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OP0047 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
  1. R. van Vollenhoven1,
  2. C. Aranow2,
  3. B. Rovin3,
  4. C. Wagner4,
  5. B. Zhou4,
  6. R. Gordon4,
  7. B. Hsu4
  1. 1The Karolinska University Hospital, Stockholm, Sweden
  2. 2Feinstein Institute For Medical Research, Manhasset
  3. 3The Ohio State University College of Medicine, Columbus
  4. 4Janssen R & D, LLC, Spring House, United States

Abstract

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.3974

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