systemic lupus erythematosus (sle).pptVIP

Arthritis Advisory Committee Meeting April 19th, 2001 NDA 21-239: GL701 for Systemic Lupus Erythematosus Genelabs Technologies, Incorporated Presentation Outline Consultants GL701 (prasterone) Prasterone is the USAN designation for DHEA Prasterone is the synthetic equivalent of DHEA GL701 is the Genelabs formulation of Prasterone Proposed Indications Improvement in SLE disease activity and/or symptoms in women with mild to moderate SLE Reduction in corticosteroid requirements in women with mild to moderate SLE Background Robert Lahita, MD PhD Systemic Lupus Erythematosus (SLE) Inflammatory autoimmune disease of unknown etiology Morbidity Disease associated Corticosteroid associated Corticosteroid use as high as 89% 1-2 Mortality 5-10% at 10 years Early - active disease and infections Late - atherosclerosis 1. Zonana-Nacach et al., 2000 2. Urowitz et al., ACR meeting 2000 (Abstract) Damage within SLESLICC/ACR Damage Index1 DHEA and SLE: Preclinical Rationale Female NZB/W murine model 100% mortality at 10 months Mortality reduced with DHEA administration 1-3 1. Lucas et al., 1985; 2. Matsunaga et al., 1989; 3. van Vollenhoven and McDevitt, 1992 Murine in vitro studies Altered cytokine profile with DHEA ? IL-6, ? IL-2 4-5 4. Padgett and Loria, 1998; 5. Daynes et al., 1990 DHEA and SLE: Clinical Rationale Sex distribution in SLE, 90% F : 10% M Low levels of DHEA and other androgens in women with SLE 1-2 1. Lahita et al., 1987; 2. Verthelyi et al., 2001 DHEA and testosterone further suppressed by corticosteroid use 3 3. Hedman et al., 1989 IL-2 levels suppressed in SLE 4-5 In vitro (T lymphocytes) DHEA increased IL-2 production 6 DHEA inhibits IL-6 secretion (mononuclear cells) 7 4. Alcocer-Varela and Alarcon-Segovia, 1982; 5. Linker-Israeli et al., 1983; 6. Suzuki et al., 1991; 7. Straub et al., 1998 Study GL95-02 Baseline Endogenous DHEA-S and Testosterone Levels with and without Corticosteroid Treatment Rationale for And