BIIB023 for Subjects with Lupus Nephritis
Trial status: 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 is eligible to participate?
Inclusion Criteria: *Diagnosis of SLE according to current ACR criteria. At least 4 ACR criteria must be documented, 1 of which must be a positive antinuclear antibody (ANA), anti Sm, or anti dsDNA antibody. *Diagnosis of ISN/RPS 2003 Class lll or IV LN with either active/chronic disease, confirmed by biopsy within 3 months prior to Screening. Subjects are permitted to have co existing Class V LN. If a renal biopsy has not been performed within 3 months of the Screening Visit, one can be performed during the Screening Period after all other eligibility criteria have been confirmed. The local histological diagnosis must be confirmed by the central study pathologist.
*Must have proteinuria at Screening (from a 24-hour urine sample collection( defined as uPCR >1.0 mg/mg.
Exclusion Criteria: *Retinitis, poorly-controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia, or dementia that is currently active and resulting from SLE at Screening *Estimated GFR <30 mL/min per 1.73 m2 (calculated using the abbreviated MDRD equation) or the presence of oliguria or ESRD requiring dialysis or transplantation *Subjects requiring dialysis within 12 months prior to Screening *History of renal transplant *Treatment with any biologic B-cell-depleting therapy (e.g., anti-CD20 [rituximab], anti-CD22 [epratuzumab], anti-BLyS/BAFF [e.g., briobacept, belimumab] therapy), or TACI-Ig within 12 months prior to Run-in Day 1.
What is involved?
There are 4 periods in this study: Screening, Run-in, Double Blind Treatment and follow up.
The screening visit is to ask questions and perform tests to see if you meet all requirments to take part in the study. If you meet all the study requirements you will return to the clinic to start a "Run-in Period".
On Day 1 of the Run-In Period you will have testing and start taking oral MMF if you are not already taking it for your lupus nephritis. Your Study doctor will also prescribe an oral corticosteroid. You will then return to the clinic on weeks 2, 3, 4, 8 and 12 for additional testing. After you have completed the Run-In Period it will be determined if you meet the requirements to receive the study drug treatment (Double-blind Treatment Period).
At the start of the Double-blind treatment Period you will be randomly assigned to your study treatment group (Group 1 BIIB023 20mg/kg, Group 2 BIIB023 3mg/kg, or Group 3 placebo). You will receive study treatment during 14 visits in the Double-blind Treatment Period (Day 1, weeks 2 and 4 and then every 4 weeks until Week 48). You will also come into the clinic at Week 26 for study assessment but not receive study treatment.
At the end of the study you will be asked to return to the clinic for 2 follow-up visits (Week 52 and Week 56). After the Week 52 Visit, you will be asked if you want to take part in another study with the study medicine BIIB023. If you choose to take part, the study will be explained to you and you will be asked to sign a seperate consent form. If you choose not to take part, you will be asked to return to the clinic at Week 56 for the end of the study tests and at Week 60 and Week 64 for some follow up urine and blood tests.
How long is the study?
You will be in the study for up to 72 weeks (approximately 17 months) from screening to the last study visit.