Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.

BACKGROUND Type 17 helper T cells have been suggested to play a pathological role in psoriasis. They secrete several proinflammatory cytokines, including interleukin-17A (also known as interleukin-17). We evaluated the safety and efficacy of ixekizumab (LY2439821), a humanized anti-interleukin-17 monoclonal antibody, for psoriasis treatment. METHODS In our phase 2, double-blind, placebo-controlled trial, we randomly assigned 142 patients with chronic moderate-to-severe plaque psoriasis to receive subcutaneous injections of 10, 25, 75, or 150 mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks. The primary end point was the proportion of patients with reduction in the psoriasis area-and-severity index (PASI) score by at least 75% at 12 weeks. Secondary end points included the proportion of patients with reduction in the PASI score by at least 90% or by 100%. RESULTS At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose)--150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%)--than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed. CONCLUSIONS Use of a humanized anti-interleukin-17 monoclonal antibody, ixekizumab, improved the clinical symptoms of psoriasis. Further studies are needed to establish its long-term safety and efficacy in patients with psoriasis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT01107457.).

[1]  S. Tyring,et al.  A calcipotriene/betamethasone dipropionate two‐compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8‐week, double‐blind phase of a clinical trial , 2010, International journal of dermatology.

[2]  M. Lotze,et al.  Interleukin-17 promotes angiogenesis and tumor growth. , 2003, Blood.

[3]  J. Lötvall,et al.  Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. , 1999, Journal of immunology.

[4]  Jia-wen Li,et al.  Expression of Th17 cytokines in skin lesions of patients with psoriasis , 2007, Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban.

[5]  P. C. van de Kerkhof,et al.  Psoriasis of the scalp. Diagnosis and management. , 2001, American journal of clinical dermatology.

[6]  A. Finlay,et al.  Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use , 1994, Clinical and experimental dermatology.

[7]  F. Nestle,et al.  Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial , 2005, The Lancet.

[8]  K. Kikly,et al.  The IL-23/Th17 axis: therapeutic targets for autoimmune inflammation [Current Opinion in Immunology 2006, 18:670–675] , 2007 .

[9]  M. Lebwohl,et al.  Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2) , 2008, The Lancet.

[10]  S. Chimenti,et al.  Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. , 2011, The Journal of investigative dermatology.

[11]  C. Caux,et al.  Up-Regulation of Macrophage Inflammatory Protein-3α/CCL20 and CC Chemokine Receptor 6 in Psoriasis1 , 2000, The Journal of Immunology.

[12]  Sarah L. Gaffen,et al.  Functional Cooperation between Interleukin-17 and Tumor Necrosis Factor-α Is Mediated by CCAAT/Enhancer-binding Protein Family Members* , 2004, Journal of Biological Chemistry.

[13]  Erin G Harper,et al.  Pathophysiology of psoriasis: Recent advances on IL-23 and Th17 cytokines , 2007, Current rheumatology reports.

[14]  P. Tak,et al.  Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis , 2010, Science Translational Medicine.

[15]  A. H. Dinsmore,et al.  New England , 1894, Letters from America.

[16]  P. Kerkhof,et al.  Psoriasis of the Scalp , 2001 .

[17]  A. Katsambas,et al.  Treatment of nail psoriasis with adalimumab: an open label unblinded study , 2010, Journal of the European Academy of Dermatology and Venereology : JEADV.

[18]  C. Albanesi,et al.  Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. , 2000, The Journal of investigative dermatology.

[19]  Kathleen M. Smith,et al.  IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2–dependent mechanisms with implications for psoriasis pathogenesis , 2006, The Journal of experimental medicine.

[20]  R. Hromas,et al.  Cutting Edge: IL-17D, a Novel Member of the IL-17 Family, Stimulates Cytokine Production and Inhibits Hemopoiesis1 , 2002, The Journal of Immunology.

[21]  J. Gelfand,et al.  The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. , 2009, Journal of the American Academy of Dermatology.

[22]  A. Gottlieb,et al.  Etanercept as monotherapy in patients with psoriasis. , 2003, The New England journal of medicine.

[23]  T Fredriksson,et al.  Severe psoriasis--oral therapy with a new retinoid. , 1978, Dermatologica.

[24]  A. Kimball,et al.  Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1) , 2008, The Lancet.

[25]  J. Ortonne,et al.  Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. , 2012, The New England journal of medicine.

[26]  O. Arican,et al.  Serum Levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in Patients With Active Psoriasis and Correlation With Disease Severity , 2005, Mediators of inflammation.

[27]  A. Lindén,et al.  Interleukin-17 family members and inflammation. , 2004, Immunity.