**4.1 Calcineurin Inhibitors**

These agents inhibit the activity of calcineurin phosphatase, an enzyme important for the translocation of the pluripotent transcription factor, nuclear factor of activated T cell, from the cytoplasm to the nucleus where it activates a number of proinflammatory cytokines associated with T-cell activation. Hence, these agents have potential for treatment of skin diseases mediated by calcineurin phosphatase (Luger & Paul 2007). Currently these calcineurin inhibitors are approved for use in mild to moderate atopic dermatitis only, any use in psoriasis is off-label, and therefore not within approved US-FDA prescribing information. A black box warning has been added to the labels of these medications stating that the long-term safety of topical calcineurin inhibitors has not been established and that rare cases of cancer have been reported in patients who used the medications, although a causal relationship in human beings has not been established. Apart from topical tacrolimus and pimecrolimus, another new oral calcineurin inhibitor, voclosporin is also in clinical development for treatment of plaque psoriasis (Papp & Carey 2010).

#### **4.1.1 Tacrolimus**

Tacrolimus is an immunosuppressive drug whose main use is after allogenic organ transplant to reduce the activity of the patient's immune system and hence reduce the risk of organ rejection. It is also used in a topical ointment preparation (Protopic) for the treatment of severe atopic dermatitis, vitiligo and psoriasis. Tacrolimus ointment was approved in the United States in 2000, and Europe in 2001 for atopic dermatitis. However, new research has proven the potential use of tacrolimus in psoriasis (Luger & Paul 2007; Beck 2005). The introduction of tacrolimus ointment marked the advent of a new, nonsteroidal drug class, topical immunomodulators, for the management of inflammatory dermatoses.

Tacrolimus ointment seems most effective in treating psoriasis where the skin is thin, that is on the face, genitelia and intertriginous areas (Martín Ezquerra et al. 2006). In one study 21 patients with facial psoriasis lesions applied tacrolimus (0.1%) ointment twice a day for 4 weeks without occlusion. A complete or good response was obtained in majority of the patients (Yamamoto & Nishioka 2003).

The efficacy and tolerability of tacrolimus ointment has also been investigated for the treatment of male genital psoriasis (Bissonnette et al., 2008). In an open-label study in 12 adult male patients with genital psoriasis, patients received topical tacrolimus 0.1% ointment twice daily for 8 weeks followed by a 4-week observational period. Psoriasis severity also improved significantly for the glans, shaft of the penis, and scrotum. The ointment was very well tolerated, with only mild pruritus or burning sensation of limited duration reported (Bissonnette et al., 2008).

The safety and efficacy of tacrolimus (0.1 %) ointment for the treatment of psoriasis on the face, intertriginous areas, or both were evaluated in an open-label, clinical trial of 21 patients with psoriasis (Freeman et al., 2003). A total of 81 percent of patients experienced complete

Topical Therapies for Psoriasis 321

weeks) in 30 patients with plaque psoriasis (Nazarian & Weinberg 2009). Preliminary data revealed that psoriatic plaques treated with AN-2728 exhibited a reduced overall target plaque severity score compared with plaques treated with vehicle alone at 8 weeks of treatment. In addition, AN-2728 topical therapy has also been reported to be well tolerated. In the phase IIA trial, no treatment-related adverse events or laboratory anomalies were reported; one patient reported mild gingivitis and diarrhea, but these effects were not

The JAK family is composed of four tyrosine kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) (Fridman et al., 2011). Members of the JAK family are essential for signaling by many cytokines and growth factors following their binding to specific receptors on the cell surface. The interaction activates one or more JAKs, JAKs in turn activate the signal transducer and activator of transcription (STAT) proteins that transmit the growth and activation signals to the nucleus. JAK signaling is involved in a number of biologic processes, including the formation and development of blood cells and the regulation of immune function. Hyperactivation of JAKs has been associated with a number of disease states, including chronic myeloproliferative disorders and inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis (Fridman et al., 2001). As a result, JAK inhibitors are currently in clinical development for treatment of psoriasis both topically (INCB18424 from

A 28-day phase Ib/IIa dose escalation trial of topical INCB18424 in patients with mild-tomoderate psoriasis demonstrated rapid onset of action, reduction in total lesion area, and

The commonly used topical medications described in this chapter provide efficacy through varying and divergent pathways. As these agents act through different mechanisms, there is a scientific rationale for their use in combination therapy. The rationale assumes that agents are selected on the basis of their individual mechanisms of action, which may offer the possibility of additive or synergistic efficacy, reduction in the dose of either or both products, and reduction in the occurrence of side effects (Norris 2005). Several studies have proven the advantages of using a combination of topical medications for treatment of psoriasis. Recently, a fixed dose combination ointment containing 50 μg/g calcipotriol and 0.5 mg/g betamethasone dipropionate (approved in US as Taclonex®) was found to be effective against psoriasis vulgaris (Claréus et al., 2009). This ointment formulation combines the keratinocyte differentiation and antiproliferative action of the vitamin D3 analogues (calcipotriol) with the anti-inflammatory effect of steroids (betamethasone dipropionate), thus enhancing effectiveness while reducing the side-effect profile of the individual agents (Saraceno et al., 2009). It was found that the combination product had a more rapid onset of action (Papp et al., 2003) than calcipotriol or betamethasone alone and was more effective (Douglas et al., 2002) than calcipotriol or betamethasone alone. In a clinical trial with 1605 randomized patients aged 18 years or older showed that the combination product (Taclonex®) was significantly more effective than betamethasone,

considered to be related to the trial medication (Nazarian & Weinberg 2009).

**4.3 Janus-Associated Kinase (JAK) inhibitors** 

Incyte Corporation) and orally (Tofacitinib from Pfizer).

**5. Combination topical therapies** 

improvement in lesion thickness, erythema, and scaling (Mesa 2010).

clearance at day 57 (end of treatment). Only 2 patients reported adverse events, which were limited to itching and the feeling of warmth at the application site (Freeman et al., 2003).

#### **4.1.2 Pimecrolimus**

Pimecrolimus is a non-steroidal immunosuppressant derived from ascomycin. Pimecrolimus 1% cream (Elidel) was approved in the United States, the European Union, and Japan as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in patients, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable (Fabroni & Wollina 2009). Pimecrolimus also has an enormous potential as topical treatment for numerous inflammatory skin diseases like psoriasis and dermatitis (Fabroni & Wollina 2009).

Pimecrolimus is not effective in plaque-type psoriasis when used as the commercially available formulation without occlusion (Wollina et al., 2006). However, pimecrolimus has been shown to be effective in intertriginous psoriasis (Wollina et al., 2006). A double-blind, randomised, vehicle-controlled study was performed in 57 patients aged 18 years or older with moderate-to-severe intertriginous psoriasis. By week 8 of treatment, 82% of patients using pimecrolimus scored their disease as being equally well, or completely controlled, compared with 41% of the vehicle group. The pimecrolimus treatment was also well tolerated (Gribetz et al., 2004).

#### **4.2 Phosphodiesterase 4 (PDE4) Inhibitors**

PDE4 is the predominant cyclic AMP degrading enzyme, present in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Due to the broad anti-inflammatory and immuno-modulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as psoriasis and atopic dermatitis (Bäumer et al., 2007). These PDE4 inhibitors displayed strong anti-inflammatory action in models of allergic contact dermatitis in mice, in the arachidonic acid induced skin inflammation in mice and in ovalbumin sensitized guinea pigs. The determination of cytokines in skin homogenates revealed that both Th1 as well as Th2 cytokines are suppressed by PDE4 inhibitors, indicating an antiinflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of atopic dermatitis. Due to the suppression of Th1 cytokines, activity can also be expected in psoriasis (Bäumer et al., 2007). Consequently PDE4 inhibitors are currently in clinical development for treatment of psoriasis both topically (AN-2728 from Anacor Pharmaceuticals) and orally (CC-10004 from Celgene Corporation).

#### **4.2.1 AN-2728**

A recent publication gives a comprehensive summary of preclinical, phase I and phase II data for topical AN-2728 (Nazarian & Weinberg 2009). Till date 3 phase IB, 1 Phase IIA and 1 phase IIB trials have been completed for AN-2728, and results suggest that AN-2728 is well tolerated with significantly better efficacy in plaque psoriasis as compared to placebo controls. A phase IIB, randomized, double-blind, placebo-controlled, parallel-assignment, single-center, safety and efficacy clinical trial assessed AN-2728 ointment (5% bid for 12

clearance at day 57 (end of treatment). Only 2 patients reported adverse events, which were limited to itching and the feeling of warmth at the application site (Freeman et al., 2003).

Pimecrolimus is a non-steroidal immunosuppressant derived from ascomycin. Pimecrolimus 1% cream (Elidel) was approved in the United States, the European Union, and Japan as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in patients, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable (Fabroni & Wollina 2009). Pimecrolimus also has an enormous potential as topical treatment for numerous inflammatory

Pimecrolimus is not effective in plaque-type psoriasis when used as the commercially available formulation without occlusion (Wollina et al., 2006). However, pimecrolimus has been shown to be effective in intertriginous psoriasis (Wollina et al., 2006). A double-blind, randomised, vehicle-controlled study was performed in 57 patients aged 18 years or older with moderate-to-severe intertriginous psoriasis. By week 8 of treatment, 82% of patients using pimecrolimus scored their disease as being equally well, or completely controlled, compared with 41% of the vehicle group. The pimecrolimus treatment was also well

PDE4 is the predominant cyclic AMP degrading enzyme, present in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Due to the broad anti-inflammatory and immuno-modulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as psoriasis and atopic dermatitis (Bäumer et al., 2007). These PDE4 inhibitors displayed strong anti-inflammatory action in models of allergic contact dermatitis in mice, in the arachidonic acid induced skin inflammation in mice and in ovalbumin sensitized guinea pigs. The determination of cytokines in skin homogenates revealed that both Th1 as well as Th2 cytokines are suppressed by PDE4 inhibitors, indicating an antiinflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of atopic dermatitis. Due to the suppression of Th1 cytokines, activity can also be expected in psoriasis (Bäumer et al., 2007). Consequently PDE4 inhibitors are currently in clinical development for treatment of psoriasis both topically (AN-2728 from Anacor

A recent publication gives a comprehensive summary of preclinical, phase I and phase II data for topical AN-2728 (Nazarian & Weinberg 2009). Till date 3 phase IB, 1 Phase IIA and 1 phase IIB trials have been completed for AN-2728, and results suggest that AN-2728 is well tolerated with significantly better efficacy in plaque psoriasis as compared to placebo controls. A phase IIB, randomized, double-blind, placebo-controlled, parallel-assignment, single-center, safety and efficacy clinical trial assessed AN-2728 ointment (5% bid for 12

skin diseases like psoriasis and dermatitis (Fabroni & Wollina 2009).

Pharmaceuticals) and orally (CC-10004 from Celgene Corporation).

**4.1.2 Pimecrolimus** 

tolerated (Gribetz et al., 2004).

**4.2.1 AN-2728** 

**4.2 Phosphodiesterase 4 (PDE4) Inhibitors** 

weeks) in 30 patients with plaque psoriasis (Nazarian & Weinberg 2009). Preliminary data revealed that psoriatic plaques treated with AN-2728 exhibited a reduced overall target plaque severity score compared with plaques treated with vehicle alone at 8 weeks of treatment. In addition, AN-2728 topical therapy has also been reported to be well tolerated. In the phase IIA trial, no treatment-related adverse events or laboratory anomalies were reported; one patient reported mild gingivitis and diarrhea, but these effects were not considered to be related to the trial medication (Nazarian & Weinberg 2009).
