Eli Lilly and Company: Zyprexa Shown to Be More Effective Than Lithium or Placebo in Mania and Similar to Lithium in Depression for Long-Term Maintenance of Bipolar Disorder.

Business Editors/Health/Medical Writers

PRAGUE, Czech Republic--(BUSINESS WIRE)--Sept. 22, 2003

Eli Lilly and Company (NYSE:LLY)

Two Studies Suggest Potential to Approach Treatment

of Bipolar Disorder in a New Way

By delaying the recurrence of extreme mood swings associated with bipolar disorder for longer periods than both lithium and placebo, Zyprexa(R) (olanzapine) has been shown to be significantly more effective as a long-term maintenance therapy for the condition. Studies comparing Zyprexa to lithium and placebo suggest the potential of a new treatment approach for bipolar disorder -- one that would allow for a greater focus on the long-term management of the condition, rather than merely the regulation of acute manic or depressive symptoms. These data were presented at the 16th European College of Neuropsychopharmacology Annual Congress.

The first study demonstrated that Zyprexa was significantly more effective than lithium, the current gold standard for bipolar disorder treatment, in delaying relapse into mania, reducing the need for hospitalization and limiting the number of patients who discontinued therapy. The second study showed that Zyprexa was significantly more effective than placebo in reducing relapse rates of manic, depressive and mixed (manic plus depressive symptoms) episodes in bipolar patients.

"Prolonged maintenance allows patients to gain greater control of their lives without the severe devastation and disruptions that bipolar mood swings can cause," said Eduard Vieta, MD, PhD, Director, Bipolar Disorders Program, Clinical Institute of Psychiatry and Psychology, Hospital Clinica, University of Barcelona. "As our understanding of this complicated condition has evolved, we have learned that treatment needs to be more than a response to acute episodes and should focus on stabilizing the patient's condition to prevent relapse over the long term. These data indicate that olanzapine is a promising choice to stabilize moods, as it prolongs periods of wellness."

Relapse can have devastating consequences for patients with bipolar disorder. During relapse into mania or depression, patients may experience disruptions in relationships and jobs, suffer feelings of failure or become suicidal. Some researchers also believe that recurring relapse can lead both to a worsening of the disease itself as well as contribute to more frequent episodes of relapse.

In July, the Committee for Proprietary Medicinal Products (CPMP) issued a positive opinion for Zyprexa as treatment for the prevention of recurrence of bipolar disorder in patients whose manic bipolar episodes have previously responded to treatment with Zyprexa. Approval of the new indication by the European Commission is expected soon. With this approval, Zyprexa will become the first medication approved to treat acute manic episodes and prevent recurrence of mania, mixed mania and depression since carbamazapine and lithium became available decades ago.

Study Highlights: Zyprexa vs. Lithium

-- Zyprexa patients had a significantly lower incidence of

relapse into a manic episode than patients treated with

lithium (14.3 percent vs. 28.0 percent). Both groups had

similar rates of relapse into a depressive episode (16.1

percent vs. 15.4 percent).

-- Estimated time to relapse for 25 percent of patients in each

treatment group was 380 days for patients treated with Zyprexa

compared to 212 days for those patients treated with lithium.

-- The incidence of hospitalization for a bipolar episode was

significantly lower among Zyprexa patients than lithium

patients (14.3 percent vs. 22.9 percent).

-- Significantly more Zyprexa patients (46.5 percent) completed

the 52-week trial than those on lithium (32.7 percent).

-- The rates of discontinuation due to adverse events were 18.9

percent for the Zyprexa group, and 25.7 percent for the

lithium group.

-- Weight gain across open-label and double-blind therapy phases

was significantly greater in the Zyprexa group than in the

lithium group (1.79 kg vs. 1.38 kg).

Study Design

In the first randomized double-blind comparison of the efficacy and safety of Zyprexa and lithium in the prevention of bipolar episode relapse, patients diagnosed with bipolar I disorder, who had at least two manic or mixed episodes within six years and a YMRS total score greater than or equal to 20, received open label combination therapy of Zyprexa and lithium for six to 12 weeks. The 431 patients who met symptomatic remission criteria were randomized to monotherapy for 52 weeks of double-blind treatment with either Zyprexa (N=217) at doses of 5 to 20 mg daily or lithium (N=214) titrated to a therapeutic serum level of 0.6 to 1.2 mEq/L at doses of 300-1800 mg daily.

Study Highlights: Zyprexa vs. Placebo

-- Zyprexa treatment (mean dose of 12.5 mg) was shown to

significantly extend time to relapse to bipolar episodes (174

days vs. 22 days), with time to relapse measured by

hospitalization or symptoms.

-- While relapse occurred in 80.1 percent of patients receiving

placebo, only 46.7 percent of patients treated with Zyprexa

relapsed.

-- Zyprexa patients had a statistically significant lower

incidence of relapse into a manic episode (16.4 percent vs.

41.2 percent), or into a depressive episode (34.7 percent vs.

47.8 percent), when compared with the placebo group.

-- Common (greater than 5%) and significant adverse events

occurring in the Zyprexa group compared to placebo were weight

gain, fatigue and akathisia. There were no statistically

significant differences between olanzapine and placebo in

incidence of treatment-emergent glucose-related abnormalities.

Study Design

Prior to the start of the year-long study, bipolar patients exhibiting acute manic or mixed symptoms of bipolar disorder were treated with Zyprexa for six to 12 weeks. The 361 patients who achieved symptomatic remission were then randomized to Zyprexa (n=225), at daily doses ranging from 5 to 20 mg, or placebo (n=136), for 52 weeks of double-blind treatment. During the study, Zyprexa treatment was administered at a mean daily dose of 12.5 mg. Time to relapse to an affective (manic, depressive, or mixed) episode, was defined as YMRS total score greater than or equal to 15 and/or HAMD-21 total score greater than or equal to 15 and/or psychiatric hospitalization.

About Bipolar Disorder

Bipolar disorder, also known as manic-depressive illness, affects an individual's mood, behavior, and thinking. Unlike many illnesses, symptoms may be quite different at different phases of the illness. Treatment is more challenging because some treatments that are effective in one phase of the illness may be counterproductive in another, such as the observation that antidepressant treatments can precipitate manic episodes. 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). Patients also experience maintenance phases, which are periods of normal mood. The World Health Organization estimates that bipolar disorder is the sixth leading cause of disability in the world.

Zyprexa Background

Zyprexa is currently indicated in the European Union and the United States for the acute and long-term treatment of schizophrenia, and the short-term treatment of acute manic episodes associated with bipolar disorder. Zyprexa was the first atypical antipsychotic to prove its long-term effectiveness in patients with schizophrenia. Since Zyprexa was introduced in 1996, it has been prescribed to nearly 12 million people worldwide.

In the original schizophrenia registration trials, Zyprexa was generally well tolerated. However, as with all medications, Zyprexa was associated with some side effects. In the original six-week, acute-phase schizophrenia trials, the most common treatment-emergent adverse event associated with Zyprexa was somnolence. Other common events were dizziness, weight gain, constipation, akathisia (restlessness) and postural hypotension. Modest elevations of prolactin were also seen, although mean changes from baseline to endpoint were not statistically significantly different between Zyprexa 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 Zyprexa 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 European Agency for the Evaluation of Medicinal Products. 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.

NOTE: The statements in this release do not necessarily reflect the positions of European College of Neuropsychopharmacology.