Results from the Phase 2 BUTTERFLY trial conducted by Pfizer suggest that an antibody against the pro-inflammatory cytokine interleukin-6 (IL-6) may be a promising treatment for systemic lupus erythematosus (SLE).
The study, “Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial,” was published in the journal Annals of the Rheumatic Diseases.
IL-6 contributes to the survival, population expansion and maturation of B-cells, a type of white blood cell that is involved in immune responses. Mature B-cells are capable of producing immunoglobulins (antibodies). Importantly, serum levels of IL-6 correlate with disease activity in several chronic inflammatory diseases, including SLE.
The production of autoantibodies is a critical feature in lupus. This process has been attributed to hyperactivity of B-cells, which has been suggested to require IL-6 modulation.
IL-6 further participates in autoimmune diseases development by regulating the production of inflammatory biomarkers and the differentiation of T-helper 17 cells, another type of immune cell.
Evidence suggests that blocking IL-6-induced effects may be a novel therapeutic approach for SLE. This hypothesis is supported by promising responses observed with tocilizumab, a soluble IL-6 receptor inhibitor, in a small Phase 1 study in patients with mild-to-moderate SLE.
PF-04236921 is a human monoclonal antibody which was shown to bind and neutralize IL-6 in early Phase 1 trials.
Now, a research team led by Daniel J. Wallace, MD, associate director of the Rheumatology Fellowship Program at Cedars-Sinai Medical Center in Los Angeles, evaluated the effectiveness and safety of PF-04236921 for SLE treatment in the BUTTERFLY Phase 2 trial (NCT01405196).
The dose-ranging, double-blind study included 183 SLE patients ages 18 to 75 with stable background therapy. The patients were randomized to either a placebo or PF-04236921 treatment at 10 mg, 50 mg or 200 mg doses. Drug delivery was subcutaneous (beneath the skin) every eight weeks. SLE activity was assessed at week 24 after the start of treatment.
Researchers found that the effectiveness of the 10 mg dose of PF-04236921 was significantly greater than placebo [as assessed by the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA)].
A lower incidence of severe flares of inflammation (a major cause of hospitalization, associated with significant morbidity and mortality) was observed in patients receiving PF-04236921 at 10 mg (no flares) and 50 mg (two cases), compared to placebo (eight cases). The 200 mg dose treatment was discontinued due to safety issues.
The most frequent adverse events included headache, nausea and diarrhea. Of note, the rate of serious adverse effects was lower for the 10 mg and 50 mg PF-04236921 groups.
The absence of a dose-response relationship in the efficacy of PF-04236921 mimics results in previous trials of SLE treatment with other antibodies.
Overall, the positive results with the 10 mg dose support “the rationale for targeting the IL-6 pathway in SLE.” The safety issues with higher doses, “possibly due to increased immunosuppression,” require a careful approach when defining treatment doses, researchers wrote.
The authors state that additional work is needed “to better define the benefit-risk of this agent.” And, given the short duration of treatment in this study, future work should enable characterization of the long-term effects of PF-04236921 in SLE.