**4.2 JAK inhibitors**

The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway plays a crucial role in intracellular signaling of cytokine of many cellular processes, important in both normal and pathological states of immune-mediated inflammatory diseases [88]. There are four different types of JAK proteins: JAK1, JAK2, JAK3 and TYK2. The IL-23 receptor relies on a heterodimer of JAK2 and TYK2 for signal transduction, thus highlighting the role of JAKs in the pathogenesis of psoriasis and the therapeutic potential of JAK inhibitors in psoriasis. TYK2-deficient mice, as compared to wild-type mice, exhibit significantly reduced ear swelling and less epidermal hyperplasia when injected with IL-23 [89, 90]. In the absence of TYK2, the production of IL-17 and IL-22 and skin infiltration of various immune cells were also impaired. Taken together with the clinical success of biologics blocking either IL-23 or IL-17 signaling (**Table 1**), these results suggest the great potential for JAK inhibitors and, especially, for TYK2 inhibitors in the treatment of psoriasis.

JAK inhibitors are already on the market for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis [24]. JAK inhibitors have been tested as potential treatments for psoriasis. The first generation of JAK inhibitors target multiple members of the JAK family and thus display a broader effect but also present more side effects. Many JAK inhibitors tested for oral treatment of psoriasis have only been examined in phase II trials except tofacitinib (reached phase III). It is doubtful that they will be tested further. In recent years, selective TYK2 inhibitors have been developed, and several phase III trials are in progress. The highly selective TYK2 inhibitor BMS-986165 has shown high efficacy toward psoriasis, confirming the important role of the IL-23/ IL-17 axis in pathogenesis of psoriasis [91]. Several JAK inhibitors with different selectivity spectrums are under clinical development for the topical treatment of psoriasis (**Table 2**).

Tofacitinib (pan-JAK inhibitor) has been approved for the treatment of psoriatic arthritis, but not of psoriasis. Oral tofacitinib has been tested in phase III for psoriasis. Although tofacitinib shows a favorable clinical effect on plaque psoriasis symptoms, herpes zoster occurs during tofacitinib treatment, especially in Asian populations including the Japanese [48]. In phase 2b trial, the ointment formulation of tofacitinib was found to have no considerable effect at week 12 in comparison to that of the vehicle [92].

Ruxolitinib is a selective JAK1 and JAK2 inhibitor that inhibits various cytokines involved in the signaling of TH1 and TH17 pathways, including IL-12, IL-23 and IFNγ, which are associated with psoriasis. Its cream formulation has been approved by FDA for the treatment of atopic dermatitis, but not of psoriasis [93]. In phase II studies, ruxolitinib was studied as a topical ointment for mild-to-moderate psoriasis (**Table 2**). In an open phase 2 study conducted with 28 patients, a greater reduction in lesion severity score was observed for topical ruxolitinib as compared with vehicle and with calcipotriene [94]. The systemic absorption of the product was minimal. In a subsequent phase IIb, double-blind, randomed, vehicle-controlled study, 200 patients with mild-to-moderate chronic plaque psoriasis were treated with topical ruxolitinib for 3 months and the results *Developing Novel Molecular Targeted Therapeutics for Topical Treatment of Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102725*

indicated the mean PASI improvement was 40% compared with placebo [95]. Both studies reported the main adverse event was local irritation, which was more frequent in patients treated with placebo. To date, no phase III study of ruxolitinib in psoriasis has begun yet.

PF-06700841 is a potent dual inhibitor of TYK2 and JAK1, which was shown to be safe and well tolerated in the oral treatment at doses up to 200 mg once daily in a phase I clinical trial [96]. No other clinical trials with oral PF-06700841 in psoriasis are now ongoing. A phase IIb study of topical application of PF-06700841 cream involving patients with mild-to-moderate psoriasis (NCT03850483) was recently completed (April 20, 2021). The trial results are not yet available.

#### **4.3 DNMT inhibitors**

DUR-928 is an endogenous sulfated oxysterol that acts as an epigenetic regulator [97]. It binds to and inhibits the activity of DNMTs, DNMT-1, 3a and 3b, inhibiting DNA methylation, and thereby modulating the expression of the genes associated with stress response, lipid biosynthesis and cell death. Improvement of cell survival and reduction of lipotoxicity and inflammation by DUR-928 were observed in animal models and from DURECT's clinical trials in alcohol-associated hepatitis (AH) and nonalcoholic steatohepatitis (NASH). The rationale of topical application of DUR-928 in psoriasis is not clear. A phase IIb study of topical application of DUR-928 topical solution in patients with mild-to-moderate psoriasis (NCT03837743) was completed on August 20, 2020 (**Table 2**). The trial results are not yet disclosed.

#### **4.4 PDE4 inhibitors**

The oral phosphodiesterase-4 (PDE4) inhibitor apremilast was approved for the treatment of moderate to severe plaque psoriasis [98]. However, apremilast has only modest efficacy with PASI75 rates clearly lower than biologics. Inhibition of PDE4 indirectly down regulates immune modulators, including TNFα, IFNγ, IL-17 and IL-23 [99]. Due to the potential adverse events associated with oral administration, the topical PDE4 inhibitors, crisaborole and roflumilast, are being investigated as an alternative treatment of psoriasis aiming to avoid systemic adverse effects (**Table 2**).

AN-2728 (crisaborole) ointment has been approved for the treatment of atopic dermatitis [100]. AN-2728 is a newer generation of PDE4 inhibitors [101]. Its binding mode to the catalytic site of PDE4 is distinct from traditional PDE4 inhibitors and can reduce pro-inflammatory cytokines TNFα, IL-2, IFNγ, and IL-5. In phase 2 studies to treat mild-to-moderate plaque-type psoriasis, AN-2728 ointment showed modest efficacy (40% of patients achieved a ≥ 2 grade improvement as assessed by the overall target Plaque Severity Score) [102]. Most adverse effects were mild to moderate.

The oral PDE4 inhibitor roflumilast has been approved by FDA for the treatment of chronic obstructive pulmonary disease (COPD) exacerbation since 2011 [103]. The topical roflumilast, in a high-water-content moisturizing cream base vehicle containing the cosmetic solvent ethoxydiglycol, is being investigated for the treatment of plaque psoriasis [104]. Its inhibitor affinity (IC50 values) is 25 to 300 folds more potent than either apremilast or crisaborole depending on PDE4 isoform analyzed [105]. In the phase 2b trial, approximately 85% of the enrolled patients had moderateto-severe psoriasis and a generally similar percentage of patients in the roflumilast 0.3% group (31%) met the criterion for the PASI75 response at week 8 although differences in trial design do not allow to make direct comparisons [104, 105].

Oral apremilast has been associated with gastrointestinal adverse events of diarrhea and nausea, whereas topical roflumilast cream was associated with less than 1% of each of these events in this phase 2b trial. This may be a result of topical administration bypassing the gastrointestinal tract. Longer and larger trials are in progress to determine the durability and safety of roflumilast in psoriasis (**Table 2**).
