Source: New York Times
Date: 3 September 2007

New Schizophrenia Drug Shows Promise in Trials


In a clinical trial of about 200 patients, an experimental drug from Eli Lilly reduced schizophrenia symptoms without the serious side effects of current treatments, according to a paper published yesterday in the journal Nature Medicine.

The drug must still be evaluated on many more patients to test for the possibility of side effects that have not yet emerged, and it is at least three to four years from completing regulatory review.

But schizophrenia researchers said the trial’s results were surprising and impressive, especially since the drug works in a different way from existing antipsychotic medicines, all of which have serious side effects, including substantial weight gain and tremors.

Lilly will begin a larger clinical trial for the drug this month. If that trial confirms the results seen so far, the new drug could mark a breakthrough in the treatment of schizophrenia — and open the way to a broad new class of treatments for the disease. Schizophrenia, a devastating mental illness that affects 1 percent of adults, or about 2.5 million in the United States, usually begins in the late teens or 20s and is marked by psychotic delusions as well as social withdrawal and cognitive impairment.

“This is potentially one giant step forward for patients,” said Dr. Jeffrey Lieberman, chairman of the psychiatry department at Columbia and the lead investigator on a federally sponsored clinical trial of schizophrenia medicines. “This drug may turn out to be not just a comparably good antipsychotic agent, but a better antipsychotic agent.”

Dr. Lieberman has not been involved with the development of the medicine and does not receive any payments or consulting fees from Lilly.

The new drug also has the potential to be a blockbuster for Lilly. Medicines for schizophrenia and bipolar disorder are the fourth-best selling class of medicines in the United States, with sales of $12 billion in the United States and $18 billion worldwide last year.

The troubled history of Zyprexa, another antipsychotic medicine from Lilly, will lead regulators and psychiatrists to scrutinize the new medicine closely for hidden dangers, Dr. Lieberman said. When it introduced Zyprexa in 1996, Lilly hailed it as a breakthrough with fewer side effects than older drugs. But Zyprexa causes severe weight gain, and the American Diabetes Association has linked it to diabetes. Internal Lilly documents show that the company played down Zyprexa’s side effects, worrying they would hurt sales.

Despite that history, psychiatrists will be eager to see whether the new Lilly medicine works, since the existing drugs are of limited help for many patients. Existing schizophrenia medicines, whether older drugs such as Thorazine or newer medicines like Zyprexa, all work by blocking the brain’s dopamine receptors.

But the new Lilly drug does not directly affect dopamine. Instead, it modulates brain activity through a different set of receptors. As a result, it has the potential to be the first truly novel treatment for schizophrenia since Thorazine was introduced 1954, Dr. Lieberman and other researchers said.

Lilly’s new drug — which does not have a name yet and is referred to as LY2140023 — emerged from almost two decades of research by Dr. Darryle D. Schoepp, a toxicologist and pharmacologist who joined Lilly in 1988.

For decades, psychiatrists have known that users of PCP, a street drug sometimes called angel dust, have symptoms nearly identical to those of people with schizophrenia. By the 1980s, scientists had discovered that PCP blocked brain receptors that are triggered by an amino acid called glutamate. This led some companies and scientists to study ways to stimulate glutamate receptors as a treatment for schizophrenia.

But the brain has many different kinds of glutamate receptors, and figuring out how to stimulate or block them in medically beneficial ways has proved complicated. Instead of focusing on the receptors blocked by PCP, Dr. Schoepp concentrated on modulating the action of glutamate receptors in the brain’s prefrontal cortex, an area responsible for personality and learning.

“This is a system that is so fundamental to the function of your brain that it is quite powerful,” said Dr. Schoepp.

But because drugs that blocked dopamine had been the only successful schizophrenia treatments, many researchers viewed the glutamate pathway as unlikely to produce useful medicines, said Dr. P. Jeffrey Conn, director of the Vanderbilt University drug discovery program and an expert on glutamate research.

Dr. Schoepp deserved praise for persuading Lilly to invest in a field that appeared to be a long shot, Dr. Conn said, adding, “He locked in very early.”

As a result, Lilly appears to have a multiyear lead over its competitors in glutamate drugs, Dr. Conn said. Dr. Schoepp left Lilly in March to become the head of neuroscience research for Merck. Dr. Schoepp and Dr. Steven Paul, the president of Lilly Research Laboratories, both said that his departure would not hurt the development of Lilly’s new medicine.

Dr. Joseph T. Coyle, a professor of psychiatry and neuroscience at Harvard Medical School, said the Lilly trial validated the theory that modulating glutamate receptors might control the symptoms of schizophrenia. Even if this drug fails in later trials, companies and scientists are likely to pursue glutamate research more aggressively, he said.

“When you see a company that comes up with something that’s completely different, completely out of the box, that attracts attention,” Dr. Coyle said.

Existing drugs are reasonably good at treating the hallucinations and delusions of schizophrenia. But they are far less effective at treating the so-called negative symptoms of the disease — the lack of motivation and emotion that leave many patients unable to work or have normal social relationships. The side effects of existing medicines, which affect nearly all patients, are also severe. Older drugs like Thorazine often cause tics and movement disorders, while newer medicines typically have fewer effects on movement but can cause weight gain and other metabolic changes.

In the clinical trial whose results were reported yesterday, LY2140023 had none of those side effects and appeared to work about as well as Zyprexa at reducing symptoms. In the trial, which was conducted in Russia from August 2005 to June 2006, patients were given the experimental drug, Zyprexa or a placebo. About 100 patients received the experimental medicine.

For the drug to be approved, Lilly will need to replicate the results in larger trials. This month, Lilly will begin a trial with 870 patients to determine the most effective dose of the drug. That trial is expected to be complete in January 2009, and if it is successful Lilly will probably start a large Phase III trial that could cover at least 2,000 patients.

“We have to confirm safety and efficacy with multiple studies,” Dr. Paul of Lilly said. He said he did not want to offer a prediction of when Lilly might ask the Food and Drug Administration for approval. But he said Lilly intended to develop the drug aggressively.

“We are very actively working on this target and related targets because we believe that this mechanism is now validated,” he said.

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