Emerging Therapies for the Treatment of Psoriasis

Mahir Patel 0 1 2 Antoinette Day 0 1 2 Richard B. Warren 0 1 2 Alan Menter 0 1 2 0 R. B. Warren The Dermatology Centre, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, The University of Manchester , Manchester M6 8HD, UK 1 A. Day College of Medicine, Texas A&M Health Science Center , 8447 State Hwy 47, Bryan, TX 77807, USA 2 M. Patel (&) A. Menter Baylor Research Institute, Baylor University Medical Center , 3900 Junius Street Suite 125, Dallas, TX 75246, USA Psoriasis is an immune-mediated disease that affects 1%-2% of the European and North American population. While topical agents such as corticosteroids and vitamin D derivatives are prescribed for mild disease, they are generally unable to adequately control patients with more severe disease. Over the past decade, research into the immunopathogenesis of psoriasis, including investigations into the role of tumor necrosis factor-alpha and more recently interleukins (IL) 12/23, has led to the advent of targeted biologic therapies based on the central role of a new subset of T cells, Th17. Because of their increased specificity, biologic agents have revolutionized short- to medium-term treatment outcomes and safety profiles for moderate to severe disease over previously gold standard systemic agents. The immunopathogenesis of the disease is still a focus for researchers and novel targets for future agents are being discovered and investigated in clinical trials. In particular, specifically targeting the IL-23/Th17 pathway has given rise to IL23p19 and IL-17 antagonists, both of which have shown significant promise in clinical trials. IL-22 is involved in keratinocyte proliferation and is being studied as a treatment target for psoriasis. New small molecule oral agents, including Janus kinase and phosphodiesterase inhibitors are currently in phase 2 and 3 clinical trials. INTRODUCTION Psoriasis is an inflammatory disease that affects 12% of the European and North American populations [1]. It typically presents with erythematous, scaly, raised, well-demarcated lesions on the scalp, trunk, and extensor surfaces; however, any body site can be involved. Up to 30% of patients suffer from an associated arthritis, known as psoriatic arthritis [2], and patients with more extensive disease have diminished quality of life because of their skin and joint disease [3]. Furthermore, there are genetic links with conditions such as Crohns disease as well as associations with obesity, type 2 diabetes, and cardiovascular mortality. Current work is attempting to establish if psoriasis is a specific risk factor per se for these conditions or if factors such as increased smoking and alcohol use in patients with psoriasis accounts for such associations [4, 5]. Typically, topical agents are first-line therapy for patients with mild psoriasis but generally ineffective for patients with more severe disease where a range of therapies, including phototherapy, systemic, and/or biological agents are often used. Current gold standard biologic therapies targeting anti-tumor necrosis factor (TNF) alpha and anti-interleukin-12p40 (anti-IL-12p40) have dramatically improved clinical outcomes in patients with psoriasis with improved short-term safety profiles (i.e., less organ specific toxicity) compared to widely used systemic agents. Despite this improvement, there are subpopulations of patients that are either nonresponders to currently available biological agents and/or have experienced diminishing therapeutic benefit over time [6, 7]. Moreover, current biologic agents still have the potential to cause significant side effects in a subset of patients with their longer-term safety yet to be fully evaluated [8]. Therefore, researchers continue to try and further elucidate the immunopathogenesis of psoriasis in an attempt to develop new therapeutic agents, including newer oral agents, a method of administration preferred by some patients. The purpose of this article is to review new therapeutic avenues, including anti-IL23, IL-17, and IL-22 antagonists and oral agents, including Janus kinase (JAK) and phosphodiesterase 4 (PDE4) inhibitors. A search for phase 13 clinical trials for treatment of moderate to severe chronic plaque psoriasis using agents targeting IL-23, IL-17, and IL-22 antagonists and oral agents, including JAK and PDE4 inhibitors, was performed in a nonsystematic fashion. Eligible participants with moderate to severe chronic plaque psoriasis typically include patients with C10% Body Surface Area (BSA), C12 Psoriasis Area and Severity Index (PASI) and are candidates for phototherapy and/or systemic therapy. Patients with non-plaque forms of psoriasis were excluded. TUMOR NECROSIS FACTOR ALPHA INHIBITORS The TNF-alpha pathway is an established target for psoriasis and psoriatic arthritis therapies, with current licensed anti-TNF medications including infliximab, adalimumab, and etanercept. Anti-TNF agents have been used to treat over 2 million patients with immunemediated diseases for extended durations. Thus its use in psoriasis has been well studied and new agents are still being developed. Certolizumab-pegol is a fragment antigen binding segment of an anti-TNF antibody and pegylated to allow for a longer half-life. In phase 2 clinical trials for the treatment of psoriasis, patients randomized to 400 mg every other week and 200 mg every other week showed PASI 75 response in 82.8% and 74.6% of patients respectively [9]. Golimumab, a newer anti-TNF therapy, with a license for psoriatic arthritis, does show efficacy in the treatment of psoriasis. Phase 3 data demonstrated PASI 75 response in patients receiving 50 or 100 mg of golimumab every 4 weeks. PASI 75 response in 50 and 100 mg were seen in 40% and 58% respectively compared to 3% in placebo at week 14 and 56% and 66% respectively, compared to 1% of placebo group seen at week 24 [10]. ART621, a low molecular weight anti-TNF agent, consists of two identical antibodies and is believed to have improved tissue penetration. In a phase 2 study for treatment in plaque psoriasis, four subjects showed a PASI 50 response in a 12-week treatment period compared to zero in the placebo arm [11]. INTERLEUKINS 12 AND 23 IL-23 is a heterodimer consisting of a p19 and a p40 subunit. IL-23 regulates Th17 CD4 cells, which produce IL-17, a proinflammatory cytokine [12]. IL-12 is a heterodimer containing a p35 and p40 subunit. Production of IL-12 by phagocytes and dendritic cells links innate and adaptive immunity and activates signal transducer and activator of transcription 4 (STAT4), which increases the production of interferon gamma [1]. Studies have shown that in psoriatic lesions there is an overexpression of both IL-12 and IL-23. Many of these studies, however, used the presence of the shared p40 subunit to measure the expression of IL-12 and thus were unable to differentiate between the presence of IL-12 and IL-23 [1316]. Ustekinumab is a human immunoglobul (...truncated)