Background/Purpose:   IL-6 is a pro-inflammatory cytokine that is over-expressed in lupus nephritis(LN). This proof-of-concept study examined the efficacy and safety of sirukumab, an anti-interleukin-6 monoclonal antibody, in patients (pts) with active, ISN/RPS class III or class IV lupus nephritis (LN).

Methods: Pts were enrolled if they had class III or IV LN on renal biopsy within 14 mo of randomization, persistent proteinuria (≥ 0.5 g/d) despite immunosuppression (MMF or AZA ± corticosteroids), and stable renin-angiotensin system blockade. Pts were randomized to IV sirukumab 10 mg/kg (n=21) or placebo (Pbo, n=4) q4wks through wk 24. Primary endpoint was % reduction from baseline in proteinuria (protein/creatinine (P/C) ratio in a 12hr urine collection) at wk 24; major secondary endpoints included the proportion of pts with: 1) ≥50% reduction of baseline proteinuria; 2) meaningful reduction in proteinuria; 3) no worsening of glomerular filtration rate (GFR) based on serum creatinine levels (defined as <15% decrease from baseline rate); all at any time through wk 24, as well as 4)% change from baseline in Patient’s and Physician’s Global Assessments of Disease Activity over time.

Results: Median time from biopsy collection to randomization was 116 days. 76% of pts (19/25) completed 2-wks of treatment. No median reduction in proteinuria at wk 24 (primary endpoint) was observed in the sirukumab group.  In contrast, the Pbo group demonstrated median 43.3% increase in proteinuria(Table), largely driven by 1 Pbo-treated pt. Secondary endpoints indicated 20% (4/20) and 15% (3/20) of sirukumab-treated pts, vs 0% of Pbo-treated pts, demonstrated a ≥50% reduction or a meaningful reduction, respectively, in proteinuria at wk 24 (Table). In contrast, at wk 24, 10/18 (56%) of sirukumab-treated pts and 3/4 (75%) of Pbo-treated pts had no worsening in GFR (Table). Neither Physician nor Patient Global Assessment scores improved in either treatment group.  Among the 12 sirukumab-treated pts positive for anti-dsDNA at baseline, there was a mean 62.3% reduction in anti-dsDNA at wk 24. Among 6 pts who discontinued study agent, 5 did so because of an adverse event(AE)(anaphylactic reaction, increased liver enzymes, neutropenia, pneumonia, and LN worsening). No deaths occurred. Approximately half (47.5%, 10/21) of sirukumab-treated pts had ≥1 serious AE, the majority of which were infections. No serious AE occurred with Pbo-treated pts, although 4/37 (10.8%) screen-failed pts had 1 or more SAEs during the 8 wk screening period.

Conclusion: IL-6 inhibition with sirukumab in pts with active LN did not result in a median improvement in proteinuria, however approx 15-20% of treated pts did show a notable reduction in proteinuria.  A high frequency of serious AE was observed in this population of immunosuppressed pts with refractory LN.