BIIB023 for Subjects with Lupus Nephritis
Open for Enrollment
Why is this study being done?
Survival of patients with systemic lupus erythematosus (SLE) has improved greatly in the last decade, but lupus nephritis remains an important cause of morbidity and mortality in these patients. Recent studies have shown that we current therapies up to 50% of the patients with lupus nephritis fail to reach primary renal remission outcomes. Thus, there is a need for more effective therapies in patients with lupus nephritis.
The primary objective of the study is to assess the efficacy of BIIB023, an inhibitor of TWEAK (TNF-related weak inducer of apoptosis), as an add-on treatment to standard therapy compared with placebo in combination with standard therapy in the treatment of subjects with active, biopsy-proven lupus nephritis.
There is substantial therapeutic rationale for inhibiting TWEAK in lupus nephritis: blocking the binding of TWEAK to Fn14 (fibroblast growth factor-inducible 14), BIIB023 attenuates TWEAK/Fn14 signaling and the downstream cellular responses of this signaling cascade; TWEAK induces the expression of proinflammatory mediators in both mesangial cells and podocytes, as well as in renal tubules, which may promote glomerulonephritis and tubulointerstitial inflammation. Since inflammation is considered to be a key mediator of tissue damage, TWEAK may promote tissue damage in lupus nephritis by promoting the recruitment of inflammatory infiltrates. TWEAK also acts in concert with other cytokines to promote renal tubular cell death. Thus, TWEAK may play an important pathogenic role in glomerulonephritis by promoting a local inflammatory environment and inducing tissue damage leading to progression to both glomerulosclerosis and tubulointerstitial fibrosis.
Elevated levels of urinary TWEAK are observed in subjects with active lupus nephritis. Analyses of urinary TWEAK demonstrated that urinary TWEAK levels in biopsy-proven lupus nephritis patients are significantly higher than those found in SLE non-lupus nephritis patients and healthy controls. A significant association was found between urinary TWEAK levels and lupus nephritis disease activity as measured by the renal Systemic Lupus Erythematosus Disease Activity Index. Urinary TWEAK levels are also higher in patients undergoing a renal flare as compared with those with stable chronic renal disease and in patients undergoing renal as opposed to non-renal flare.
Because TWEAK may promote multiple pathogenic activities locally in the kidney, it represents a promising target for therapeutic intervention. Inhibition of the TWEAK/Fn14 pathway with anti-TWEAK monoclonal antibodies has proven effective in multiple animal models of inflammatory diseases, suggesting that TWEAK blockade by BIIB023 may be clinically beneficial in lupus nephritis.
The lack of a prominent impact on normal tissue homeostasis and adaptive immunity suggest that anti-TWEAK agents may have an attractive profile with respect to susceptibility to opportunistic infections and may therefore be combined with existing immunosuppressive therapies for LUPUS NEPHRITIS to achieve a novel more effective therapeutic approach without increased risk of infection.
Who can I contact for additional information about this study?
Fernando C. Fervenza, M.D., 507-266-7083, fervenza, fernando @mayo.edu
Shirley Jennison, 507-255-0231, email@example.com