Lilly: Landmark, Placebo-Controlled Trial Suggests Olanzapine May Delay and Reduce Rates of Manic and Depressive Relapse in Patients With Bipolar Disorder.

Business Editors/Health/Medical Writers

SAN FRANCISCO--(BUSINESS WIRE)--May 19, 2003

Eli Lilly and Company (NYSE:LLY)

Relapse Can Be Devastating to People With Bipolar Disorder 

A landmark, placebo-controlled study presented today at the American Psychiatric Association's 156th annual meeting in San Francisco suggests that olanzapine may be useful in delaying relapse of both manic and depressive episodes of bipolar disorder. Olanzapine is the only agent other than lithium to demonstrate that it may delay relapse to both poles of bipolar disorder in a placebo-controlled, double-blind study.

"The major challenge in the management of bipolar disorder is how to maintain mood stability over the long haul, once the manic or depressive episode is resolved," said Dr. Frederick K. Goodwin, director, Center on Neuroscience, Medical Progress, and Society, George Washington University Medical Center, Washington, D.C. "These results with olanzapine are encouraging, especially in light of another recent study in which olanzapine demonstrated lower rates of relapse into mania than lithium, the gold standard mood stabilizer."

Olanzapine is currently indicated for the short-term treatment of acute manic episodes associated with bipolar disorder, and is under review by the FDA for long-term maintenance of response in the treatment of bipolar disorder.

Key Findings

In the double-blind study, 361 patients with bipolar disorder were randomly selected to receive either olanzapine (n=225) or placebo (n=136) for 52 weeks after achieving remission during a six-to 12-week period of open-label treatment with olanzapine.

-- Time to relapse of either mania or depression was

significantly longer for olanzapine patients than

placebo-treated patients (median times: 174 days versus

22 days).

-- Compared with the placebo group, olanzapine-treated patients

had a significantly lower rate of either a mania

(16.4 percent, olanzapine vs. 41.2 percent, placebo) or

depression relapse (34.7 percent vs. 47.8 percent).

-- Olanzapine also delayed relapse in the subgroup of

"rapid-cycling patients" (n=179). Rapid-cycling patients

(patients with four or more episodes of either mania or

depression per year) taking olanzapine (n=119) had a bipolar

relapse rate of 49 percent, compared to 87 percent in those on

placebo (n=60). Stability is particularly elusive for

rapid-cycling patients, providing significant challenges to

clinicians treating these patients.

"Relapse into mania or depression can be devastating to a person with bipolar disorder, shattering the confidence that the patient has in himself as well as the relationship he has with his physician," said Mauricio Tohen, M.D., Dr. PH., Lilly Clinical Research Fellow, Lilly Research Laboratories. "Furthermore, more than half of the patients in this study were rapid-cycling patients - a particularly difficult-to-treat group. Olanzapine is the first treatment to delay relapse in patients with a rapid cycling course in a placebo-controlled double-blind study, making these results even more important," he added.

Study Design

Seven hundred and thirty-one patients in acute manic or mixed episodes of bipolar I disorder received open-label olanzapine for 6-12 weeks. At the end of this first phase of the study, researchers evaluated patients for symptomatic remission, employing two commonly used scales, the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HAMD). The 361 patients who achieved remission in relapse prevention during the open-label phase were then randomized to receive either olanzapine (n=225), 5-20 milligrams per day, or placebo (n=136) for 52 weeks. The study included 179 rapid-cycling patients (olanzapine - 119; placebo - 60). YMRS and HAMD scales and/or psychiatric hospitalization were used to determine relapse during the placebo-controlled second phase of the study.

Significantly more olanzapine-treated patients (23.6%) completed the 52-week trial than those on placebo (9.6%). Common and significant adverse events for the olanzapine group were weight gain, fatigue and inner and outer restlessness (akathisia).

About Bipolar Disorder

Bipolar disorder, also known as manic-depressive illness, affects an individual's mood, behavior, and thinking. Symptoms vary as moods swing from the manic phase of the illness (characterized by feelings of elation/euphoria, extreme optimism, inflated self-esteem, difficulty sleeping, engaging in risky activities) to the depressive phase (feelings of extreme guilt, sadness, anxiety, and at times, suicidal thoughts).

More than 2.5 million Americans live with a diagnosis of bipolar disorder but recent research indicates the real number may be as high as 10 million. The results of untreated bipolar disorder can be catastrophic. According to the National Institute of Mental Health, nearly one in every five people with the illness ends their life by suicide. The World Health Organization estimates that bipolar disorder is the sixth leading cause of disability in the world.

Olanzapine Background

Olanzapine is indicated in the United States for the treatment of schizophrenia, the short-term treatment of acute manic episodes associated with bipolar disorder and for the long-term therapy and maintenance of treatment response of schizophrenia. Olanzapine was the first atypical antipsychotic to prove its long-term effectiveness in patients with schizophrenia. Since olanzapine was introduced in 1996, it has been prescribed to 11 million people worldwide.

In the original schizophrenia registration trials, olanzapine was generally well tolerated. However, as with all medications, olanzapine was associated with some side effects. In the original six-week, acute-phase schizophrenia trials, the most common treatment-emergent adverse event associated with olanzapine was somnolence. Other common events were dizziness, weight gain, constipation, inner and outer restlessness (akathisia) and postural hypotension. Modest elevations of prolactin were also seen, although mean changes from baseline to endpoint were not statistically significantly different between olanzapine and placebo. A small number of patients experienced asymptomatic elevations of hepatic transaminase; none of these patients developed jaundice or drug-induced hepatitis.

In short-term (three- and four-week) acute bipolar mania trials, the most common treatment-emergent adverse event associated with olanzapine was somnolence. Other common events were dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite and tremor.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.

This press release contains forward-looking statements reflecting Lilly's current beliefs about the potential of Zyprexa for the maintenance treatment of patients with bipolar disorder. As with any pharmaceutical under development, there are substantial risks and uncertainties in the process of development and regulatory review. There is no guarantee that the product will receive additional regulatory approvals, and any indication for which it is approved will be determined at the discretion of the Food and Drug Administration. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.