A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SIRUKUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS

Background: Interleukin-6 is a pro-inflammatory cytokine that is over-expressed in LN. Objectives: 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 intravenous sirukumab 10 mg/kg (n=21) or placebo (Pbo, n=4) q4wks through wk 24. The primary endpoint was the percent reduction from baseline in proteinuria (protein/creatinine (P/C) ratio in a 12-hour 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) the percent 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 24-wks of treatment. No median reduction in proteinuria at wk 24 (primary endpoint) was observed in the sirukumab treatment group. In contrast, the Pbo treatment group demonstrated median 43.3% increase in proteinuria, (Table), largely driven by 1 Pbo-treated subject. Secondary endpoints indicated 20% (4/20) and 15% (3/20) of sirukumab-treated pts, versus 0% of Pbo-treated pts, demonstrated a ≥50% reduction or a meaningful reduction, respectively, in proteinuria at wk 24 (Table). In contrast, at week 24, 10/18 (56%) of sirukumab-treated patients and 3/4 (75%) of Pbo-treated patients had no worsening in GFR (Table). Neither Physician nor Patient Global Assessment scores improved in either treatment group. 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 subjects, although 4/37 (10.8%) screen-failed subjects had 1 or more SAEs during the 8 week screening period. Conclusions: IL-6 inhibition with sirukumab in pts with active lupus nephritis did not result in a median improvement in proteinuria, however approximately 15-20% of treated patients did show a notable reduction in proteinuria. A high frequency of serious adverse events was observed in this population of immunosuppressed patients with refractory lupus nephritis. Disclosure of Interest: R. van Vollenhoven Grant/research support: Janssen R & D, LLC, C. Aranow Grant/research support: Janssen R & D, LLC, B. Rovin Grant/research support: Janssen R & D, LLC, C. Wagner Employee of: Janssen R & D, LLC, B. Zhou Employee of: Janssen R & D, LLC, R. Gordon Employee of: Janssen R & D, LLC, B. Hsu Employee of: Janssen R & D, LLC DOI: 10.1136/annrheumdis-2014-eular.3974Citation: Annals of the Rheumatic Diseases, volume 73, supplement 2, year 2014, page 78Session: Abstract session: SLE, Sjögren's syndrome - streatment (Oral Presentations )