New Interleukin-23 Pathway Inhibitors in Dermatology

Abstract

Interleukin (IL)-23 is an important regulator of T helper-17 lymphocytes, which influence the cutaneous immune system by production of IL-17 and several other proinflammatory cytokines. This pathway has been recently linked to the pathogenesis of psoriasis and numerous other skin diseases. A newly developed biologic drug, ustekinumab (CNTO-1275), which targets the p40 subunit of IL-12 and IL-23, was approved by the US FDA and the European Medicines Agency in 2009 for the treatment of moderate to severe psoriasis. Administered as subcutaneous injections of 45 mg at weeks 0 and 4, and then every 12 weeks, ustekinumab produces a 75% improvement in the Psoriasis Area and Severity Index (PASI) in 66.4-75.7% of patients and a Dermatology Life Quality Index (DLQI) score of 0 or 1 in 55-56% of patients after 12 weeks of therapy. A recent clinical trial also indicates the possible efficacy of ustekinumab in psoriatic arthritis. The proportion of patients who had at least one adverse event through 12 weeks in clinical studies was 51.6-57.6% in the ustekinumab group and 50.4% in the placebo group. Serious adverse events were observed in 1.4-1.6% of patients treated with ustekinumab and in 1.4% of patients receiving placebo. Injection-site reactions occurred in 1-2% of patients and 5% of patients developed anti-ustekinumab antibodies. Further studies are needed to evaluate the long-term efficacy and safety of ustekinumab. Another biologic drug that targets the same molecules, briakinumab (ABT-874), has recently had its approval application withdrawn in the US and Europe to conduct further analysis and clinical trials. The company plans resubmission at a later date. Other IL-23 pathway inhibitors in the pipeline include anti-p19 monoclonal antibody and apilimod (STA-5326), which interfere with IL-23 activity, as well as secukinumab (AIN-457), LY-2439821, and AMG-827, which exhibit their activity at other targets of the IL-23 pathway.