New and emerging biologic therapies for moderate-to-severe plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors

Abstract

The development of effective and well-tolerated biologic therapies has advanced the management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological basis of psoriasis has led to the development of biologic agents targeting specific downstream mediators in the psoriatic cascade. These drugs inhibit cytokines and cytokine signaling/transcription mediators like interleukin-17, which plays an important role in immunopathogenesis. Several interleukin-17 inhibitors are undergoing phase 3 clinical studies. In addition, biologics that selectively inhibit interleukin-23 have been assessed in phase 2 studies. This review describes how the dissection of pathways in the immunopathogenesis of psoriasis has led to the development of therapeutic agents and highlights the latest clinical efficacy, safety and tolerability data on new and emerging biologic therapies that selectively target interleukin-17 or interleukin-23.

Keywords: biologic; interleukin-17; interleukin-23; psoriasis.

FIG. 1

Immunopathogenesis of psoriasis and sites of action of biologics. It is proposed that an initial trigger (e.g., injury, infection, stress, etc.) precipitates a cascade of events that starts with the activation of innate immune cells (plasmacytoid dendritic cells, natural killer cells, and keratinocytes). These activated cells secrete cytokines (e.g., interferon [IFN] α, tumor necrosis factor [TNF] α, interleukin [IL]-1β, and IL-6), which in turn activate myeloid dendritic cells (DC). DC are central to the immune system, providing a link between innate and adaptive responses. The activated myeloid DC enter the draining lymph nodes, causing naive T cells (T-naive) to differentiate into helper type 17 (TH17) and type 1 (TH1) cells via the presentation of antigens and secretion of IL-12 and IL-23. These effector T cells then migrate into skin tissue, where they secrete mediators (eg, IL-17A, IL-17F, and IL-22 from TH17/cytotoxic T17 [TC17] cells, and IFNγ and TNFα from TH1/cytotoxic T1 [TC1] cells) that stimulate keratinocyte activation and proliferation, leading to plaque formation (12,13,20). Activated keratinocytes produce antimicrobial peptides, proinflammatory cytokines (IL-1β, TNF, and IL-6), and various chemokines that feedback into the proinflammatory cycle. This feedback loop, as well as others involving fibroblasts and endothelial cells, results in the continued immunopathologic progression of psoriasis.

FIG. 2

Targeting the interleukin (IL)-17 signaling pathway. IL-17RC and IL-17RA are subunits of the IL-17 receptor, which is present on various cell types including keratinocytes, dendritic cells, dermal fibroblasts, and endothelial cells. Secukinumab, a fully human immunoglobulin (Ig)G1κ monoclonal antibody, and ixekizumab, a humanized IgG4 monoclonal antibody, target the cytokine IL-17A. These agents prevent inflammatory-mediated effects by neutralizing IL-17 and therefore inhibit the binding of IL-17A to its receptor. Brodalumab is a human IgG2 monoclonal antibody that binds to IL-17RA, thereby blocking signaling of IL-17 via its receptor. Another agent, RG7624, is a fully human IgG1 monoclonal antibody against both IL-17A and IL-17F. All four agents are in clinical development for the treatment of psoriasis, with secukinumab and ixekizumab being the furthest along (–42). Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Drug Discov 12: 815–816, © 2013.