Eli Lilly and Company: Long-Term Study Suggests Cymbalta Demonstrates High Tolerability and Safety; One-Year Data Shows High Likelihood of Remission from Depression.

Business Editors/Health/Medical Writers

INDIANAPOLIS--(BUSINESS WIRE)--Nov. 19, 2003

Cymbalta(TM) (duloxetine HCl)(TM) was safe and well tolerated in a 52-week open-label study of 1,279 patients with major depressive disorder, according to data published in the current issue of the Journal of Clinical Psychiatry.

There were no significant tolerability issues attributable to chronic vs. acute use of the investigational agent Cymbalta; patients who tolerated Cymbalta during the early period of the trial were likely to tolerate long-term dosing. Of the patients in the study, 520 remained on Cymbalta for at least 360 days, yielding approximately 808 patient-years of total exposure.

In addition, patients in the study who responded to treatment with Cymbalta had a high probability of achieving remission. Remission rates at 52 weeks in this study were close to response rates (81.8 percent and 89.1 percent, respectively), implying that patients who responded had a high probability of achieving complete resolution of their depressive symptoms.

"Long-term tolerability is important for antidepressant effectiveness in the complete treatment of depression. The higher-than-expected completion rate in this open-label study implies that Cymbalta was well-tolerated in these patients and was effective in helping them relieve their depressive illness," said Joel Raskin, MD, Lilly senior clinical research physician and lead author of the study.

Study Highlights

-- Cymbalta was safely administered and well-tolerated in

long-term chronic dosing, despite higher dosages than those

used in most other Cymbalta studies.

-- Most treatment-emergent adverse events were either mild or

moderate in severity and occurred early in the study.

-- Efficacy was demonstrated on all assessed measures, both

clinician- and patient-rated. Furthermore, discontinuation due

to adverse events over the entire 52-week study was 17 percent

- a favorable rate given the long duration of the study.

Methods

Data were gathered from a 52-week, open-label, multinational study of 1,279 adult outpatients who met the criteria for major depressive disorder. Patients were administered duloxetine 80 to 120 mg/day as two equal doses of 40 mg or 60 mg.

Efficacy was assessed using the Clinical Global Impression-Severity (CGI-Severity) scale, the Hamilton Depression Rating Scale (HAMD(17)), the Beck Depression Inventory-II and the Patient Global Impression-Improvement (PGI-Improvement) scale. Patient-rated quality was evaluated with the Sheehan Disability Scale. Response was defined as a 50 percent decrease from baseline on the HAMD(17) total score and remission was defined as a HAMD(17) total score of less than or equal to 7.

Mean changes from baseline to last observation in laboratory analyses, vital signs and electrocardiograms intervals were assessed using an analysis of variance with models that included the investigator. Longitudinal mean changes and categorical changes were assessed using likelihood-based, mixed-models repeated measures and last observation carried forward.

Tolerability/Safety

Discontinuation due to adverse events over the entire 52-week study was 17 percent -- a favorable rate given the long duration of the study. The most common reasons for discontinuation included adverse event (17 percent), personal conflict/other reasons (10.2 percent), and lost to follow-up (9.3 percent).

The most common treatment-emergent adverse events in the study included nausea (34 percent), somnolence (29.8 percent), insomnia (31.3 percent), headache (30.4 percent), dry mouth (23.5 percent), constipation (21.3 percent) and dizziness (23.3 percent). Most side effects occurred early in the study and generally dissipated over time. Only one side effect (headache) occurred in more than 10 percent of patients in weeks 9-52 of the study.

The rate of serious adverse events per patient-year-exposure was low -- roughly 1 event per 13 years of exposure. A total of 64 patients experienced serious adverse events, but investigators considered most unrelated to the study medication.

Efficacy/Remission

Efficacy was demonstrated on all assessed measures, both clinician-and patient-rated. The high rates of improvement at week one and two, while difficult to define and assess, were consistent with results from double-blind, placebo-controlled studies.(1-3)

Accumulating evidence suggests complete resolution of disease symptoms, or remission, rather than simple treatment response, should be the primary goal of depression treatment. Current medical literature suggests that depressed patients frequently experience lingering symptoms, such as persistent unexplained pain, putting them at a higher risk for relapse or recurrence.(4)

Although interpreting results in an open-label study can be problematic, the remission rates in this 52-week study were high, implying Cymbalta was effective in relieving the symptoms of major depression in these patients.

"By treating a broad spectrum of depressive symptoms - emotional and physical - Cymbalta, once approved by the FDA, may help more patients achieve remission," Raskin said. "These data show that these patients were able to easily tolerate Cymbalta over the long-term, enabling them to achieve even higher rates of response and remission the longer they remain on therapy."

About Cymbalta

In placebo-controlled clinical trials for major depressive disorder, Cymbalta had a favorable safety profile. The most commonly observed adverse events (greater than or equal to 5% and at least twice placebo) for Cymbalta vs. placebo (n = 1,139 vs. 777) were: nausea (20% vs. 7%), dry mouth (15% vs. 6%), constipation (11% vs. 4%), decreased appetite (8% vs. 2%), fatigue (8% vs. 4%), somnolence (7% vs. 3%) and increased sweating (6% vs. 2%). In these studies, anxiety was reported as an adverse event (3% vs 2%). The overall discontinuation rate due to adverse events for Cymbalta vs. placebo was 10% vs. 4%. Nausea was the only common adverse event reported as a reason for discontinuation and considered to be drug related (1.4% vs. 0.1 %).

The US Food and Drug Administration issued an approvable letter for Cymbalta (duloxetine for depression) in September 2003 based upon eight- and nine-week trials. Duloxetine hydrochloride