Meeting with father leads scientist to development of possible medication to treat Fragile X Syndrome

From Bloomberg News:

Researcher Luca Santarelli wasn’t sure what do to with an experimental medicine developed in the labs of his employer, Roche Holding AG, until a 2007 meeting with a concerned father led to a “Eureka moment.”

Mike Tranfaglia, whose son has the rare brain disorder Fragile X syndrome, met Santarelli to present new research linking the disease to a chemical in the brain that may also play a role in Alzheimer’s and autism. Santarelli, 41, says this made him see how the experimental drug could be used to treat Fragile X, the most common inherited form of retardation. Roche may test the pill in patients this year.

“In one hour the whole relevant literature is presented to you and you come away with a gut feeling that this could work out,” Santarelli, Roche’s head of central nervous system exploratory development, said in an interview. “For a scientist, a Eureka moment is why we live and do this job. You have very few, but that was one of them.”

Armed with newly uncovered links between biology and brain disorders, Roche and Novartis AG are racing smaller drugmakers to develop the first medicine to treat Fragile X, a genetic disease thought to affect about 250,000 people. While analysts estimate such a pill may generate as little as $250 million in annual sales, studying the treatment may reveal ways to treat other illnesses of the central nervous system, estimated by London-based Datamonitor Plc to have been worth $96 billion in 2007 in seven major markets.

“For us, Fragile X is like a proof of concept,” Santarelli said. “If we can crack this, then we can move into a broader range of neuro-developmental disorders.”

Developing a treatment for the disease may prove to be a challenge. While the early results look promising, most experimental medicines fail to make it through the three phases of clinical testing needed for marketing approval.

The link between the diseases comes from studying glutamate, the most common neurotransmitter, or chemical that allows for communication between neurons in the brain. Perturbations in glutamate signaling are now thought to contribute not only to Fragile X, but also to conditions such as Alzheimer’s, depression, autism and even heartburn.

Since many people with forms of autism that are genetically unrelated to Fragile X seem to have defects in the same cellular pathways, they may respond to the same treatments, according to the Newburyport, Massachusetts-based Fragile X Research Foundation. Tranfaglia, a psychiatrist, founded the organization, known as FRAXA, in 1994 after his son Andrew, now 20, was diagnosed.

There’s no cure for Fragile X, which can cause a broad range of symptoms, from fidgeting to impulsive actions, according to the U.S. National Institutes of Health. About 33 percent of males with the disorder have autism or autistic-like behavior, the NIH says. Fragile X is also the most common cause of autism that has been identified so far, according to the National Fragile X Foundation.

Scientists may be on the cusp of developing treatments for Fragile X because of two breakthroughs in neuroscience. One was the discovery in 1991 by a team headed by scientist Stephen Warren at Emory University in Atlanta that the syndrome is linked to the mutation of a specific gene located on the X chromosome. The disease got its name from the abnormal appearance of the end of the X chromosome’s long arm.

The fault in the gene inhibits the production of a protein called FMRP, which is responsible for keeping levels of other neuronal proteins in check. The excess of some proteins that results from the FMRP deficit impairs brain development and causes Fragile X.

The other breakthrough was work done by neuroscientists led by Mark Bear, then at Brown University in Providence, Rhode Island, who in 2000 showed that blocking the production of glutamate can help counterbalance the effects of reduced FMRP levels. This was the finding that Tranfaglia gave Santarelli.

“Only a few years back people would have thought it was impossible to treat diseases like schizophrenia and autism with drugs that are not just targeting symptoms but that address the molecular basis of the disease,” Santarelli said. “But we think we can do that now.”

Roche’s experimental medicine inhibits glutamate production and prevents the excessive output of other proteins by binding to a specific receptor called mGluR5.

“FMRP is the brake and glutamate is the throttle” in the production of many proteins in nerve cells, Santarelli said. “If you take away the brake, you have only the throttle, so you want to take that away too.” By keeping the level of proteins in check, the treatment may prevent damage and reverse symptoms such as learning problems, anxiety and autistic behaviors caused by Fragile X.

Basel, Switzerland-based Roche has said study results obtained so far with its compound have been “encouraging.” The drugmaker probably will test the experimental medicine in autism if the results of animal studies are positive, Santarelli said. Roche declined to give details about the trials.

Drugs currently used in autistic patients are focused on treating symptoms such as anxiety and depression, aggression, seizures and hyperactivity. Medicines used include Pfizer Inc.’s antidepressant Zoloft, the generic antipsychotic medicine haloperidol and Novartis AG’s attention deficit disorder pill Ritalin. Behavioral therapy is the standard approach to treatment, according to the patient organization Autism Speaks.

This medicine “could be the first to reverse mental retardation,” Randi Hagerman, a professor at the University of California at Davis who’s working with Roche on the clinical trials, said in an interview. “What everyone is hoping is that the causes of autism may converge on a final common pathway that may be sensitive to this drug. The secret hope is that we might find it can be used much more broadly than for Fragile X.”

The first Fragile X medicine that targets the mGluR5 receptor may reach the market by 2011 or 2012, said Hagerman, who has also worked with Cortex Pharmaceuticals Inc., Neuropharm Group Plc and Seaside Therapeutics. Children would likely get medication soon after diagnosis, typically at two or three years old, Tranfaglia said.

“Most Fragile X kids are born as essentially normal babies,” Tranfaglia said. “There’s really nothing wrong with them at first, but they simply don’t develop at the normal rate. The hope is that down the line you would start the medication shortly after diagnosis, and this would prevent much of the abnormal development of the brain that leads to the symptoms.”

The market may be worth from $250 million to $1 billion a year, depending on pricing and what exactly the drug is approved for, said Robin Davison, an analyst at Edison Investment Research in London. Symptoms of Fragile X tend to be much more pronounced in men than in women because males only have one X chromosome. If one of a woman’s X chromosomes has a genetic mutation, the other, unaffected one can compensate for it and females may not need treatment.

Neuropharm is testing a compound called fenobam, which also targets mGluR5. A study in the second of the three stages of testing generally required for approval found last year that four of six males and two of six females responded to the treatment. There were no significant side effects.

Novartis is in the second of three stages of clinical testing with its compound, spokesman Jeff Lockwood said in an e- mailed statement. The company declined to give additional details about the trials.

Seaside, co-founded by Bear, expects to begin clinical trials with its mGluR5 compound this year and already has another kind of compound that targets glutamate in the second of three phases of testing.

Swiss biotechnology company Addex Pharmaceuticals Ltd. is also working on compounds that target mGluR5, though it has no plans to test them in Fragile X.

“Our two lead products could certainly be developed by Addex or a potential partner of Addex for Fragile X, but we’ve chosen to prioritize other indications like heartburn, migraine and Parkinson’s where the market potential is big and clinical testing is faster and cheaper,” spokesman Chris Maggos said in a telephone interview.

Medicines being developed for Fragile X are likely to benefit from so-called orphan drug status, Hagerman said. Neuropharm’s fenobam has already been granted the designation, which is given to treatments aimed at serious diseases affecting fewer than 200,000 people in the U.S. or fewer than five of 10,000 people in Europe. It gives companies a seven-year period of market exclusivity in the U.S. The medicines also get a speedier review.

“Fragile X is certainly an unmet medical need,” Bear, now professor of neuroscience at the Massachusetts Institute of Technology in Cambridge, Massachusetts, said in an interview. “It’s a severe psychiatric disorder with a lot of features like epilepsy, obsessive compulsive behavior, autistic behavior, cognitive impairment. Everyone will be looking very closely to see which aspects of the disease are going to respond to these drugs.”