Re: New Schizophrenia drug shows promise in Trials

[Guest guest]

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. "

New Schizophrenia Drug Shows Promise in Trials by _ALEX BERENSON_

(http://topics.nytimes.com/top/reference/timestopics/people/b/alex_berenson/inde\

x.html?in

line=nyt-per)

Published: September 3, 2007

In a clinical trial of about 200 patients, an experimental drug from _Eli

Lilly_

(http://topics.nytimes.com/top/news/business/companies/lilly_eli_and_company/ind\

ex.html?inline=nyt-org) reduced _schizophrenia_

(http://health.nytimes.com/health/guides/disease/schizophrenia/overview.html?inl\

ine=nyt-classifier)

symptoms without the serious side effects of current treatments, according to

a paper published yesterday in the journal Nature.

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.

Lieberman, chairman of the _psychiatry_

(http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/psy\

chiatry_and_psychiatrists/index.html

?inline=nyt-classifier) 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.â€

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_

(http://health.nytimes.com/health/guides/disease/bipolar-disorder/overview.html?\

inline=nyt-classifier) 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_

(http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/psy\

chiatry_and_psychiatrists/index.html

?inline=nyt-classifier) 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_

(http://health.nytimes.com/health/guides/disease/diabetes/overview.html?inline=n\

yt-classifier) . 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. Conn, director of the

_Vanderbilt University_

(http://topics.nytimes.com/top/reference/timestopics/organizations/v/vanderbilt_\

university/index.html?inline=nyt-org) 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.â€

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_

(http://topics.nytimes.com/top/news/business/companies/merck_and_company/index.h\

tml?inline=nyt-org) . Dr. Schoepp

and Dr. , the president of Lilly Research Laboratories, both said

that his departure would not hurt the development of Lilly’s new medicine

Dr. ph 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. of

Lilly said. He said he did not want to offer a prediction of when Lilly might

ask the _Food and Drug Administration_

(http://topics.nytimes.com/top/reference/timestopics/organizations/f/food_and_dr\

ug_administration/index.html?inline=

nyt-org) 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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