Arthritis Advisory Committee Meeting.ppt

Arthritis mittee 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 SLE/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