Lilly's Zyprexa - olanzapine - cleared for marketing for treatment of psychotic disorders.

INDIANAPOLIS--(HealthWire)--Oct. 1, 1996--The United States Food and Drug Administration today granted Eli Lilly and Company permission to market Zyprexa(TM) (olanzapine) for the treatment of the symptoms of psychotic disorders.

"Zyprexa represents hope to the millions of patients whose lives are devastated by schizophrenia and the manifestations of psychotic disorders," said August M. Watanabe, M.D., Lilly executive vice president, science and technology. "Schizophrenia puts both an emotional and financial burden on its patients and their caregivers. Its cost to society is tremendous. Zyprexa may allow patients to take the first step toward becoming self-sufficient and productive."

Schizophrenia, a clinical syndrome that affects 1 percent of the world's population, is characterized by the presence of positive psychotic symptoms, such as delusions and hallucinations, and negative symptoms, such as diminished emotions and low motivation. People with schizophrenia can have difficulty distinguishing fantasy from reality, thinking clearly and managing emotions. They may lose their social skills, their schooling and jobs, or their ability to communicate.

This is the second major regulatory clearance for Zyprexa. Zyprexa was cleared for marketing in 15 European countries by the European Medicine Evaluation Agency (EMEA) on September 27, 1996.

Key data from Zyprexa clinical trials

In clinical trials, Zyprexa was superior to placebo in treating the symptoms of schizophrenia. The efficacy of Zyprexa in the management of the symptoms of psychotic disorders was established in two six-week placebo controlled trials of schizophrenic inpatients.

"Zyprexa has demonstrated a promising therapeutic profile, including once daily dosing, low risk of drug interactions, no requirement for blood monitoring and a therapeutic starting dose without a requirement for titration for most patients," said Gary D. Tollefson, M.D., Ph.D., vice president of Lilly Research Laboratories, and head of the olanzapine heavyweight team. "Based on our clinical trials, we believe Zyprexa will be an innovative option for health care providers."

Patients were assessed using several test instruments, including the Brief Psychiatric Rating Scale (BPRS), an 18-item inventory of symptoms traditionally used to evaluate the effects of drug treatment in psychosis. The BPRS score was extracted from the Positive and Negative Syndrome scale (PANSS), a 30-item rating instrument that evaluates each symptom item on a scale of 1 (absent) to 7 (extreme). The BPRS psychosis cluster assessed psychotic symptoms, such as conceptual disorganization, hallucinatory behavior, suspiciousness and unusual thought content.

A second assessment, the Clinical Global Impression (CGI), measures the overall severity of the illness. In addition, patients were evaluated on the PANSS and the Scale for Assessing Negative Symptoms (SANS).

In a six-week, placebo-controlled trial involving 149 patients, patients received either placebo or a fixed dose of Zyprexa at 1 and 10 mg/day. In this trial, Zyprexa at 10 mg/day (but not 1 mg/day) was superior to placebo on the PANSS total score, the BPRS total, the BPRS psychosis cluster, the PANSS negative symptom subscale and on CGI severity.

In a six-week, placebo-controlled trial involving 253 patients, patients received placebo or one of three fixed dose ranges of Zyprexa (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day and 15 +/- 2.5 mg/day). The two highest Zyprexa doses (but not the lowest) were superior to placebo on the BPRS total score, BPRS psychosis cluster and CGI severity score. The highest Zyprexa dose was statistically superior to placebo on the SANS.

The overall rate of early discontinuation due to an adverse event was comparable to placebo.

Lilly's clinical trials also included a 1,996-patient trial in which patients were given either Zyprexa or the most commonly prescribed antipsychotic. In addition, Lilly is currently conducting trials comparing Zyprexa with other newer antipsychotics on the market.

Extrapyramidal syndrome events

Many currently available older antipsychotic medications, although effective, have been linked to extrapyramidal syndrome (EPS) events, including abnormal muscle spasms, Parkinson's-disease-like symptoms, abnormal jerking or writhing, and an inability to sit still.

Clinical studies have associated Zyprexa with a low incidence of EPS. In clinical trials, treatment-emergent EPS assessed by formal rating scales occurred at incidences comparable to placebo. As assessed by these scales, the incidence of EPS did not increase as the dose of Zyprexa was increased.

"Our studies corroborate preclinical predictions that Zyprexa would have a favorable EPS profile and would be a well-tolerated, first-line agent for treatment of schizophrenia," Tollefson said. "We're seeing an effective antipsychotic with a safety profile that would permit routine use."

Additional patient data

Given the concern about agranulocytosis, a sometimes fatal blood disorder associated with other psychotropic compounds, careful attention was given to the examination of hematologic parameters in clinical trials. There is no indication of a risk of clinically significant agranulocytosis associated with olanzapine treatment. Consequently, Zyprexa patients will not have to submit to weekly blood monitoring tests.

As with all antipsychotics, Zyprexa was associated with some side effects. In acute-phase, placebo-controlled trials, the most frequently observed treatment-emergent events associated with olanzapine at an incidence statistically greater than placebo were somnolence, dizziness and weight gain. The incidence of elevated hepatic transaminase levels was greater with Zyprexa; these elevations were generally transient and asymptomatic. About 1 percent of patients in clinical trials discontinued treatment due to transaminase increases. Other commonly observed adverse events associated with the use of Zyprexa were constipation, personality disorder and postural hypotension; these event rates were not statistically greater than placebo. In only one analysis of a placebo-controlled study, only one specific form of EPS, akathesia, was reported significantly more often with Zyprexa (at 10 +/- 2.5 mg/day or 15 +/- 2.5 mg/day) compared with placebo.

Schizophrenia is one of the most chronic and debilitating of the mental illnesses, costing $65 billion in health care and lost resources annually in the United States alone, according to a study by R.J. Wyatt, I. Henter, M.C. Leary and E. Taylor.

"Schizophrenia patients account for a significant number of all beds in U.S. psychiatric hospitals," Tollefson said. "This represents a tremendous cost, which is often borne by public sources, such as state and federal governments."

Zyprexa was approved in just over a year after Lilly submitted its New Drug Application to the U.S. Food and Drug Administration. In keeping with the company's commitment to bring new therapeutic options to patients in a timely manner, a team of dedicated Lilly health care professionals have worked diligently throughout the year with the FDA to ensure this rapid approval. This same team has worked with members of the European Medicinal Evaluation Agency and regulatory authorities around the world to facilitate a timely approval in those countries as well.

"By minimizing the time it takes to ensure that Zyprexa is safe and effective, the FDA and Lilly have given schizophrenia patients and their loved ones a new treatment option today," Tollefson said.

Zyprexa should be available to consumers in the United States in early October.

Eli Lilly and Company is a global, research-based pharmaceutical corporation headquartered in Indianapolis, Ind., that is dedicated to creating and delivering superior health care solutions -- by combining pharmaceutical innovation, existing pharmaceutical technology, disease prevention and management and information technologies -- in order to provide customers worldwide with optimal clinical and economic outcomes. -0-

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CONTACT: Eli Lilly and Company, Indianapolis

Lori Roberts, 317/277-1588