**3. Clinical proof of concept of targeting the IL-23/IL-17 axis for the treatment of plaque psoriasis**

**Table 1** summarizes biologics approved by the US Food and Drug Administration (FDA) for the systemic treatment of plaque psoriasis [45–48]. These biologics specifically target cytokines and the receptors involved in psoriasis pathogenesis. Treatment with biologics results in a greater efficacy and better safety profile compared to conventional systemic agents that do not target specific components of the immune system, and demonstrates the essential role of the IL-23/IL-17 axis in psoriasis [49, 50].

The first-generation anti-psoriatic biologics targeting cytokines focussed on TNF, an inflammatory cytokine implicated in psoriasis pathogenesis for a long time. High levels of TNF and its receptors (TNFR1 and TNFR2) are expressed in psoriatic lesional skin [51]. Four TNF blockers were approved by the FDA for psoriasis treatment (**Table 1**). TNF inhibition showed good therapeutic efficacy. At week 24, about 50 to 80 percent of patients reached 75% improvement in the psoriasis area and severity index (PASI75), and 10 to 20 percent got PASI100, which means 100% improvement [14]. Infliximab is the most efficacious TNF blocker followed by adalimumab and etanercept [50]. The primary mechanism of action of TNF blockers in improvement of psoriasis treatment is most likely due to its indirect effect on IL-23/ IL-17 signaling pathway. The therapeutic effects of TNF blockade are observed to be associated with a strong reduction of IL-17-dependent genes [52]. In addition, TNF induces IL-23 expression in keratinocytes [53]. The exact roles of TNF in the pathogenesis of psoriasis are not yet completely understood.

Nevertheless, TNF is a versatile cytokine that not only involves inflammatory immune responses, but also contributes to cell death, cell cycling and tissue remodeling [54]. TNF blockers are well-known associated risk factors of serious infections,


*Developing Novel Molecular Targeted Therapeutics for Topical Treatment of Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102725*

*TNF = tumor necrosis factor; IL = interleukin; S.C. = subcutaneous; I.V. = intravenous; RA = rheumatoid arthritis; JIA = juvenile idiopathic arthritis; PsA = psoriatic arthritis; AS = ankylosing spondylitis; CD = crohn's disease; UC = ulcerative colitis; HS = hidradenitis suppurativa.*

#### **Table 1.**

*FDA approved biologics for systemic treatment of moderate-to-severe plaque psoriasis.*

such as lower respiratory tract and skin and soft tissue infections like pneumonia and cellulitis [55]. After initial treatment of around 2 weeks, 2% ~ 5% of the patients developed paradoxical psoriasis: new lesions developed or the existing lesions got worse [54]. This side effect also happened when TNF blockers were used to treat other autoimmune diseases, including Crohn's disease and rheumatoid arthritis [53, 56]. It has been reported that IL-17A expression was strong in skin lesions from patients who had paradoxical psoriasis and needed other therapy [57]. This suggests that under some conditions, IL-17 is not down-regulated while blocking TNFα so that skin lesions continue to develop.

After TNF blockers, biologics that directly target the IL-23/IL-17 axis have been developed. The second-generation monoclonal antibody, ustekinumab, is targeting the subunit p40 common to IL-12 and IL-23, blocking signaling of their cognate receptors that induce a nonspecific inhibition of TH1 and TH17 [58, 59]. Ustekinumab has efficacy similar to TNFα inhibitors. It is better than etanercept, but not as good as infliximab. Ustekinumab received FDA approval for the treatment of moderate-tosevere psoriasis in 2009 (**Table 1**).

IL-17 is a central proinflammatory effector cytokine downstream of IL-23 and implicated in the pathogenesis of psoriasis. The third-generation monoclonal antibodies that neutralize IL-17 became available for the treatment of psoriasis (**Table 1**). Secukinumab and ixekizumab are human monoclonal antibodies against IL-17A. Brodalumab is blocking IL-17RA, which is the receptor for IL-17A, IL-17C, IL-17E, IL-17F and IL-17 A/F heterodimers. As IL-17A, IL-17C and IL-17F are all up-regulated in psoriatic skin [31], it is likely that brodalumab would have a better effect. In a study that brodalumab was given to patients who experienced unsuccessful treatment with either secukinumab or ixekizumab, PASI75, PASI90 and PASI100 scores were achieved in 69%, 44% and 28% of patients [60]. In phase III trials, 30–60% of patients treated with IL-17 antagonists reached PASI100 [61–65]. The superior efficacy of IL-17 blockade over neutralizing IL-12/IL23 and blocking TNF has been demonstrated in head-to-head clinical trials of brodalumab versus ustekinumab [62] and ixekizumab versus etanercept [61, 62].

The most common adverse effects of IL-17 antagonists are nasopharyngitis, upper respiratory tract infections, mucocutaneous candidiasis, transient neutropenia and injection site reactions. Mucocutaneous candidiasis observed by IL-17 inhibition or inborn genetic errors of IL-17 gene [66] suggests the innate, protective role of IL-17 against microbial pathogens on the skin. There is a black box warning for brodalumab due to the results from AMAGINE 1 and 2, where four patients committed suicide during the treatment period [64, 65].

IL-23 is known as the master regulator of TH17 cells. A fourth-generation of monoclonal antibodies against p19 subunits of IL-23, guselkumab, tildrakizumab and risankizumab, have been approved for treatment of moderate-to-severe psoriasis (**Table 1**). In contrast to ustekinumab, these biologics target IL-23 by neutralizing the p19 subunit without disrupting the IL-12 signaling pathway. Selectively targeting IL-23p19 provides better efficacy than ustekinumab [50]. IL-23 antagonists can reach a PASI90 in more than 50% of patients, confirming the provital role of IL-23 in the pathogenesis of psoriasis [67–69].

The head-to-head trial of guselkumab versus ustekinumab demonstrates superiority of selectively targeting p19 subunit of IL-23 among patients who had an inadequate response to ustekinumab with similar types of safety profiles [70]. As demonstrated by clinical trial outcomes, double blockade of IL-12 and IL-23 with ustekinumab resulted in lesser disease improvement versus single blockade of IL-23, confirming IL-23, but not IL-12, is a major player in psoriasis.

#### *Developing Novel Molecular Targeted Therapeutics for Topical Treatment of Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102725*

In addition, IL-23p19 antagonists exhibit significantly higher efficacy compared to all tested TNF blockers while maintaining a favorable safety profile [69, 71]. For example, guselkumab was superior (p < 0.001) to adalimumab for PASI90 response at week 48 (76.3% versus 47.9%), respectively. Compared with IL-17 antagonists, guselkumab exhibits a longer duration of therapeutic effect in patients with psoriasis [69]. This is probably because IL-23 is a key driver of TH17 cell differentiation and survival, and an upstream regulator of IL-17A. IL-17 producing cells are dependent on IL-23 for survival. IL-23 stimulates production of not only IL-17, but also other TH17 cytokines (for example, IL-22) by other immune cell types, including γδ T cells.

The most common adverse events with the use of guselkumab and tildrakizumab are nasopharyngitis, upper respiratory tract infections, and headaches [67–69]. In contrast to IL-17 antagonists, the rate of mucocutaneous candidiasis was infrequent and comparable to healthy control subjects.

In conclusion, clinical outcomes of these biologics targeting IL-23p19 and IL17 are a strong argument for the IL-23/IL-17 axis in driving disease pathology. These molecular targeted therapies not only remarkably alleviate symptoms but also provide a deep understanding of the molecular mechanism of psoriatic disease.
