neuroscience research unit labs, senior scientist Edward Guilmette already is starting to target certain genes that could have an effect on autism. The effect of turning on or off various genes then is studied in mice models by senior associate scientist Sharon O'Neill, who charts changes in behaviors.

Autistic mice, for instance, might spend more time staring at an inanimate object than interacting with another mouse, O'Neill said.

"That's probably as close as we're going to get (to mimicking autism) in an animal model," she added.

Although 15 researchers may seem like a big commitment, Pfizer scientists said their numbers are small compared to the vastness of research yet to be done on autism. So Pfizer has reached out to a variety of collaborators - at the Massachusetts Institute of Technology, the Yale Child Study Center and New York University, for instance - to develop and expand on their groundbreaking work.

Right now, most of the work being done involves biology and animal studies. But as scientists develop specific small-molecule drug targets, more chemists will be enlisted to help, said Villalobos.

Examining the portfolio

For now, though, it looks as if the first Pfizer medicines targeting autism likely will come from its established drug portfolio. One possibility mentioned by the autism unit's lone remaining founder, Stephenson, is the pain medication Lyrica, though she emphasized that drug trials have yet to establish any clinical support for the hypothesis and that the company was not suggesting any off-label uses.

Dr. Tranfaglia, who has a 20-year-old son with Fragile X, is hopeful that pharmaceutical companies will now be trying to match up established drugs such as Lyrica with potential treatments for specific forms of autism.

He said finding uses for established drugs will be much less costly than the $1 billion price tag of bringing a new drug to market. Drugs currently on the market already have gone through clinical trials showing their safety, he added.

Another factor reducing the cost of developing autism drugs, he said, is that several of the spectrum disorders, including Fragile X, currently have no approved treatment, meaning companies won't have to prove to the FDA that their drugs are more effective than others on the market.

The long-term hope, said Tranfaglia and Stephenson, is to actually reverse the course of autism - an idea that would have seemed magical a few years ago but already has been shown to be possible in animal studies.

"The sooner you intervene, the better," said Stephenson.

"You can actually normalize development," Tranfaglia said. "It's entirely reasonable to think you could completely alter the course of the disease."