Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial

Daniel J Wallace, Vibeke Strand, Joan T Merrill, Serghei Popa, Alberto J Spindler, Alicia Eimon, Michelle Petri, Josef S Smolen, Joseph Wajdula, Jared Christensen, Cheryl Li, Annette Diehl, Michael S Vincent, Jean Beebe, Paul Healey, Sudhakar Sridharan, Daniel J Wallace, Vibeke Strand, Joan T Merrill, Serghei Popa, Alberto J Spindler, Alicia Eimon, Michelle Petri, Josef S Smolen, Joseph Wajdula, Jared Christensen, Cheryl Li, Annette Diehl, Michael S Vincent, Jean Beebe, Paul Healey, Sudhakar Sridharan

Abstract

Objectives: This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE).

Methods: Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses.

Results: 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea.

Conclusions: PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings.

Trial registration number: NCT01405196; Pre-results.

Keywords: Autoimmune Diseases; Cytokines; Systemic Lupus Erythematosus; Treatment.

Conflict of interest statement

Competing interests: DJW is a consultant for GlaxoSmithKline, Lilly, Merck Serono and UCB. VS is a consultant for, or received grants or research support from, Amgen, Anthera, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Lilly, Merck Serono, Mount Tam Biotechnologies, Novartis, Pfizer Inc and UCB. JTM is a consultant for, or received research support from, AbbVie, Anthera, AstraZeneca, Biogen-IDEC, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, GlaxoSmithKline, Lilly, Neovacs, Pfizer Inc, Takeda, Questcor and UCB, and has performed clinical trial services (adjudication, training and/or quality assurance) for Lilly, Pfizer Inc and Xencor. AE is a consultant for, or received grants or research support from, Abbot, Biogen, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Lilly and Pfizer Inc. JSS is a consultant for, or received grants from, AstraZeneca, GlaxoSmithKline, Pfizer Inc, Roche and Sanofi. JW, JC, CL, AD, MSV, JB and PH are all employees of Pfizer Inc and hold stock or options in Pfizer Inc. SS is a former employee of Pfizer Inc. SP, AJS and MP have no conflicts of interest to report.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Patient disposition. *Treatment group terminated prematurely. AE, adverse event.
Figure 2
Figure 2
SRI-4 and BICLA responder rates at week 24 (A) in the total population, and (B) in the enriched population (GLMM model). *p

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