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

Abstract

ObjectivesThis phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE).MethodsPatients 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.Results183 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.ConclusionsPF-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 numberNCT01405196; Pre-results.

The phenolic fraction of extra virgin olive oil modulates the activation and the inflammatory response of T cells from patients with systemic lupus erythematosus and healthy donors

“…Several elements of the immune system are potential targets for therapeutic intervention in patients with SLE. In this sense, IL‐6 is implicated in the development and progression of SLE in mice and it is identified as one of the major genetic risk factors for SLE in humans ; thus, its modulation seems to be a potential therapeutic approach in SLE management . In the present study, we found a remarkable increase of IL‐6 production in patients with SLE compared with healthy subjects.…”

“…Targeting IL‐6 signaling may offer a novel therapeutic approach for SLE since IL‐6 is critically involved in the B cell hyperactivity of SLE and it may also mediate tissue damage in this disease . In our study, we examined IL‐6 induced production on PBMC isolated from patients with SLE and healthy subjects.…”

Pharmacokinetics and C‐reactive protein modelling of anti‐interleukin‐6 antibody (PF‐04236921) in healthy volunteers and patients with autoimmune disease

“…Therefore, serum C‐reactive protein (CRP), whose hepatic production is predominantly mediated by IL6 , was used as the pharmacology marker for PF‐04236921. Overall, PF‐04236921 demonstrated desirable pharmacokinetic (PK) and pharmacodynamic (PD) properties supporting sustained target inhibition, and low incidence of immunogenicity upon single and multiple dose administrations . Efficacy and safety findings were discussed previously.…”

Variability in Antinuclear Antibody Testing to Assess Patient Eligibility for Clinical Trials of Novel Treatments for Systemic Lupus Erythematosus

“…In view of the emerging use of ANA testing in the trial setting, we have therefore extended this investigation to specifically assess responses of patients with sufficient disease activity for clinical trial eligibility. For this purpose, we evaluated samples from a phase II study of a monoclonal antibody to interleukin‐6 (IL‐6) . At study enrollment, 23.8% of the patients had a negative ANA value at 1:80 dilution as assessed at the central laboratory, although a detailed review of medical records by experts confirmed historically positive ANA status and clinically active disease.…”