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Abstract Number: 2835

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

Cynthia Aranow1, R. van Vollenhoven2, Brad H. Rovin3, Carrie Wagner4, Bei Zhou4, Robert Gordon4 and Benjamin Hsu4, 1The Feinstein Institute for Medical Research, Manhasset, NY, 2The Karolinska Institute, Stockholm, Sweden, 3Division of Nephrology, Ohio State University Medical Center, Columbus, OH, 4Janssen Research & Development, LLC., Spring House, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: IL-6 and lupus nephritis

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Session Information

Session Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment: Novel Therapies for Systemic Lupus Erythematosus

Session Type: Abstract Submissions (ACR)

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.

Table.   Summary of primary and major secondary efficacy endpoints  at wk 24

Placebo

CNTO 136

Modified intent-to-treat pts

4

20 a

Proteinuria % change from baseline at wk24a

Median

(95% CI)

43.3

0.00

(-61.8, 39.6)

Pts with decrease ≥50% in proteinuria at  wk24a

0

4/20 (20.0%)

95% confidence interval

(5.7, 43.7)

Pts with meaningful reduction in proteinuria at wk24a,b

0

3/20 (15.0%)

95% confidence interval

(3.2, 37.9)

Pts with no worsening in GFR at wk24

3 (75.0%)

10/18 (55.6%)

95% confidence interval

(30.8, 78.5)

 aA last-observation-carried-forward procedure was used to impute missing proteinuria values if a pt had data for ≥1 post- baseline evaluation. Of 21 randomized pts, 20 were included in the efficacy analyses.

bMeaningful reduction in proteinuria was defined as P/C (protein/creatinine) ratio < 0.5 for non-nephrotic pts ; and ≥50% reduction in P/C ratio and P/C ratio < 3.0 for nephrotic pts.


Disclosure:

C. Aranow,
None;

R. van Vollenhoven,

Janssen Research and Development, LLC,

2;

B. H. Rovin,

Genentech and Biogen IDEC Inc.,

2,

Questcor,

2,

Centocor, Inc.,

5,

Lilly,

5,

GlaxoSmithKline,

5,

Medimmune,

5,

aurina,

5;

C. Wagner,

Janssen Research and Development, LLC,

3;

B. Zhou,

Janssen Research and Development, LLC,

3;

R. Gordon,

Janssen Research and Development, LLC,

3;

B. Hsu,

Janssen Research & Development, LLC.,

3.

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