Background/Purpose:  TNF-related weak inducer of apoptosis (TWEAK) promotes renal inflammation, mesangial proliferation, tubular cell death and fibrosis in lupus nephritis (LN). TWEAK acts through its receptor, Fn14, which is upregulated in inflamed tissue but not expressed on T or B cells. We postulated that blocking the TWEAK/FN14 pathway in lupus nephritis with BIIB023, a humanized monoclonal antibody against TWEAK, would attenuate inflammation and enhance the renal response to standard-of-care (SOC) therapy without compromising safety.

Methods:  ATLAS is a phase II, placebo controlled, double blind, RCT to determine whether the addition of BIIB023 (3 mg/kg or 20 mg/kg q4wk) to MMF and steroids could increase the 52-week complete or partial renal response (RR) rates in patients with proliferative lupus nephritis. Patients had centrally verified biopsies demonstrating ISN/RPS class III or IV LN and urine protein creatinine ratio (UPCR) >1 mg/mg. All patients were induced with MMF and steroids during the run-in period, but only patients with persistent UPCR >0.5 mg/mg at week 12 were eligible for the addition of BIIB023 or placebo to SOC.

Results:  The study enrolled 276 subjects and randomized 188 subjects. 38 (14%) subjects completed run-in but did not qualify for randomization. The trial was prematurely terminated with 145 completing BIIB023/placebo infusions through wk 44. This group was designated the modified-ITT group, with 48 patients on placebo, 49 patients on 3 mg/kg and 48 patients on 20 mg/kg. At wk 52, complete and partial RR were: placebo: 25% (95% CI 15-35); BIIB023 3 mg/kg: 16% (8-25), and BIIB023 20 mg/kg: 31% (20-42). There were no differences between placebo and BIIB023 in time to RR or duration of RR. Dose-dependent reductions of serum and urinary TWEAK were observed. Treatment emergent adverse events were reported in 76% and 85% of placebo and BIIB023-treated subjects respectively. Serious adverse events were reported in 11% and 17% of placebo and BIIB023-treated patients, respectively.

Conclusion:  The addition of an anti-TWEAK monoclonal antibody to SOC LN therapy did not improve 52-week RR rates in proliferative LN despite observed pharmacodynamic effects. This unique LN trial design, which excluded subjects who responded rapidly to SOC, requires additional assessment in order to determine the merits of studying a cohort enriched in potentially less responsive patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluation-of-the-efficacy-safety-and-tolerability-of-biib023-as-an-adjunct-to-standard-of-care-in-subjects-with-lupus-nephritis/