Clinical trials suggest Lilly's olanzapine may treat symptoms of schizophrenia.

INDIANAPOLIS--(HealthWire)--Dec. 14, 1995--Results of a 1,996-patient study of olanzapine, Eli Lilly and Company's investigational antipsychotic, suggest that the compound may treat the symptoms of schizophrenia. The company is seeking worldwide approval to market olanzapine for the treatment of schizophrenia and other psychotic disorders.

Charles Beasley, M.D., Lilly clinical research advisor and global physician for olanzapine, will present the results for the acute treatment period (up to six weeks) of the Phase III trial on Friday, Dec. 15, at the American College of Neuropsychopharmacology (ACNP) meeting in San Juan, Puerto Rico. This double-blind, randomized study involved 1,996 patients and 174 investigators in 17 countries. Patients were randomly selected to receive either olanzapine or haloperidol, the antipsychotic drug most often globally prescribed for the treatment of schizophrenia.

According to data gathered from this study, patients treated with olanzapine had statistically significant differences across several key test instruments measuring symptoms of schizophrenia.

"We are encouraged by the results of our Phase III trials on olanzapine," said August M. Watanabe, M.D., vice president of the company and president, Lilly Research Laboratories. "This drug appears to represent hope for millions of patients with schizophrenia--and hope for moderating the cost of treating and supporting people afflicted with this illness."

Schizophrenia is a clinical syndrome marked by the presence of positive symptoms such as delusions and hallucinations, and negative symptoms, such as diminished emotions and low motivation. Many currently available older antipsychotic medications are perceived as having little or no effect on negative symptoms.

However, data gathered during Lilly's phase III trials suggest that olanzapine may treat both the positive and negative symptoms of schizophrenia.

Overall symptoms: The study measured symptom severity using a Brief Psychiatric Rating Scale (BPRS) score. The BPRS score was extracted from the Positive and Negative Syndrome Scale (PANSS), a 30-item rating instrument that evaluates each symptom item on the scale of 1 (absent) to 7 (extreme).

Patients treated with olanzapine showed an average decrease of 10.9 points on the BPRS total; patients treated with haloperidol reported an average decrease of 7.9 points. This difference was statistically significant.

Also used to measure overall symptoms was the Clinical Global Impression (CGI) scale, which measures the overall severity of the illness. Patients treated with olanzapine showed an average decrease of 1 point on the CGI severity scale; patients treated with haloperidol reported an average decrease of 0.7 points. This difference was statistically significant.

Response rates: Of olanzapine patients who had a score of at least 18 on their baseline BPRS total and who remained in the study at least three weeks, 51.6 percent were reported to have improvement of at least 40 percent in their BPRS total scores after at least three weeks of treatment. Of haloperidol patients who had a score of at least 18 on their baseline BPRS total and remained in the study for at least three weeks, 34.2 percent were reported to have improvement of at least 40 percent in their BPRS total scores after at least three weeks of treatment. This difference was statistically significant.

Positive symptoms: Patients treated with olanzapine averaged a decrease of 4.7 points on the PANSS positive symptom scale; patients treated with haloperidol were reported to have an average decrease of 3.8 points. This difference was not statistically significant.

Negative symptoms: At study conclusion, olanzapine patients were reported to have an average decrease of 4.5 points on the PANSS negative symptom scale; patients treated with haloperidol were reported to have an average decrease of 3.2 points. This difference was statistically significant.

EPS events: The trial also measured extrapyramidal syndrome (EPS) events, which have been linked to currently available antipsychotic medications. EPS events include dystonias (abnormal muscle spasm), akathisia (an inability to sit still), Parkinson's disease-like symptoms (rigidity, tremors) and dyskinesias (abnormal jerking and/or writhing movements).

o Olanzapine patients averaged a one-point decrease (an improvement) on the Simpson-Angus Scale, a scale that measures Parkinsonian-like EPS. Haloperidol patients averaged a .8-point increase on the Simpson-Angus Scale.

This difference was statistically significant.

o Olanzapine patients averaged a .2-point decrease (an improvement) on the Barnes Akathisia Scale, a measurement of akathisia-type EPS. Haloperidol patients averaged a .4-point increase on the Barnes Akathisia Scale. This difference was statistically significant.

o Olanzapine patients averaged a .8-decrease (an improvement) on the AIMS total score, a measurement of dyskinetic involuntary muscle movements (tardive dyskinesia). Haloperidol patients averaged a .2-point decrease on the AIMS total score. This difference was statistically significant as well.

Completion rates: 66.4 percent of olanzapine patients completed the study; 46.8 percent of haloperidol patients completed the study. This difference was statistically significant. Lack of efficacy was the most frequent reason for discontinuing the study early, with 20.7 percent of olanzapine patients and 32.1 percent of haloperidol patients discontinuing early for that reason. This difference was statistically significant as well. Adverse events were cited as the reason for discontinuing the study early by 3.6 percent of olanzapine patients and 7.4 percent of haloperidol patients. This difference was also statistically significant.

Of adverse events reported by at least 2 percent of patients in either treatment group where there was a statistically significant difference in the reported rate between the two groups, the most common side effects associated with olanzapine were insomnia (10.4 percent), dry mouth (7.5 percent), akathisia (6.6 percent) and nervousness (5.6 percent). There were no reported cases of agranulocytosis, a sometimes fatal blood disorder that has been reported in 1 to 2 percent of patients who take clozapine, an atypical antipsychotic used as a treatment for schizophrenia.

Schizophrenia is one of the most chronic and debilitating of the mental illnesses, striking about 1 percent of the world's population. Its economic impact parallels its clinical impact, with costs of approximately $33 billion in health care and lost resources annually in the United States alone, according to some studies.

"The goal of current research into new antipsychotic compounds is to bring patients back to society as productive and self-sufficient individuals," said Gary D. Tollefson, M.D., Ph.D., vice president of Lilly Research Laboratories. "To do that, new compounds will need to improve positive and negative symptoms, while causing fewer of the side effects associated with currently available medications. Both of these factors are likely to have direct relevance to patient outcomes."

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

CONTACT: Eli Lilly and Company, Indianapolis

Jeff Newton, 317/276-3570

Lori Darvas, 317/277-1588