12 Nevertheless, a phase III study of ustekinumab has recently been discontinued.
In addition to targeting IFNs, a proof of concept study targeting IL-6 has reported potential efficacy, 11 and in a phase II study targeting the p40 subunit shared by IL-12 and IL-23, patients treated with mAb ustekinumab 10 mg had a higher response rate according to SRI-4 than patients in the placebo group.
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7 8 Subsequently, two phase III clinical trials, TULIP 1 and TULIP 2, have been completed using anifrolumab, 9 10 while one met the primary endpoint of British Isles Clinical Lupus Activity index, a second trial failed to meet its primary endpoint of the SRI-4 response. 6 In a phase II trial of a mAb targeting the IFN-α receptor, which blocks all type I IFN species, the mAb anifrolumab met the study primary endpoint of Systemic Lupus Responder Index (SRI)-4 at week 24 with a sustained reduction in oral corticosteroids from weeks 12 to 24. Among these, rontalizumab was not efficacious in treating active SLE, 5 and only a modest clinical effect was observed in a trial testing another anti-IFN mAb: sifalizumab. 3 4 Several anti-IFN-specific monoclonal antibodies have been studied in clinical trials to determine their efficacy and safety in SLE. Many studies have reported elevation of IFN in SLE either measured directly or more often indirectly through elevation of IFN response gene mRNA expression. 2 Treatments are under study that target these cytokines, such as type I IFN, to potentially mitigate against SLE pathogenesis.
A plethora of cytokines have been implicated in the pathogenesis of SLE, including an excess of interferons (IFNs), B cell activating factor (BAFF), a proliferation inducing ligand, interleukin (IL)-6, IL-12, IL-17, IL-23, tumour necrosis factor, as well as deficiency of IL-2 and IL-10.
1 2 Despite improvements in therapy, substantial unmet medical need exists in SLE. SLE is an autoimmune disease that is characterised by systemic inflammation in multiple organs.