Review
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
New topical treatments for psoriasis Andrea Chiricozzi, Rossella Pitocco, Rosita Saraceno, Steven Paul Nistico, Alessandro Giunta & Sergio Chimenti†
1.
Introduction
2.
Emerging vitamin D3 derivates
3.
Combined therapies
4.
New steroidal agents
5.
Blockade of neurogenic
†
inflammation 6.
Phosphodiesterase inhibitors
7.
Janus-associated kinase inhibitors
8.
Other non-steroidal anti-inflammatory agents
9.
Topical calcineurin inhibitors
10.
Anti-proliferative agents
11.
New coal tar formulations
12.
Conclusion
13.
Expert opinion
University of Rome Tor Vergata, Department of Dermatology, Rome, Italy
Introduction: Psoriasis is a common immune-mediated disorder that in 70% of cases appears in mild or mild-to-moderate form. Psoriasis is usually treated with topical medications and/or phototherapy with variable efficacy in controlling the disease. Areas covered: For the past three decades, research has been focused on systemic agents for the treatment of moderate-to-severe psoriasis, particularly with the introduction of biologic agents or ‘small molecules’. In parallel, novel advances in topical antipsoriatic agents have been made, experiencing a ‘new era’, with the development of new formulations and the identification of new therapeutic targets. These agents, having a different spectrum of action from traditional agents, are actually being tested in pre-marketing clinical trials and they may potentially represent promising treatment options that could enlarge the therapeutic armamentarium for the treatment of psoriasis. Expert opinion: Future antipsoriatic topical agents show new modality of action in blocking the pathogenic process leading to psoriatic plaque formation. Keywords: E6201, pazopanib, psoriasis, tofacitinib, topical therapy, WBI-1001 Expert Opin. Pharmacother. (2014) 15(4):461-470
1.
Introduction
Psoriasis is a chronic inflammatory skin disease that affects approximately 2 -- 3% of the Caucasian population [1]. The most common form, called ‘plaque-type psoriasis,’ is characterized by the presence of red and scaly plaques, usually localized at the scalp, elbows, knees and buttock. Lesional psoriatic skin histologically reflects marked thickening of the epidermis, cutaneous infiltration of inflammatory cells and an increase in the number of dilated blood vessels in the upper dermis [2]. Epidermal acanthosis is determined by keratinocyte proliferation associated with an altered keratinocyte differentiation process, as the maturation of keratinocytes from the basal to the conrinifed layer, which typically lasts 28 days, is shortened to 5 days [3], and an evident reduction of the granular layer occurs with an aberrant terminal differentiation of keratinocytes, which is mainly reflected by parakeratosis. Initially it was believed that the pathogenic mechanism primarily involved keratinocytes, but different observations fostered the hypothesis about the contribution of immune cells in the pathogenesis of psoriasis [4]. These studies proved that T cells played a crucial role in the pathogenesis of the disease, especially Th1 cells and Th17 cells, two CD4+ T lineages mainly producing IFN-g and IL-17, respectively, which have been found markedly upregulated in lesional psoriatic skin. Recent models of psoriasis addressed the Th17 pathway as the main pathogenic axis involved in psoriasis pathogenesis [5,6]. Conventional topical or systemic treatments behave as anti-proliferative agents or unspecific immunomodulants that broadly suppress the inflammatory response characterizing the psoriatic plaque formation. Their efficacy is variable and, especially with systemic therapeutics, the occurrence of organ-specific toxicity may be 10.1517/14656566.2014.875159 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
461
A. Chiricozzi et al.
Article highlights. . . . .
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
.
A wide array of new topical therapies is now tested in clinical trials. Some new topical agents selectively target pathogenic mediators. Nanotechnology or new vehicles will probably increase efficacy and patients’ adherence to treatment. New formulations, cosmetically more appealing, will be available. These agents will beneficially enlarge the therapeutic armamentarium for the treatment of mild or mild-to-moderate psoriasis.
This box summarizes key points contained in the article.
observed. Conversely, systemic biologic agents, similarly to new topical drugs, target key cytokines or specific inflammatory pathways, determining a highly selective suppression of the immune activation. The severity of the disease drives the therapeutic choice and it is usually evaluated by Psoriasis Area and Severity Index (PASI) score. Commonly used in conjunction with the physician’s global assessment (PGA), the PASI score is employed in both daily clinical practice and clinical trials to evaluate the therapeutic response to systemic treatments. PASI is less frequently used, however, to measure the efficacy of topical products, as it is not very accurate in patients with < 5 -- 10% body surface area (BSA) or in those patients who had a PASI < 3 [7,8]. An effective and standardized method evaluating the therapeutic response of small levels of psoriasis is also needed. Some assessment tools have been recently introduced for measuring mild or circumscribed psoriasis, including overall lesion assessment and target lesion severity scores (TLSSs). TLSS score assesses scaling, infiltration and erythema of a single lesion, providing an estimation of the response to treatment. As suggested by Feldman et al., it might be effectively used in clinical trials and, if necessary, it might be supported by PGA and quality-of-life measures [7]. The National Psoriasis Foundation Psoriasis Score represents another tool that could prove valuable as a therapeutic response index [9]. Patients are often dissatisfied with current therapeutic approaches, and the adherence to treatment could be poor. The management of psoriasis is thereby challenging and novel therapeutic options are greatly needed. 2.
formulation for approved and marketed agents is STF 115469 (GlaxoSmithKline), 0.005% calcipotriene formulated in foam. Calcipotriene is approved as cream, ointment and, just recently, as foam in adult subjects. In a randomized, double-blind, vehicle-controlled, parallel-group, Phase IIIb study, calcipotriene 0.005% foam was administered to 363 patients older than 12, affected by plaque-type psoriasis with scalp involvement [14]. Eight-week treatment with 0.005% calcipotriene foam induced a ‘complete’ or ‘almost complete’ resolution of scalp psoriasis in 40.9% of treated patients versus 24.2% of vehicle group (p £ 0.001), measured by Investigator’s Static Global Assessment (ISGA). Conversely, a poor response to STF 115469 was observed in treating body lesions, as the percentage of patients achieving ‘clear’ or ‘almost clear’ score by ISGA was 17.7 versus 15.4% of vehicle group. Now, calcipotriene foam is being tested in pediatric psoriasis patients (age of 2 -- 11) in a multicenter, randomized, double-blind, Phase III study to evaluate safety, tolerability and efficacy compared to vehicle foam [15]. Other vitamin D3 derivates such as maxacalcitol and becocalcidiol have been investigated and preliminary results are promising. Maxacalcitol proved more effective compared to calcipotriol, though burning sensation occurred in the treated lesions. Maxacalcitol ointment 25 µg/g was shown superior in terms of efficacy to other maxacalcitol concentrations (6, 12.5 and 50 µg/g) [16]. Mild side effects including erythema, burning, pruritus and edema have been observed in maxacalcitol-treated patients with negligible systemic effects. Becocalcidiol (QRX-101, QuatRx Pharmaceuticals Co.) is a vitamin D analog formulated as a 75 µg/g ointment. Preclinical studies showed a good safety profile and tolerability. A Phase IIb study assessed efficacy and safety in 185 subjects affected by chronic plaque-type psoriasis, randomly treated either with becocalcidiol, applied once or twice daily, or vehicle [17]. After 8 weeks, PGA score and psoriasis symptom severity (PSS) were evaluated showing superior efficacy of twice-daily becocalcidiol versus QRX-101 vehicle (p = 0.002), with 16 of 61 (26%) subjects achieving a PGA score of ‘clear’ or ‘almost clear’. PSS score confirmed a higher efficacy, though not statistically significant, of twice-daily becocalcidiol compared to vehicle. Overall, therapy was safe and well tolerated. Twice-daily becocalcidiol also demonstrated higher efficacy compared to once-daily becocalcidiol [17].
Emerging vitamin D3 derivates 3.
Vitamin D3 analogs were introduced in the treatment of psoriasis more than two decades ago. Three vitamin D3 analogs (calcitriol, calcipotriol and tacalcitol) resulted efficacious in the treatment of psoriasis [10-12]. Their efficacy is given by their capability in normalizing keratinocyte proliferation and differentiation [13]. Moreover, it has been demonstrated that they modulate the immune response and, thus, have an anti-inflammatory activity. An example of new 462
Combined therapies
Vitamin D3 derivatives and corticosteroids The efficacy in treating psoriasis with the combination of calcipotriol and betamethasone dipropionate as two-compound topical ointment is well documented. This combination synergistically acts on multiple steps of the pathogenic cascade as calcipotriol regulates keratinocyte differentiation and proliferation, and betamethasone shows anti-inflammatory 3.1
Expert Opin. Pharmacother. (2014) 15(4)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
New topical treatments for psoriasis
effects [18-21]. Because the beneficial effect of each agent is potentiated by this synergism, two combined compound may offer the possibility to reduce overall exposure to corticosteroids and occurrence of side effects [22,23]. Clinical studies revealed a reduction of local side effects induced by calcipotriol (irritant contact dermatitis and erythema) because of the antiinflammatory steroidal activity, though steroid-related side effects were still observed [22,23]. Because the ointment formulation, greasy and sticky, limits patient’s adherence to treatment, new formulations such as gel vehicle or spray were needed. New spray ointment (LEO 90100, LEO-Pharma A/S) and lipophilic, nonalcoholic gel formulations (LEO 80185, LEO-Pharma A/S) have been introduced as vehicle for calcipotriol/betamethasone combination [24,25]. LEO 80185 is an innovative two combined gel that has been recently marketed for the treatment of plaquetype psoriasis, while safety and efficacy of 4-week LEO 90100 treatment are investigated in Phase II trials [24,25]. Salicylic acid and corticosteroids Salicylic acid is a keratolytic agent usually formulated in ointment at 2 -- 6% concentration. Salicylic acid disrupts intra-keratinocyte adhesion in the upper most layer of the epidermis, facilitating the physiological shedding process [26]. Higher concentrations are usually prescribed with caution in case of hyperkeratotic areas occurring, for example, in palmoplantar or scalp localization. A topical ointment compound combining mometasone furoate 0.1% and salicylic acid 5% (SPS4251, Glenmark Pharmaceuticals Ltd.) has been evaluated to treat psoriatic lesions (evaluation of lesional parameters: erythema, size, scaling, itching, thickness). Safety, tolerability and antipsoriatic efficacy of three SPS4251 concentrations have been investigated in Phase I and II trials comparing SPS4251 to other topical agents (0.1% mometasone furoate, and one vitamin D derivate), though clinical results have not been reported yet [27]. 3.2
Nortriptyline HCl-containing compounds CRx-191 (Zalicus, Inc.) is a novel combined compound consisting in 0.1% mometasone furoate + 0.05% nortriptyline HCl [28]. The synergistic effect on psoriasis seems to be promising as it is reported to have anti-inflammatory effects, inhibiting key-pathogenic cytokines such as TNF-a and IFN-g. A Phase II trials will evaluate safety and efficacy comparing CRx-191 with CRx-191 vehicle and single CRx-191 agents in monotherapy (mometasone furoate and nortriptyline), intra-individually. Another two-compound topical combining nortriptyline is CRx-197-002, which consists in 0.1% nortriptyline HCl and 0.1/0.3% loratadine formulated as cream [29]. Its safety and efficacy was assessed in a single-center, randomized, blinded, Phase IIa trial comparing two strengths of CRx-197-002 (0.1% nortriptyline HCl + 0.1% loratadine and 0.1% nortriptyline HCl + 0.3% loratadine) with: i) vehicle; ii) a marketed topical agent (0.005% calcipotriol); and iii) 0.1% nortriptyline HCl topical cream [29]. 3.3
4.
New steroidal agents
Similarly to clobetasol, halobetasol propionate (Desenvolvimento Ltda.) is an ultra-potent corticosteroid with an apparent stronger anti-inflammatory and anti-proliferative activity compared to clobetasol. It is now investigated in Phase II trials as 0.05% lotion applied twice daily [30]. 5.
Blockade of neurogenic inflammation
It is likely an involvement of neurogenic inflammation in the pathogenesis of psoriasis, though its role and its relevance have not been yet clarified. Neuropeptides such as substance P, vasoactive intestinal peptide and nerve growth factor (NGF), which also act on the immune system, were found upregulated in lesional psoriatic skin [31]. Especially NGF seems to be immunologically active as it may stimulate T-cell activation, keratinocyte proliferation, neoangiogenesis, and the expression of adhesion molecules [31]. The potential efficacy of neuropeptide blockers in treating psoriasis has been suggested by the preliminary observations about the improvement of psoriasis phenotype using capsaicin and somatostatin [32,33]. CT-327 This new topical medication developed by Creabilis is an inhibitor of the kinase domain of TrkA, a high-affinity receptor for NGF. Acting on neurogenic inflammation and pruritus it was considered for the treatment of psoriasis and atopic dermatitis, two chronic skin disorders both characterized by itching [34]. After successfully passed Phase I trials, CT-327 has been investigated in Phase II studies, including a randomized, double-blind, placebo-controlled, dose-ranging Phase IIb trial investigating effectiveness, safety and tolerability of three dose strengths of CT-327 ointment (0.05, 0.1 and 0.005%) applied twice daily for 8 weeks in 160 patients affected by plaque-type psoriasis [34]. At baseline, 69% of patients reported at least moderate pruritus with a visual analog scale (VAS) > 40 mm. CT-327 therapy demonstrated significant benefits in treating skin symptoms, in particular, CT-327 was tested for the treatment of chronic pruritus associated with psoriasis showing a score reduction, assessing itching severity [34]. Overall, a significant hitching reduction was rendered with a VAS score a slow as 20 mm, observed in 79% of CT-327-treated patients, compared to 36% of vehicle group (p < 0.05). At week 8, CT-327 induced a 60% reduction of pruritus VAS score from baseline, compared to 20% of vehicle alone (p < 0.05) [34]. This clinical improvement correlated with a reduction in terms of PASI (mPASI, modified PASI) in all subjects. Regarding the safety profile, the drug proved to be safe and well tolerated. Subjects receiving CT-327 reported a low occurrence of adverse events with no system absorption and fewer number of withdrawals due to pruritus compared to patients using vehicle. Overall, Phase II studies enrolled 225 patients showing promising clinical outcomes, with no 5.1
Expert Opin. Pharmacother. (2014) 15(4)
463
A. Chiricozzi et al.
serious adverse events reported. Different concentrations (0.05, 0.1 and 0.5%) of topical CT327, applied twice daily for 8 weeks, have been tested in a multicenter, double-blind, randomized, placebo-controlled, Phase IIb study. Based on the satisfactory safety and efficacy profile, Phase III studies are currently in progress for the treatment of psoriasis [35,36].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
6.
Phosphodiesterase inhibitors
AN2728 [(5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole)] (Anacor Pharmaceuticals, Inc.) represents a synthetic phenoxybenzoxaborole, which inhibits phosphodiesterase 4 (PDE4) activity, and the release of TNF-a, IL-12, IL-23 and other cytokines [37]. Safety and efficacy of AN2728 have been tested in five Phase II trials and two Phase I trials (Table 1). Among them, a proof of concept study tested antipsoriatic effects of 5% AN2728 ointment versus 5% AN2728 cream, compared with their corresponding vehicles in subjects with stable psoriatic plaques [38]. As reported by the manufacturer, a clinical response was assessed after 12-day occlusive treatment with both AN2728 formulations on the basis of the sonographic and clinical measurements [38]. The improvement was significantly higher with both AN2728 formulations compared to vehicles, though no difference was detected between AN2728 formulations. In a single-center, vehicle- and comparator-controlled, randomized, observer-blind, initial dose-ranging, Phase Ib study comparing three strengths of AN2728 (5, 2 and 0.5%) with 0.1% tacrolimus, 0.1% valerate betamethasone and AN2728 ointment vehicle. Twelve subjects affected by psoriasis were treated applying each medication in occlusion to 6 different test areas for 12 days. A reduction in terms of infiltrate thickness was observed by sonographic and clinical measurement, though again, it was only statistically significant versus vehicle [38]. Overall, in both studies no adverse events occurred. MK-0873 (Merck & Co., Inc.) is a novel selective PDE4 inhibitor, initially evaluated for the treatment of chronic obstructive pulmonary disease [39]. Recently, it has been tested for psoriasis in various clinical trials as 0.5 or 2% cream applied once or twice daily compared to MK-0873 vehicle or to calcitriol 0.0003% (3 µg/g) in subjects affected by plaque-type psoriasis [40]. Manufacturer reported an amelioration of psoriasis phenotype using this medication. 7.
Janus-associated kinase inhibitors
In recent years, various therapeutics targeting janus-associated kinases (JAKs) have undergone design and development. JAKs constitute a family of protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK2, that, by activating signal transducers and activators of transcriptions (STATs), transduce pro-inflammatory and pro-proliferative stimuli [41,42]. In fact, multiple inflammatory and proliferative cytokines, considered pathogenically relevant in such as IL-12, IL-23, IL-17, IL-21, IL-22, IL-20 and interferons, signal through 464
the JAK/STAT pathway [41-44]. STAT1 and STAT3, which are both upregulated in lesional psoriatic skin, respectively, characterize Th1 and Th17 signaling. Selective JAK inhibition blocks both keratinocytes proliferation and inflammation, resulting in the reduction of epidermal hyperplasia, erythema and scaling [45]. Tofacitinib (CP-690,550, Pfizer), a JAKs inhibitor, interferes with the production of inflammatory cytokines involved in the pathogenesis of psoriasis [45,46]. It resulted effective as oral medication in treating psoriasis and topical formulation has been recently evaluated in a randomized, double-blind, vehicle-controlled Phase IIb trial [47]. In this study, two concentrations of tofacitinib ointment (10 and 20 mg/g) were administered once or twice daily for 12 weeks [47]. Another oral JAK-inhibitors used for prevention of rejection in transplantation and for treatment of immune-mediated inflammatory disorder is Ruxolitinib (INCB018424), a cyclopentyl propionitrile small molecule with pan-JAK inhibitory activity, that suppresses the production of inflammatory cytokines related to JAK signaling, such as IL-22, and IL-17 [48]. Safety, efficacy, tolerability and pharmacokinetics of INCB018424 were also investigated as phosphate cream in three concentrations (0.5, 1.0 and 1.5%) [49]. Topical applications once or twice daily proved effective in treating psoriasis with a clinical improvement of the lesion score (thickness, erythema and scaling) > 50%. The cream was applied and subsequently compared with vehicle and calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream [49]. No serious adverse events were reported [49].
Other non-steroidal anti-inflammatory agents
8.
MEK1/MEKK1 inhibitor E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (Eisai, Inc.) is a MEK1/MEKK1 inhibitor showing anti-inflammatory effects suppressing the production of pro-inflammatory cytokines from leukocytes and keratinocytes [50]. Moreover, E6201 has been shown to induce: i) in vitro suppression of lymphocyte activation and proliferation; and ii) an inhibition of neutrophil migration due to the suppression of IL-8 production by activated human keratinocytes [50]. E6201 also presents direct antiproliferative activity on cultured keratinocytes. Due to the in vitro activities on both immune cells and keratinocytes, it may thereby result effective in the treatment of psoriasis. Pre-clinical studies revealed the effectiveness of topical E6201, formulated as either an ointment or cream, in reducing acute edema formation and neutrophil infiltration into mouse skin [50]. A multicenter, double-blind, Phase II trial assessed efficacy and safety of topical E6201, administered once or twice daily, treating pre-identified target lesions in patients with chronic plaque-type psoriasis. The duration of treatment was 8 weeks, followed by a 4-week follow-up period. A 12-day, 8.1
Expert Opin. Pharmacother. (2014) 15(4)
New topical treatments for psoriasis
Table 1. Antipsoriatic topical agents in development.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
Agent
Manufacturer
Target
Phase of development
Formulation
AN2728 CT 327 E6201
Anacor Pharmaceuticals, Inc. Creabilis Therapeutics Eisai Ltd.
Phosphodiesterase-4 inhibitor TrkA kinase blocker MEK kinase inhibitor
II III II
Ruxolintinib (INCB18424) LEO 90100
Incyte Corp. - Novartis
JAK kinase inhibitor
III
Ointment 5%, cream 5% 0.05, 0.1 and 0.5% cream 0.03, 005, 0.01, 0.1, 0.2 and 0.05% gel 0.5, 1.0 and 1.5% cream
LEO Pharma
II
Spray, ointment
PH-10
Provectus Pharmaceuticals
Anti-inflammatory/anti-proliferative effect (proprietary) Skin cell inhibitor (Rose Bengal)
II
WBI-1001 Tofacitinib (CP-690,550) M518101
Welichem Biotech, Inc. Pfizer, Inc.
Anti-inflammatory (proprietary) JAK kinase inhibitor
II II
0.002, 0.005 and 0.01% Aqueous hydrogel 1% cream Ointment
Maruho Co., Ltd.
III
Ointment
BCT194 Pazopanib (GW786034) Bimosiamose (TBC1269) LAS41004
Novartis GlaxoSmithKline
Anti-inflammatory/skin cell inhibitor (proprietary) p38 kinase Anti-angiogenic and anti-proliferative effect Pan-selectin antagonist
I I
0.5% cream Ointment
II
5% cream
MK-0873 SPS4251 Antiflammin-2 ALT-2074 (SYI-2074) SHP-141
Revotar Biopharmaceuticals AG Almirall, S.A.
III
Proprietary
Merck & Co., Inc. Glenmark Pharmaceuticals Ltd. National Cancer Institute (NCI) Synvista Therapeutics, Inc.
Anti-inflammatory/skin cell inhibitor (proprietary) Phosphodiesterase-4 inhibitor Salicylic acid + corticosteroid Phospholipase A2 (PLA2) inhibitor Cytochrome P450 3A inhibitor
I II Pilot study II
0.5 and 2% cream Ointment Ointment 0.5% cream
Shape Pharmaceuticals Pty Ltd.
Histone deacetylase inhibitor
I
Cream
single-center, randomized, blinded, vehicle and active comparator (calcipotriene)-controlled, dose-ranging Phase II trial, which is designed to assess efficacy and safety of six concentrations of topical E6201 gel, was also performed. In this study, intra-individual comparison consisted of five topical treatments: three different concentrations of E6201, one gel vehicle (negative control) and one calcipotriene cream (positive control), simultaneously administered to each patients [51]. WBI-1001 WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene-1, 3-diol) is a synthetic compound with non-steroidal antiinflammatory properties (Table 1). The anti-inflammatory activity is primarily attributed to the suppression of T-cellderived pro-inflammatory cytokine production. Efficacy and safety of WBI-1001 have been evaluated for the treatment of various skin disorders. It has been successfully tested in both Phase I and II studies for the treatment of atopic dermatitis and psoriasis [52,53]. Bissonette et al. tested WBI-1001 in 61 psoriatic patients showing an involvement of 1 -- 10% of the BSA and a PGA score of 2 -- 4 [53]. Patients were randomly treated with either 1% WBI-1001 cream or placebo (ratio 2:1), applied twice daily for 12 weeks. Efficacy was evaluated using PGA, BSA and 8.2
PASI scores. After 12 weeks of treatment, a significant PGA and BSA amelioration was observed in 62.8% of WBI-1001-treated patients compared to placebo (13.0%, p < 0.0001). Additionally, 67.5% of patients randomized to WBI-1001 achieved a PGA of ‘clear’ or ‘almost clear’ and 79.1% showed an amelioration in terms of BSA, compared to 4.8% (p < 0.0001) and 9.4% (p < 0.0001) of placebo-treated patients, achieving the same response in terms of PGA and BSA scores, respectively [53]. Adverse events occurred more frequently in WBI-1001-treated patients than in those randomized to placebo. These adverse drug reactions appeared to be mild or moderate in intensity. PH-10 PH-10 (Provectus Pharmaceuticals) is an aqueous hydrogel formulation of 0.001% rose bengal disodium, designed for the treatment of inflammatory skin disorders, such as psoriasis and atopic dermatitis. Overall, previous Phase I and II trials tested PH-10 in 217 patients affected by psoriasis. Other Phase II trials completed patient recruitment such as a multicenter study using different concentrations of topical PH-10 (0.002, 0.005 and 0.01%), applied once daily; another trial investigating safety and efficacy of 0.001% PH-10 aqueous hydrogel combined with ambient 8.3
Expert Opin. Pharmacother. (2014) 15(4)
465
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
A. Chiricozzi et al.
light exposure or 544 nm light-emitting diodes light illumination at 10 J/cm2 [54]. The manufacturer reported clinical outcomes from a multicenter, randomized, placebocontrolled Phase IIc trial (PH-10-PS-23) including 99 subjects affected by mild-to-moderate plaque type psoriasis, receiving daily application of PH-10 (0.01, 0.005 or 0.002%) or placebo for 28 days. Clinical success was defined as the achievement of a 0 or 1 score for all Psoriasis Severity Index (PSI) components, and 0 or 1 score on the Plaque Response Scale. Pruritus (itching) Self-Assessment Scale was also measured. At Day 29, a better efficacy profile was obtained with low dose of PH-10 (0.002%) [55]. After a 28-day treatment with PH-10 (all strengths), 23 -- 29% of subjects experienced a ‘complete’ or ‘nearly complete’ resolution of all PSI components, compared to none of the subjects in the placebo arm [55]. Pan-selectin antagonist Usually selectins are considered crucial adhesion molecules mediating migration (rolling and trafficking) of blood inflammatory cells into peripheral tissue. Bimosiamose/TBC1269 (Revotar Biopharmaceuticals AG) is an anti-inflammatory agent antagonizing P-selectin, E-selectin and L-selectin and, thus, blocking leukocyte extravasation (Table 1). It is now being tested for topical use in psoriasis, delivering satisfactory preliminary results in both pre-clinical and clinical studies. A multicenter, randomized, double-blind, placebo-controlled, Phase II trial was executed to evaluate safety and efficacy of 5% Bimosiamose/TBC1269 cream in 107 patients affected by plaque-type psoriasis [56]. 8.4
BCT194 Among the signal transducers playing a key role in inflammatory response, the p38 kinase is central in the regulation of inflammatory mediator production such as TNF-a, IL-1b, IL-6 and IL-8 (Table 1). The inflammatory pathways mediated by p38 kinase suggest a potential indication for the treatment of psoriasis. The p38 inhibitor, BCT194 (Novartis), is topically used as 0.5% cream. Recently pharmacodynamics and pharmacokinetics were explored in two Phase I studies. Preliminary results were described in a Phase I study assessing pharmacodynamics and pharmacokinetics in nine subjects affected by psoriasis [57]. The drug was applied once daily for 8 days showing a satisfactory safety profile associated with a conspicuous drug concentrations within tested skin areas, which was measured using membrane-free dermal open-flow microperfusion probes. 8.5
Indirubin This oil ointment containing indigo naturalis is now tested at different concentrations 200, 100, 50 and 10 µg/g. Indigo naturalis is traditional Chinese herbal medicine derived from Strobilanthes formosanus Moore plant. It may be effective in treating psoriasis because it interferes with various pathogenic mechanisms as shown by in vitro 8.6
466
inhibition of TNF-a and vascular cell adhesion molecule1 (VCAM-1) expression in primary cultured human umbilical vein endothelial cells [58]. Therefore, indigo naturalis demonstrated anti-inflammatory effects helping to improve psoriasis. Phase II and III studies are currently ongoing. 9.
Topical calcineurin inhibitors
Calcineurin inhibitors show the capability in suppressing T-cell activation and proliferation as they prevent the dephosphorylation of the nuclear factor of activated T cells inhibiting the production of pro-inflammatory cytokines such as TNF-a, IFN-g, IL-2, IL-17 and IL-22 [59]. Topical calcineurin inhibitors, namely pimecrolimus and tacrolimus, are only approved for the treatment of atopic dermatitis, though their off-label use is progressively more common also for the treatment of psoriasis. Their efficacy in treating psoriasis is still controversial because their penetration into hyperkeratotic psoriatic plaques seems to be limited, and thus, they might be considered as valid alternatives for the treatment of intertriginous areas and more sensitive body sites such as the face and genital areas where the absorption is naturally increased [60-63]. A double-blind, randomized, vehicle-controlled study, testing 0.1% tacrolimus ointment on 167 subjects affected by facial or intertriginous psoriasis, showed a ‘clear’ or ‘almost clear’ outcome in 65% of cases after 8-week treatment compared to 31% of placebo group [64]. In a double-blind, randomized, vehicle-controlled study, 57 patients with intertriginous psoriasis were treated twice daily with 0.1% pimecrolimus cream for 8 weeks. Seventy-one percent of cases achieved a ‘clear’ or ‘almost clear’ clinical assessment after 8 weeks in the pimecrolimus group, compared to 21% of the placebo group [65]. Calcineurin inhibitors proved a satisfactory safety profile as mild side effects (itching, stinging and feeling of warmth) may occur. The advantage related to the use of calcineurin inhibitors is the absence of typical long-term side effects of steroids (i.e., atrophy), although no long-term and large studies, so far, have confirmed their safety in psoriasis treatment [66]. Their efficacy is likely comparable to medium/high topical corticosteroids [67]. They might be used in combination with phototherapy [68]. For the management of psoriasis, they may be used for not only the treatment of ‘special areas’ such as face, genital and flexural areas, but also as maintenance therapy after a satisfactory steroid therapy, in order to gradually obtain a reduced steroid exposure. Eventually, to increase the limited penetration of these agents, they could be applied under occlusion or in combination with keratolytics such as salicylic acid and urea [69]. 10.
Anti-proliferative agents
PTH (1-34) PTH (1-34) (Manhattan Pharmaceuticals) represents a topical parathyroid hormone (1-34) [PTH (1-34)] compound 10.1
Expert Opin. Pharmacother. (2014) 15(4)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
New topical treatments for psoriasis
showing potent inhibitory effects on keratinocyte proliferation. Cream and gel have been selected as topical formulations for PTH (1-34). In 2003, topical PTH (1-34), formulated in Novasome A cream, was tested at two different strengths and with two different therapeutic schemes [70]. Patients, who failed at least one of the conventional topical medications, were treated with 20 or 50 µg PTH (1-34), applied twice daily or once daily, respectively, for 2 months, and they experienced 67.3% improvement in psoriasis severity compared with the vehicle-treated patients, showing a 17.8% improvement. Overall, an improvement of 42.6% in terms of PASI score (p < 0.02) was observed using PTH (1-34) without the occurrence of hypercalcaemia or hypercalciuria [70]. Furthermore, different concentrations (0.10 and 0.05%) of PTH (1-34) have been used in gel formulation in a multi-center, randomized, double-blind, placebo-controlled, Phase II trial, assessing their safety and efficacy. M518101 M518101 (Maruho North America, Inc.) is defined as a skin cell inhibitor/anti-inflammatory, similar to a vitamin D derivate (Table 1). It is formulated as an ointment and is currently being tested in Phase III trials. Interestingly, a head-to-head Phase II study compared two different doses of M518101, applied twice daily, to a vitamin D3 ointment already on the market (calcipotriol) [71]. Clinical outcomes have not yet been published, but the comparison between M518101 and calcipotriol would be relevant should M518101 prove as effective as calcipotriol with the benefit of a reduced occurrence of side effects. 10.2
Topical epidermal growth factor Topical epidermal growth factor (EGF) (Ennar Pharmaceuticals) represents an interesting approach to contrast keratinocyte proliferation and, therefore, to block the formation of pathogenic auto-sustaining circuits. EGF-receptor (EGFR) was found overexpressed in lesional psoriatic skin and effective antipsoriatic therapies induced its suppression [72,73]. EGF is shown to downregulate EGFR expression [74]. Because of these observations, it has been hypothesized an eventual therapeutic approach based on EGF stimulation. First studies using topical EGF are being reported more than two decades ago [75]. Experimental psoriasis model treated with topical EGF showed a regression of the psoriasis skin phenotype. Beside a marked anti-proliferative effect on keratinocytes, the blockade of EGFR may interfere with the innate immune activation (IL-8 and AMPs production), occurring in the early phase of psoriasis [76]. 10.3
11.
New coal tar formulations
Coal tar may be considered a historical therapeutic that has been used for > 100 years. It is available in various formulations including ointment, cream, gel, lotion, shampoo and soap. Its efficacy in treating psoriasis is likely due to its
suppressive effect on keratinocyte proliferation. Therapeutic benefit of coal tar therapy seems to maintain with a liquor carbonis distillate (LCD) in a novel solution. Psorent (Neo Strata Co.) is constituted by 15% LCD, showing rapid absorption, ease of use and a better odor compared to the traditional coal tar products. Indeed, the uncomfortable cosmetic feature of coal tar-derived products (its natural odor and staining formulations) strongly limited their use with a poor adherence to treatment. This new solution will be aesthetically and cosmetically more appealing in order to increase patient acceptability. 12.
Conclusion
This overview is aimed to increase the interest on topical therapies and update the ‘state of the art’ on this field reporting those compounds that are currently available or tested in clinical trials. New formulations and novel therapeutic agents will increase the opportunity to treat patients topically and more effectively. 13.
Expert opinion
The large majority of psoriatic patients suffer from a mild or mild-to-moderate that is conventionally treated with topical therapies or phototherapy. Topical medications have shown an important limit in terms of efficacy and patient adherence. Notably, mild to moderate psoriasis may impair patient’s quality of life or it may harm psycho-social life, particularly for psoriasis localized at the scalp, face or genital areas. Actually two consistent classes of agents are commonly used: corticosteroids and vitamin D analogs, both prescribed as monotherapy or in two combined treatments. Additionally, salicylic acid, coal tar and calcineurin inhibitors represent other agents that may be topically administered. The use of topical agents including vitamin D derivates, salicylic acid or coal tar may be associated with poor tolerability while the continuous long-term treatment with corticosteroids may cause skin atrophy, telangiectasias and tachyphylaxis. The introduction of two combined compounds (corticosteroids associated with vitamin D derivates, coal tar or salicylic acid) represents an advanced approach as the two agents can act in synergism allowing to use lower concentrations of medium-potency corticosteroids. Greasy or oily medications negatively affect patient’s adherence to treatment as well as the time spent per day to apply topical medications. In order to increase patient’s adherence and thus efficacy, cosmeceutical engineering is keen to improve drug formulations creating more agreeable, aesthetically more appealing (color, odor), cosmetically easy to use (gel, spray, foam) and sparing-time compounds. A better efficacy and a better control of the disease with topical agents constitute a crucial goal as it would delay the use of systemic therapies, with important implication for patient’s health and public health economy.
Expert Opin. Pharmacother. (2014) 15(4)
467
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
A. Chiricozzi et al.
Because topical therapies are conventionally considered the first-line therapeutic approach, a broader array of compounds in different formulations is needed. Although it apparently seems that a large number of topical medications is available (active drugs, over-the-counter products), in daily clinical practice, it resulted smaller because of intolerability and inefficacy, thus, limiting the opportunity to ‘tailor’ the treatment on patient’s needs. Following the high interest in developing systemic drugs for the treatment of moderate-to-severe psoriasis, pharmaceutical companies are deeply committed to design new topical medications. Some of these new agents are constituted by innovative vehicles that may help to improve skin penetration, exploiting, for instance, the nanotechnology. In fact, traditional emollients or moisturizing cream are insufficient to deliver active ingredients in adequate amounts to active sites, conversely, nano-emulsions may increase drug delivery to the skin [77]. Oil/water nano-sized carriers are promising colloidal drug carrier systems for diverse therapeutic applications showing favorable properties as they become invisible with a good sensory texture and non-greasy feel. Furthermore some emerging topical agents selectively target disease-defining pathogenic pathways such as JAK/STAT signaling or PDE signaling. It is highly interesting the Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
8.
Scha¨fer T. Epidemiology of psoriasis. Review and the German perspective. Dermatology 2006;212:327-37 9.
development of topically delivered selective blockers targeting pathogenic aspects such as neurogenic inflammation, immune-mediated inflammation or epidermal hyperplasia. Preliminary clinical outcomes seem to be promising although there is a limited availability of long-term and large-scale studies assessing safety and efficacy of these new agents. Moreover, it is hard to predict their potentiality as head-to-head studies comparing them with approved therapeutics are lacking. Overall, we may hypothesize that the advantage of having new topical therapies is given by a larger array of topical options, allowing controlling the disease for longer periods, through rotational or combined schemes and thus, beneficially delaying the use of systemic therapies. Having some novel topical therapies in an advanced stage of development, broader therapeutic armamentarium will be possibly available, giving the chance to associate different medications and seek to personalize the topical treatment approach to each patient.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Walsh JA, McFadden M, Woodcock J, et al. Product of the Physician Global Assessment and body surface area: a simple static measure of psoriasis severity in a longitudinal cohort. J Am Acad Dermatol 2013;69:931-7 Gottlieb AB, Chaudhari U, Baker DG, et al. The National Psoriasis Foundation Psoriasis Score (NPF-PS) system versus the Psoriasis Area Severity Index (PASI) and Physician’s Global Assessment (PGA): a comparison. J Drugs Dermatol 2003;2:260-6
2.
Bowcock AM, Krueger JG. Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 2005;5:699-711
3.
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866-73
4.
Voorhees JJ. Pathophysiology of psoriasis. Annu Rev Med 1977;28:467-73
10.
5.
Barker JN, Karabin GD, Stoof TJ, et al. Detection of interferon-gamma mRNA in psoriatic epidermis by polymerase chain reaction. J Dermatol Sci 1991;2:106-11
Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol. Arch Dermatol 1989;125:1647-52
11.
Reichrath J, Perez A, Muller SM, et al. Topical calcitriol (1,25-dihydroxyvitamin D3) treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997;77:268-72
6.
7.
..
468
Chiricozzi A, Zhang S, Dattola A, et al. Role of Th17 in the pathogenesis of cutaneous inflammatory diseases. J Biol Regul Homeost Agents 2012;26:313-18 Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis 2005;64:ii65-8; discussion ii69 Comprehensive overview on clinical severity assessment tools.
12.
O Neill JL, Feldman SR. Vitamin D analogue-based therapies for psoriasis. Drugs Today (Barc) 2010;46:351-60
13.
Tanghetti EA. The role of topical vitamin D modulators in psoriasis therapy. J Drugs Dermatol 2009;8:s4-8
14.
Feldman SR, Eastman WJ, Brundage T, et al. A multicenter, randomized, Expert Opin. Pharmacother. (2014) 15(4)
.
double-blind study of the efficacy and safety of calcipotriene foam, 0.005%, vs vehicle foam in the treatment of plaque-type psoriasis of the scalp. J Drugs Dermatol 2013;12:300-6 First publication on efficacy and safety of calcipotriene in foam formulation.
15.
Available from: http://clinicaltrials.gov/ ct2/results?term=calcipotriene+FOAM +0%2C005%25&Search=Search
16.
Barker JN, Ashton RE, Marks R, et al. Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator. Br J Dermatol 1999;141:274-8 Relevant publication on efficacy and safety of maxacalcitol in treating psoriasis.
.
17.
.
18.
Helfrich YR, Kang S, Hamilton TA, et al. Topical becocalcidiol for the treatment of psoriasis vulgaris: a randomized, placebo-controlled, double-blind, multicentre study. Br J Dermatol 2007;157:369-74 Efficacy and safety of becocalcidiol in treating psoriasis. Anstey AV, Kragballe K. Retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/
New topical treatments for psoriasis
betamethasone dipropionate ointment. Int J Dermatol 2006;45:970-5 19.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
20.
21.
22.
23.
Papp KA, Guenther L, Boyden B, et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol 2003;48:48-54 Saraceno R, Gramiccia T, Frascione P, et al. Calcipotriene/betamethasone in the treatment of psoriasis: a review article. Expert Opin Pharmacother 2009;10:2357-65 Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002;82:131-5 Kragballe K, Austad J, Barnes L, et al. A 52 -week randomized safety study of calcipotriol/betamethasone dipropionate two compound product (Dovobet/ Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol 2006;154:1155-60 Saraceno R, Camplone G, D’Agostino M, et al. Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiol gel) in the treatment of scalp psoriasis: results from a study in 885 patients. J Dermatolog Treat 2013. [Epub ahead of print]
24.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01347255?term=LEO +90100+and+psoriasis&rank=1
25.
Fleming C, Ganslandt C, Guenther L, et al. Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol 2010;20:465-71
26.
Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol 1999;38:16-24
27.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01743118?term=SPS4251 +and+psoriasis&rank=1
28.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00557739?term=CRx-191 +and+psoriasis&rank=1
29.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00796211?term=CRx-197002&rank=1
30.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01610596? term=halobetasol+propionate+and +psoriasis&rank=3
31.
Saraceno R, Kleyn CE, Terenghi G, Griffiths CE. The role of neuropeptides in psoriasis. Br J Dermatol 2006;155:876-82
32.
Bernstein JE, Parish LC, Rapaport M, et al. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15:504-7
33.
Weber G, Klughardt G, Neidhart M, et al. Treatment of psoriasis with somatostatin. Arch Dermatol Res 1982;272:31-6
34.
Available from: http://www.creabilis-sa. com/ct-327/
35.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01465282?term=CT+327 +and+psoriasis&rank=2
36.
Available from: http://www.centerwatch. com/news-online/article/3070/creabilisbegins-phase-iib-trial-of-ct327-in-psoriasis
37.
Nazarin R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs 2009;10:1236-42 First publication on AN-2728 as potential therapeutic agents for the treatment of inflammatory skin disorders.
.
38.
Available from: http://www.anacor.com
39.
Available from: http://clinicaltrials.gov/ show/NCT00132730
40.
Available from: http://clinicaltrials.gov/ ct2/results?term=MK-0873+AND +PSORIASIS&Search=Search
41.
Cassano N, Vena GA. Janus kinase inhibition as a potential strategy for the treatment of psoriasis: state of the art and future perspectives. J Biol Regul Homeost Agents 2012;26:587-96
42.
Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol 2012;83:1136-45
43.
Mak RK, Hundhausen C, Nestle FO, et al. Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr 2009;100:2-13
44.
Jabbari A, Jhonson-Huang LM, Krueger JG. Role of the immune system and immunological circuits in psoriasis. G Ital Dermatol Venereol 2011;146:17-30
Expert Opin. Pharmacother. (2014) 15(4)
45.
.
Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol 2013;169:137-45 First publication regarding the treatment of psoriasis with tofacitinib.
46.
Flagan ME, Blumenkopf TA, Brisette WH, et al. Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem 2010;53:8468-84
47.
Available from: http://clinicaltrials.gov/ct2/ show/NCT01831466?term=CP-690% 2C550%2CPfizer+and+psoriasis&rank=13
48.
Callis Duffin K, Luchi M, et al. Novel mechanism for topical treatment of plaque psoriasis - results of a randomized, double blind, concentration ranging, vehicle controlled 12 week study with JAK 1/2 inhibitor INCB018424 cream [abstract 261]. 2010 Annual Meeting of the Society for Investigative Dermatology, Hilton Atlanta, Atlanta, Georgia, May 5-8. J Invest Dermatol 2010;130:S44 Important clinical outcomes using INCB018424 cream.
.
49.
.
Punwani N, Scherle P, Flores R, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol 2012;67:658-64 Another relevant paper about the use of INCB018424 cream.
50.
Muramoto K, Goto M, Inoue Y, et al. E6201, a novel kinase inhibitor of mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase -1 and mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. J Pharmacol Exp Ther 2010;335:23-31
51.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00539929? term=E6201&rank=2
52.
Bissonnette R, Chen G, Bolduc C, et al. Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis: results from a phase 2 a, randomized, placebo-controlled clinical trial. Arch Dermatol 2010;146:446-9 Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis.
.
469
A. Chiricozzi et al.
Bissonnette R, Bolduc C, Maari C, et al. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial. J Eur Acad Dermatol Venereol 2012;26:1516-21 Efficacy and safety of topical WBI-1001 in the treatment of psoriasis.
62.
Bissonette R, Nigen S, Bolduc C. Efficacy and tolerability of topical tacrolimus of male genital psoriasis. J Cutan Med Surg 2008;12:230-4
63.
Freeman AK, Linowski GJ, Brady C, et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 2003;48:564-8
54.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00941278?term=PH-10 +and+psoriasis&rank=2
64.
55.
Available from: http://www.centerwatch. com/news-online/article/3092/alerts.aspx
56.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00823693? term=bimosiamose+AND+5+%25+cream +AND+psoriasi&rank=1
57.
Bodenlenz M, H€offerer C, Magnes C, et al. Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling. Eur J Pharm Biopharm 2012;81:635-41
53.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
.
58.
59.
60.
61.
470
Chang HN, Pang JH, Yang SH, et al. Inhibitory effect of indigo naturalis on tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells. Molecules 2010;15:6423-35 Haider AS, Lowes MA, Suarez-Farinas M, et al. Identification of cellular pathways of “Type1”, Th17 cells, and TNF-and inducible nitril oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine a in psoriasis. J Immunol 2008;180:1913-20 Brune A, Miller DW, Lin P, et al. Tacrolimus ointment is effective for psoriasis on the face intertriginous areas in pediatrics patients. Pediatr Dermatol 2007;24:76-80 Steele JA, Choi C, Kwong PC. Topical tacrolimus in the treatment of inverse psoriasis in children. J Am Acad Dermatol 2005;53:713-16
Lebwohl M, Freeman AK, Chapman MS, et al. Tacrolimus ointment is effective for facial and intertriginous psoriasis. J Am Acad Dermatol 2004;51:723-30
65.
Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol 2004;51:731-8
66.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009;60:643-59
67.
68.
Kreuter A, Sommer A, Hyun J, et al. 1% pimecrolimus, 0.005% calcipotriol, and 0.1% bethamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study. Arch Dermatol 2006;142:1138-43 Ahn SJ, Oh SH, Chang SE, et al. A case of infantile psoriasis with pseudoainhum successfully treated with topical pimecrolimus and low-dose narrowband UVB phototherapy. J Eur Acad Dermatol Venereol 2006;20:1332-4
69.
Chiricozzi A, Chimenti S. Effective topical agents and emerging perspectives in the treatment of psoriasis. Expert Rev Dermatol 2012;7:283-93
70.
Holick MF, Chimeh FN, Ray S. Topical PTH (1-34) is a novel, safe and effective treatment for psoriasis: a randomized self-controlled trial an open trial. Br J Dermatol 2003;149:370-6
71.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01873677?term=M518101 +and+psoriasis&rank=2
Expert Opin. Pharmacother. (2014) 15(4)
72.
Boisseau-Garsaud AM, Donatien P, Margerin C, et al. EGF Receptor expression and growth of psoriatic and normal human keratinocytes are modulated by 1,25 (OH)2-vitamin D3 ex vivo. Arch Dermatol Res 1996;288:453-7
73.
Keme´ny L, Michel G, Arenberger P, Ruzicka T. Down-regulation of epidermal growth factor receptors by dithranol. Acta Derm Venereol 1993;73:37-40
74.
Gilligan A, Bushmeyer S, Knowles BB. Variation in EGF-induced EGF receptor downregulation in human hepatomaderived cell lines expressing different amounts of EGF receptor. Exp Cell Res 1992;200:235-41
75.
Nanney LB, Yates RA, King LE Jr. Modulation of epidermal growth factor in psoriatic lesions during treatment with topical EGF. J Invest Dermatol 1992;98:296-301
76.
Roupe´ KM, Nybo M, Sj€obring U, et al. Injury is a major inducer of epidermal innate responses during wound healing. J Invest Dermatol 2010;130:1167-77
77.
Saraceno R, Chiricozzi A, Gabellini M, et al. Emerging applications of nanomedicine in dermatology. Skin Res Technol 2013;19:e13-19
Affiliation Andrea Chiricozzi1,2 MD, Rossella Pitocco1 MD, Rosita Saraceno1 MD, Steven Paul Nistico3 MD, Alessandro Giunta1 MD & Sergio Chimenti†1 MD † Author for correspondence 1 University of Rome Tor Vergata, Department of Dermatology, Via Montpellier 1, 00133 Rome, Italy Tel: +39 339 566 8320; Fax: +39 062 090 2742; E-mail: [email protected] 2 The Rockefeller University, Laboratory for Investigative Dermatology, 1230 York Avenue, 10065 New York, NY, USA 3 Magna Graecia University, Department of Health Sciences, Catanzaro, Italy
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
New topical treatments for psoriasis Andrea Chiricozzi, Rossella Pitocco, Rosita Saraceno, Steven Paul Nistico, Alessandro Giunta & Sergio Chimenti†
1.
Introduction
2.
Emerging vitamin D3 derivates
3.
Combined therapies
4.
New steroidal agents
5.
Blockade of neurogenic
†
inflammation 6.
Phosphodiesterase inhibitors
7.
Janus-associated kinase inhibitors
8.
Other non-steroidal anti-inflammatory agents
9.
Topical calcineurin inhibitors
10.
Anti-proliferative agents
11.
New coal tar formulations
12.
Conclusion
13.
Expert opinion
University of Rome Tor Vergata, Department of Dermatology, Rome, Italy
Introduction: Psoriasis is a common immune-mediated disorder that in 70% of cases appears in mild or mild-to-moderate form. Psoriasis is usually treated with topical medications and/or phototherapy with variable efficacy in controlling the disease. Areas covered: For the past three decades, research has been focused on systemic agents for the treatment of moderate-to-severe psoriasis, particularly with the introduction of biologic agents or ‘small molecules’. In parallel, novel advances in topical antipsoriatic agents have been made, experiencing a ‘new era’, with the development of new formulations and the identification of new therapeutic targets. These agents, having a different spectrum of action from traditional agents, are actually being tested in pre-marketing clinical trials and they may potentially represent promising treatment options that could enlarge the therapeutic armamentarium for the treatment of psoriasis. Expert opinion: Future antipsoriatic topical agents show new modality of action in blocking the pathogenic process leading to psoriatic plaque formation. Keywords: E6201, pazopanib, psoriasis, tofacitinib, topical therapy, WBI-1001 Expert Opin. Pharmacother. (2014) 15(4):461-470
1.
Introduction
Psoriasis is a chronic inflammatory skin disease that affects approximately 2 -- 3% of the Caucasian population [1]. The most common form, called ‘plaque-type psoriasis,’ is characterized by the presence of red and scaly plaques, usually localized at the scalp, elbows, knees and buttock. Lesional psoriatic skin histologically reflects marked thickening of the epidermis, cutaneous infiltration of inflammatory cells and an increase in the number of dilated blood vessels in the upper dermis [2]. Epidermal acanthosis is determined by keratinocyte proliferation associated with an altered keratinocyte differentiation process, as the maturation of keratinocytes from the basal to the conrinifed layer, which typically lasts 28 days, is shortened to 5 days [3], and an evident reduction of the granular layer occurs with an aberrant terminal differentiation of keratinocytes, which is mainly reflected by parakeratosis. Initially it was believed that the pathogenic mechanism primarily involved keratinocytes, but different observations fostered the hypothesis about the contribution of immune cells in the pathogenesis of psoriasis [4]. These studies proved that T cells played a crucial role in the pathogenesis of the disease, especially Th1 cells and Th17 cells, two CD4+ T lineages mainly producing IFN-g and IL-17, respectively, which have been found markedly upregulated in lesional psoriatic skin. Recent models of psoriasis addressed the Th17 pathway as the main pathogenic axis involved in psoriasis pathogenesis [5,6]. Conventional topical or systemic treatments behave as anti-proliferative agents or unspecific immunomodulants that broadly suppress the inflammatory response characterizing the psoriatic plaque formation. Their efficacy is variable and, especially with systemic therapeutics, the occurrence of organ-specific toxicity may be 10.1517/14656566.2014.875159 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
461
A. Chiricozzi et al.
Article highlights. . . . .
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
.
A wide array of new topical therapies is now tested in clinical trials. Some new topical agents selectively target pathogenic mediators. Nanotechnology or new vehicles will probably increase efficacy and patients’ adherence to treatment. New formulations, cosmetically more appealing, will be available. These agents will beneficially enlarge the therapeutic armamentarium for the treatment of mild or mild-to-moderate psoriasis.
This box summarizes key points contained in the article.
observed. Conversely, systemic biologic agents, similarly to new topical drugs, target key cytokines or specific inflammatory pathways, determining a highly selective suppression of the immune activation. The severity of the disease drives the therapeutic choice and it is usually evaluated by Psoriasis Area and Severity Index (PASI) score. Commonly used in conjunction with the physician’s global assessment (PGA), the PASI score is employed in both daily clinical practice and clinical trials to evaluate the therapeutic response to systemic treatments. PASI is less frequently used, however, to measure the efficacy of topical products, as it is not very accurate in patients with < 5 -- 10% body surface area (BSA) or in those patients who had a PASI < 3 [7,8]. An effective and standardized method evaluating the therapeutic response of small levels of psoriasis is also needed. Some assessment tools have been recently introduced for measuring mild or circumscribed psoriasis, including overall lesion assessment and target lesion severity scores (TLSSs). TLSS score assesses scaling, infiltration and erythema of a single lesion, providing an estimation of the response to treatment. As suggested by Feldman et al., it might be effectively used in clinical trials and, if necessary, it might be supported by PGA and quality-of-life measures [7]. The National Psoriasis Foundation Psoriasis Score represents another tool that could prove valuable as a therapeutic response index [9]. Patients are often dissatisfied with current therapeutic approaches, and the adherence to treatment could be poor. The management of psoriasis is thereby challenging and novel therapeutic options are greatly needed. 2.
formulation for approved and marketed agents is STF 115469 (GlaxoSmithKline), 0.005% calcipotriene formulated in foam. Calcipotriene is approved as cream, ointment and, just recently, as foam in adult subjects. In a randomized, double-blind, vehicle-controlled, parallel-group, Phase IIIb study, calcipotriene 0.005% foam was administered to 363 patients older than 12, affected by plaque-type psoriasis with scalp involvement [14]. Eight-week treatment with 0.005% calcipotriene foam induced a ‘complete’ or ‘almost complete’ resolution of scalp psoriasis in 40.9% of treated patients versus 24.2% of vehicle group (p £ 0.001), measured by Investigator’s Static Global Assessment (ISGA). Conversely, a poor response to STF 115469 was observed in treating body lesions, as the percentage of patients achieving ‘clear’ or ‘almost clear’ score by ISGA was 17.7 versus 15.4% of vehicle group. Now, calcipotriene foam is being tested in pediatric psoriasis patients (age of 2 -- 11) in a multicenter, randomized, double-blind, Phase III study to evaluate safety, tolerability and efficacy compared to vehicle foam [15]. Other vitamin D3 derivates such as maxacalcitol and becocalcidiol have been investigated and preliminary results are promising. Maxacalcitol proved more effective compared to calcipotriol, though burning sensation occurred in the treated lesions. Maxacalcitol ointment 25 µg/g was shown superior in terms of efficacy to other maxacalcitol concentrations (6, 12.5 and 50 µg/g) [16]. Mild side effects including erythema, burning, pruritus and edema have been observed in maxacalcitol-treated patients with negligible systemic effects. Becocalcidiol (QRX-101, QuatRx Pharmaceuticals Co.) is a vitamin D analog formulated as a 75 µg/g ointment. Preclinical studies showed a good safety profile and tolerability. A Phase IIb study assessed efficacy and safety in 185 subjects affected by chronic plaque-type psoriasis, randomly treated either with becocalcidiol, applied once or twice daily, or vehicle [17]. After 8 weeks, PGA score and psoriasis symptom severity (PSS) were evaluated showing superior efficacy of twice-daily becocalcidiol versus QRX-101 vehicle (p = 0.002), with 16 of 61 (26%) subjects achieving a PGA score of ‘clear’ or ‘almost clear’. PSS score confirmed a higher efficacy, though not statistically significant, of twice-daily becocalcidiol compared to vehicle. Overall, therapy was safe and well tolerated. Twice-daily becocalcidiol also demonstrated higher efficacy compared to once-daily becocalcidiol [17].
Emerging vitamin D3 derivates 3.
Vitamin D3 analogs were introduced in the treatment of psoriasis more than two decades ago. Three vitamin D3 analogs (calcitriol, calcipotriol and tacalcitol) resulted efficacious in the treatment of psoriasis [10-12]. Their efficacy is given by their capability in normalizing keratinocyte proliferation and differentiation [13]. Moreover, it has been demonstrated that they modulate the immune response and, thus, have an anti-inflammatory activity. An example of new 462
Combined therapies
Vitamin D3 derivatives and corticosteroids The efficacy in treating psoriasis with the combination of calcipotriol and betamethasone dipropionate as two-compound topical ointment is well documented. This combination synergistically acts on multiple steps of the pathogenic cascade as calcipotriol regulates keratinocyte differentiation and proliferation, and betamethasone shows anti-inflammatory 3.1
Expert Opin. Pharmacother. (2014) 15(4)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
New topical treatments for psoriasis
effects [18-21]. Because the beneficial effect of each agent is potentiated by this synergism, two combined compound may offer the possibility to reduce overall exposure to corticosteroids and occurrence of side effects [22,23]. Clinical studies revealed a reduction of local side effects induced by calcipotriol (irritant contact dermatitis and erythema) because of the antiinflammatory steroidal activity, though steroid-related side effects were still observed [22,23]. Because the ointment formulation, greasy and sticky, limits patient’s adherence to treatment, new formulations such as gel vehicle or spray were needed. New spray ointment (LEO 90100, LEO-Pharma A/S) and lipophilic, nonalcoholic gel formulations (LEO 80185, LEO-Pharma A/S) have been introduced as vehicle for calcipotriol/betamethasone combination [24,25]. LEO 80185 is an innovative two combined gel that has been recently marketed for the treatment of plaquetype psoriasis, while safety and efficacy of 4-week LEO 90100 treatment are investigated in Phase II trials [24,25]. Salicylic acid and corticosteroids Salicylic acid is a keratolytic agent usually formulated in ointment at 2 -- 6% concentration. Salicylic acid disrupts intra-keratinocyte adhesion in the upper most layer of the epidermis, facilitating the physiological shedding process [26]. Higher concentrations are usually prescribed with caution in case of hyperkeratotic areas occurring, for example, in palmoplantar or scalp localization. A topical ointment compound combining mometasone furoate 0.1% and salicylic acid 5% (SPS4251, Glenmark Pharmaceuticals Ltd.) has been evaluated to treat psoriatic lesions (evaluation of lesional parameters: erythema, size, scaling, itching, thickness). Safety, tolerability and antipsoriatic efficacy of three SPS4251 concentrations have been investigated in Phase I and II trials comparing SPS4251 to other topical agents (0.1% mometasone furoate, and one vitamin D derivate), though clinical results have not been reported yet [27]. 3.2
Nortriptyline HCl-containing compounds CRx-191 (Zalicus, Inc.) is a novel combined compound consisting in 0.1% mometasone furoate + 0.05% nortriptyline HCl [28]. The synergistic effect on psoriasis seems to be promising as it is reported to have anti-inflammatory effects, inhibiting key-pathogenic cytokines such as TNF-a and IFN-g. A Phase II trials will evaluate safety and efficacy comparing CRx-191 with CRx-191 vehicle and single CRx-191 agents in monotherapy (mometasone furoate and nortriptyline), intra-individually. Another two-compound topical combining nortriptyline is CRx-197-002, which consists in 0.1% nortriptyline HCl and 0.1/0.3% loratadine formulated as cream [29]. Its safety and efficacy was assessed in a single-center, randomized, blinded, Phase IIa trial comparing two strengths of CRx-197-002 (0.1% nortriptyline HCl + 0.1% loratadine and 0.1% nortriptyline HCl + 0.3% loratadine) with: i) vehicle; ii) a marketed topical agent (0.005% calcipotriol); and iii) 0.1% nortriptyline HCl topical cream [29]. 3.3
4.
New steroidal agents
Similarly to clobetasol, halobetasol propionate (Desenvolvimento Ltda.) is an ultra-potent corticosteroid with an apparent stronger anti-inflammatory and anti-proliferative activity compared to clobetasol. It is now investigated in Phase II trials as 0.05% lotion applied twice daily [30]. 5.
Blockade of neurogenic inflammation
It is likely an involvement of neurogenic inflammation in the pathogenesis of psoriasis, though its role and its relevance have not been yet clarified. Neuropeptides such as substance P, vasoactive intestinal peptide and nerve growth factor (NGF), which also act on the immune system, were found upregulated in lesional psoriatic skin [31]. Especially NGF seems to be immunologically active as it may stimulate T-cell activation, keratinocyte proliferation, neoangiogenesis, and the expression of adhesion molecules [31]. The potential efficacy of neuropeptide blockers in treating psoriasis has been suggested by the preliminary observations about the improvement of psoriasis phenotype using capsaicin and somatostatin [32,33]. CT-327 This new topical medication developed by Creabilis is an inhibitor of the kinase domain of TrkA, a high-affinity receptor for NGF. Acting on neurogenic inflammation and pruritus it was considered for the treatment of psoriasis and atopic dermatitis, two chronic skin disorders both characterized by itching [34]. After successfully passed Phase I trials, CT-327 has been investigated in Phase II studies, including a randomized, double-blind, placebo-controlled, dose-ranging Phase IIb trial investigating effectiveness, safety and tolerability of three dose strengths of CT-327 ointment (0.05, 0.1 and 0.005%) applied twice daily for 8 weeks in 160 patients affected by plaque-type psoriasis [34]. At baseline, 69% of patients reported at least moderate pruritus with a visual analog scale (VAS) > 40 mm. CT-327 therapy demonstrated significant benefits in treating skin symptoms, in particular, CT-327 was tested for the treatment of chronic pruritus associated with psoriasis showing a score reduction, assessing itching severity [34]. Overall, a significant hitching reduction was rendered with a VAS score a slow as 20 mm, observed in 79% of CT-327-treated patients, compared to 36% of vehicle group (p < 0.05). At week 8, CT-327 induced a 60% reduction of pruritus VAS score from baseline, compared to 20% of vehicle alone (p < 0.05) [34]. This clinical improvement correlated with a reduction in terms of PASI (mPASI, modified PASI) in all subjects. Regarding the safety profile, the drug proved to be safe and well tolerated. Subjects receiving CT-327 reported a low occurrence of adverse events with no system absorption and fewer number of withdrawals due to pruritus compared to patients using vehicle. Overall, Phase II studies enrolled 225 patients showing promising clinical outcomes, with no 5.1
Expert Opin. Pharmacother. (2014) 15(4)
463
A. Chiricozzi et al.
serious adverse events reported. Different concentrations (0.05, 0.1 and 0.5%) of topical CT327, applied twice daily for 8 weeks, have been tested in a multicenter, double-blind, randomized, placebo-controlled, Phase IIb study. Based on the satisfactory safety and efficacy profile, Phase III studies are currently in progress for the treatment of psoriasis [35,36].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
6.
Phosphodiesterase inhibitors
AN2728 [(5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole)] (Anacor Pharmaceuticals, Inc.) represents a synthetic phenoxybenzoxaborole, which inhibits phosphodiesterase 4 (PDE4) activity, and the release of TNF-a, IL-12, IL-23 and other cytokines [37]. Safety and efficacy of AN2728 have been tested in five Phase II trials and two Phase I trials (Table 1). Among them, a proof of concept study tested antipsoriatic effects of 5% AN2728 ointment versus 5% AN2728 cream, compared with their corresponding vehicles in subjects with stable psoriatic plaques [38]. As reported by the manufacturer, a clinical response was assessed after 12-day occlusive treatment with both AN2728 formulations on the basis of the sonographic and clinical measurements [38]. The improvement was significantly higher with both AN2728 formulations compared to vehicles, though no difference was detected between AN2728 formulations. In a single-center, vehicle- and comparator-controlled, randomized, observer-blind, initial dose-ranging, Phase Ib study comparing three strengths of AN2728 (5, 2 and 0.5%) with 0.1% tacrolimus, 0.1% valerate betamethasone and AN2728 ointment vehicle. Twelve subjects affected by psoriasis were treated applying each medication in occlusion to 6 different test areas for 12 days. A reduction in terms of infiltrate thickness was observed by sonographic and clinical measurement, though again, it was only statistically significant versus vehicle [38]. Overall, in both studies no adverse events occurred. MK-0873 (Merck & Co., Inc.) is a novel selective PDE4 inhibitor, initially evaluated for the treatment of chronic obstructive pulmonary disease [39]. Recently, it has been tested for psoriasis in various clinical trials as 0.5 or 2% cream applied once or twice daily compared to MK-0873 vehicle or to calcitriol 0.0003% (3 µg/g) in subjects affected by plaque-type psoriasis [40]. Manufacturer reported an amelioration of psoriasis phenotype using this medication. 7.
Janus-associated kinase inhibitors
In recent years, various therapeutics targeting janus-associated kinases (JAKs) have undergone design and development. JAKs constitute a family of protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK2, that, by activating signal transducers and activators of transcriptions (STATs), transduce pro-inflammatory and pro-proliferative stimuli [41,42]. In fact, multiple inflammatory and proliferative cytokines, considered pathogenically relevant in such as IL-12, IL-23, IL-17, IL-21, IL-22, IL-20 and interferons, signal through 464
the JAK/STAT pathway [41-44]. STAT1 and STAT3, which are both upregulated in lesional psoriatic skin, respectively, characterize Th1 and Th17 signaling. Selective JAK inhibition blocks both keratinocytes proliferation and inflammation, resulting in the reduction of epidermal hyperplasia, erythema and scaling [45]. Tofacitinib (CP-690,550, Pfizer), a JAKs inhibitor, interferes with the production of inflammatory cytokines involved in the pathogenesis of psoriasis [45,46]. It resulted effective as oral medication in treating psoriasis and topical formulation has been recently evaluated in a randomized, double-blind, vehicle-controlled Phase IIb trial [47]. In this study, two concentrations of tofacitinib ointment (10 and 20 mg/g) were administered once or twice daily for 12 weeks [47]. Another oral JAK-inhibitors used for prevention of rejection in transplantation and for treatment of immune-mediated inflammatory disorder is Ruxolitinib (INCB018424), a cyclopentyl propionitrile small molecule with pan-JAK inhibitory activity, that suppresses the production of inflammatory cytokines related to JAK signaling, such as IL-22, and IL-17 [48]. Safety, efficacy, tolerability and pharmacokinetics of INCB018424 were also investigated as phosphate cream in three concentrations (0.5, 1.0 and 1.5%) [49]. Topical applications once or twice daily proved effective in treating psoriasis with a clinical improvement of the lesion score (thickness, erythema and scaling) > 50%. The cream was applied and subsequently compared with vehicle and calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream [49]. No serious adverse events were reported [49].
Other non-steroidal anti-inflammatory agents
8.
MEK1/MEKK1 inhibitor E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (Eisai, Inc.) is a MEK1/MEKK1 inhibitor showing anti-inflammatory effects suppressing the production of pro-inflammatory cytokines from leukocytes and keratinocytes [50]. Moreover, E6201 has been shown to induce: i) in vitro suppression of lymphocyte activation and proliferation; and ii) an inhibition of neutrophil migration due to the suppression of IL-8 production by activated human keratinocytes [50]. E6201 also presents direct antiproliferative activity on cultured keratinocytes. Due to the in vitro activities on both immune cells and keratinocytes, it may thereby result effective in the treatment of psoriasis. Pre-clinical studies revealed the effectiveness of topical E6201, formulated as either an ointment or cream, in reducing acute edema formation and neutrophil infiltration into mouse skin [50]. A multicenter, double-blind, Phase II trial assessed efficacy and safety of topical E6201, administered once or twice daily, treating pre-identified target lesions in patients with chronic plaque-type psoriasis. The duration of treatment was 8 weeks, followed by a 4-week follow-up period. A 12-day, 8.1
Expert Opin. Pharmacother. (2014) 15(4)
New topical treatments for psoriasis
Table 1. Antipsoriatic topical agents in development.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
Agent
Manufacturer
Target
Phase of development
Formulation
AN2728 CT 327 E6201
Anacor Pharmaceuticals, Inc. Creabilis Therapeutics Eisai Ltd.
Phosphodiesterase-4 inhibitor TrkA kinase blocker MEK kinase inhibitor
II III II
Ruxolintinib (INCB18424) LEO 90100
Incyte Corp. - Novartis
JAK kinase inhibitor
III
Ointment 5%, cream 5% 0.05, 0.1 and 0.5% cream 0.03, 005, 0.01, 0.1, 0.2 and 0.05% gel 0.5, 1.0 and 1.5% cream
LEO Pharma
II
Spray, ointment
PH-10
Provectus Pharmaceuticals
Anti-inflammatory/anti-proliferative effect (proprietary) Skin cell inhibitor (Rose Bengal)
II
WBI-1001 Tofacitinib (CP-690,550) M518101
Welichem Biotech, Inc. Pfizer, Inc.
Anti-inflammatory (proprietary) JAK kinase inhibitor
II II
0.002, 0.005 and 0.01% Aqueous hydrogel 1% cream Ointment
Maruho Co., Ltd.
III
Ointment
BCT194 Pazopanib (GW786034) Bimosiamose (TBC1269) LAS41004
Novartis GlaxoSmithKline
Anti-inflammatory/skin cell inhibitor (proprietary) p38 kinase Anti-angiogenic and anti-proliferative effect Pan-selectin antagonist
I I
0.5% cream Ointment
II
5% cream
MK-0873 SPS4251 Antiflammin-2 ALT-2074 (SYI-2074) SHP-141
Revotar Biopharmaceuticals AG Almirall, S.A.
III
Proprietary
Merck & Co., Inc. Glenmark Pharmaceuticals Ltd. National Cancer Institute (NCI) Synvista Therapeutics, Inc.
Anti-inflammatory/skin cell inhibitor (proprietary) Phosphodiesterase-4 inhibitor Salicylic acid + corticosteroid Phospholipase A2 (PLA2) inhibitor Cytochrome P450 3A inhibitor
I II Pilot study II
0.5 and 2% cream Ointment Ointment 0.5% cream
Shape Pharmaceuticals Pty Ltd.
Histone deacetylase inhibitor
I
Cream
single-center, randomized, blinded, vehicle and active comparator (calcipotriene)-controlled, dose-ranging Phase II trial, which is designed to assess efficacy and safety of six concentrations of topical E6201 gel, was also performed. In this study, intra-individual comparison consisted of five topical treatments: three different concentrations of E6201, one gel vehicle (negative control) and one calcipotriene cream (positive control), simultaneously administered to each patients [51]. WBI-1001 WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene-1, 3-diol) is a synthetic compound with non-steroidal antiinflammatory properties (Table 1). The anti-inflammatory activity is primarily attributed to the suppression of T-cellderived pro-inflammatory cytokine production. Efficacy and safety of WBI-1001 have been evaluated for the treatment of various skin disorders. It has been successfully tested in both Phase I and II studies for the treatment of atopic dermatitis and psoriasis [52,53]. Bissonette et al. tested WBI-1001 in 61 psoriatic patients showing an involvement of 1 -- 10% of the BSA and a PGA score of 2 -- 4 [53]. Patients were randomly treated with either 1% WBI-1001 cream or placebo (ratio 2:1), applied twice daily for 12 weeks. Efficacy was evaluated using PGA, BSA and 8.2
PASI scores. After 12 weeks of treatment, a significant PGA and BSA amelioration was observed in 62.8% of WBI-1001-treated patients compared to placebo (13.0%, p < 0.0001). Additionally, 67.5% of patients randomized to WBI-1001 achieved a PGA of ‘clear’ or ‘almost clear’ and 79.1% showed an amelioration in terms of BSA, compared to 4.8% (p < 0.0001) and 9.4% (p < 0.0001) of placebo-treated patients, achieving the same response in terms of PGA and BSA scores, respectively [53]. Adverse events occurred more frequently in WBI-1001-treated patients than in those randomized to placebo. These adverse drug reactions appeared to be mild or moderate in intensity. PH-10 PH-10 (Provectus Pharmaceuticals) is an aqueous hydrogel formulation of 0.001% rose bengal disodium, designed for the treatment of inflammatory skin disorders, such as psoriasis and atopic dermatitis. Overall, previous Phase I and II trials tested PH-10 in 217 patients affected by psoriasis. Other Phase II trials completed patient recruitment such as a multicenter study using different concentrations of topical PH-10 (0.002, 0.005 and 0.01%), applied once daily; another trial investigating safety and efficacy of 0.001% PH-10 aqueous hydrogel combined with ambient 8.3
Expert Opin. Pharmacother. (2014) 15(4)
465
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
A. Chiricozzi et al.
light exposure or 544 nm light-emitting diodes light illumination at 10 J/cm2 [54]. The manufacturer reported clinical outcomes from a multicenter, randomized, placebocontrolled Phase IIc trial (PH-10-PS-23) including 99 subjects affected by mild-to-moderate plaque type psoriasis, receiving daily application of PH-10 (0.01, 0.005 or 0.002%) or placebo for 28 days. Clinical success was defined as the achievement of a 0 or 1 score for all Psoriasis Severity Index (PSI) components, and 0 or 1 score on the Plaque Response Scale. Pruritus (itching) Self-Assessment Scale was also measured. At Day 29, a better efficacy profile was obtained with low dose of PH-10 (0.002%) [55]. After a 28-day treatment with PH-10 (all strengths), 23 -- 29% of subjects experienced a ‘complete’ or ‘nearly complete’ resolution of all PSI components, compared to none of the subjects in the placebo arm [55]. Pan-selectin antagonist Usually selectins are considered crucial adhesion molecules mediating migration (rolling and trafficking) of blood inflammatory cells into peripheral tissue. Bimosiamose/TBC1269 (Revotar Biopharmaceuticals AG) is an anti-inflammatory agent antagonizing P-selectin, E-selectin and L-selectin and, thus, blocking leukocyte extravasation (Table 1). It is now being tested for topical use in psoriasis, delivering satisfactory preliminary results in both pre-clinical and clinical studies. A multicenter, randomized, double-blind, placebo-controlled, Phase II trial was executed to evaluate safety and efficacy of 5% Bimosiamose/TBC1269 cream in 107 patients affected by plaque-type psoriasis [56]. 8.4
BCT194 Among the signal transducers playing a key role in inflammatory response, the p38 kinase is central in the regulation of inflammatory mediator production such as TNF-a, IL-1b, IL-6 and IL-8 (Table 1). The inflammatory pathways mediated by p38 kinase suggest a potential indication for the treatment of psoriasis. The p38 inhibitor, BCT194 (Novartis), is topically used as 0.5% cream. Recently pharmacodynamics and pharmacokinetics were explored in two Phase I studies. Preliminary results were described in a Phase I study assessing pharmacodynamics and pharmacokinetics in nine subjects affected by psoriasis [57]. The drug was applied once daily for 8 days showing a satisfactory safety profile associated with a conspicuous drug concentrations within tested skin areas, which was measured using membrane-free dermal open-flow microperfusion probes. 8.5
Indirubin This oil ointment containing indigo naturalis is now tested at different concentrations 200, 100, 50 and 10 µg/g. Indigo naturalis is traditional Chinese herbal medicine derived from Strobilanthes formosanus Moore plant. It may be effective in treating psoriasis because it interferes with various pathogenic mechanisms as shown by in vitro 8.6
466
inhibition of TNF-a and vascular cell adhesion molecule1 (VCAM-1) expression in primary cultured human umbilical vein endothelial cells [58]. Therefore, indigo naturalis demonstrated anti-inflammatory effects helping to improve psoriasis. Phase II and III studies are currently ongoing. 9.
Topical calcineurin inhibitors
Calcineurin inhibitors show the capability in suppressing T-cell activation and proliferation as they prevent the dephosphorylation of the nuclear factor of activated T cells inhibiting the production of pro-inflammatory cytokines such as TNF-a, IFN-g, IL-2, IL-17 and IL-22 [59]. Topical calcineurin inhibitors, namely pimecrolimus and tacrolimus, are only approved for the treatment of atopic dermatitis, though their off-label use is progressively more common also for the treatment of psoriasis. Their efficacy in treating psoriasis is still controversial because their penetration into hyperkeratotic psoriatic plaques seems to be limited, and thus, they might be considered as valid alternatives for the treatment of intertriginous areas and more sensitive body sites such as the face and genital areas where the absorption is naturally increased [60-63]. A double-blind, randomized, vehicle-controlled study, testing 0.1% tacrolimus ointment on 167 subjects affected by facial or intertriginous psoriasis, showed a ‘clear’ or ‘almost clear’ outcome in 65% of cases after 8-week treatment compared to 31% of placebo group [64]. In a double-blind, randomized, vehicle-controlled study, 57 patients with intertriginous psoriasis were treated twice daily with 0.1% pimecrolimus cream for 8 weeks. Seventy-one percent of cases achieved a ‘clear’ or ‘almost clear’ clinical assessment after 8 weeks in the pimecrolimus group, compared to 21% of the placebo group [65]. Calcineurin inhibitors proved a satisfactory safety profile as mild side effects (itching, stinging and feeling of warmth) may occur. The advantage related to the use of calcineurin inhibitors is the absence of typical long-term side effects of steroids (i.e., atrophy), although no long-term and large studies, so far, have confirmed their safety in psoriasis treatment [66]. Their efficacy is likely comparable to medium/high topical corticosteroids [67]. They might be used in combination with phototherapy [68]. For the management of psoriasis, they may be used for not only the treatment of ‘special areas’ such as face, genital and flexural areas, but also as maintenance therapy after a satisfactory steroid therapy, in order to gradually obtain a reduced steroid exposure. Eventually, to increase the limited penetration of these agents, they could be applied under occlusion or in combination with keratolytics such as salicylic acid and urea [69]. 10.
Anti-proliferative agents
PTH (1-34) PTH (1-34) (Manhattan Pharmaceuticals) represents a topical parathyroid hormone (1-34) [PTH (1-34)] compound 10.1
Expert Opin. Pharmacother. (2014) 15(4)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
New topical treatments for psoriasis
showing potent inhibitory effects on keratinocyte proliferation. Cream and gel have been selected as topical formulations for PTH (1-34). In 2003, topical PTH (1-34), formulated in Novasome A cream, was tested at two different strengths and with two different therapeutic schemes [70]. Patients, who failed at least one of the conventional topical medications, were treated with 20 or 50 µg PTH (1-34), applied twice daily or once daily, respectively, for 2 months, and they experienced 67.3% improvement in psoriasis severity compared with the vehicle-treated patients, showing a 17.8% improvement. Overall, an improvement of 42.6% in terms of PASI score (p < 0.02) was observed using PTH (1-34) without the occurrence of hypercalcaemia or hypercalciuria [70]. Furthermore, different concentrations (0.10 and 0.05%) of PTH (1-34) have been used in gel formulation in a multi-center, randomized, double-blind, placebo-controlled, Phase II trial, assessing their safety and efficacy. M518101 M518101 (Maruho North America, Inc.) is defined as a skin cell inhibitor/anti-inflammatory, similar to a vitamin D derivate (Table 1). It is formulated as an ointment and is currently being tested in Phase III trials. Interestingly, a head-to-head Phase II study compared two different doses of M518101, applied twice daily, to a vitamin D3 ointment already on the market (calcipotriol) [71]. Clinical outcomes have not yet been published, but the comparison between M518101 and calcipotriol would be relevant should M518101 prove as effective as calcipotriol with the benefit of a reduced occurrence of side effects. 10.2
Topical epidermal growth factor Topical epidermal growth factor (EGF) (Ennar Pharmaceuticals) represents an interesting approach to contrast keratinocyte proliferation and, therefore, to block the formation of pathogenic auto-sustaining circuits. EGF-receptor (EGFR) was found overexpressed in lesional psoriatic skin and effective antipsoriatic therapies induced its suppression [72,73]. EGF is shown to downregulate EGFR expression [74]. Because of these observations, it has been hypothesized an eventual therapeutic approach based on EGF stimulation. First studies using topical EGF are being reported more than two decades ago [75]. Experimental psoriasis model treated with topical EGF showed a regression of the psoriasis skin phenotype. Beside a marked anti-proliferative effect on keratinocytes, the blockade of EGFR may interfere with the innate immune activation (IL-8 and AMPs production), occurring in the early phase of psoriasis [76]. 10.3
11.
New coal tar formulations
Coal tar may be considered a historical therapeutic that has been used for > 100 years. It is available in various formulations including ointment, cream, gel, lotion, shampoo and soap. Its efficacy in treating psoriasis is likely due to its
suppressive effect on keratinocyte proliferation. Therapeutic benefit of coal tar therapy seems to maintain with a liquor carbonis distillate (LCD) in a novel solution. Psorent (Neo Strata Co.) is constituted by 15% LCD, showing rapid absorption, ease of use and a better odor compared to the traditional coal tar products. Indeed, the uncomfortable cosmetic feature of coal tar-derived products (its natural odor and staining formulations) strongly limited their use with a poor adherence to treatment. This new solution will be aesthetically and cosmetically more appealing in order to increase patient acceptability. 12.
Conclusion
This overview is aimed to increase the interest on topical therapies and update the ‘state of the art’ on this field reporting those compounds that are currently available or tested in clinical trials. New formulations and novel therapeutic agents will increase the opportunity to treat patients topically and more effectively. 13.
Expert opinion
The large majority of psoriatic patients suffer from a mild or mild-to-moderate that is conventionally treated with topical therapies or phototherapy. Topical medications have shown an important limit in terms of efficacy and patient adherence. Notably, mild to moderate psoriasis may impair patient’s quality of life or it may harm psycho-social life, particularly for psoriasis localized at the scalp, face or genital areas. Actually two consistent classes of agents are commonly used: corticosteroids and vitamin D analogs, both prescribed as monotherapy or in two combined treatments. Additionally, salicylic acid, coal tar and calcineurin inhibitors represent other agents that may be topically administered. The use of topical agents including vitamin D derivates, salicylic acid or coal tar may be associated with poor tolerability while the continuous long-term treatment with corticosteroids may cause skin atrophy, telangiectasias and tachyphylaxis. The introduction of two combined compounds (corticosteroids associated with vitamin D derivates, coal tar or salicylic acid) represents an advanced approach as the two agents can act in synergism allowing to use lower concentrations of medium-potency corticosteroids. Greasy or oily medications negatively affect patient’s adherence to treatment as well as the time spent per day to apply topical medications. In order to increase patient’s adherence and thus efficacy, cosmeceutical engineering is keen to improve drug formulations creating more agreeable, aesthetically more appealing (color, odor), cosmetically easy to use (gel, spray, foam) and sparing-time compounds. A better efficacy and a better control of the disease with topical agents constitute a crucial goal as it would delay the use of systemic therapies, with important implication for patient’s health and public health economy.
Expert Opin. Pharmacother. (2014) 15(4)
467
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
A. Chiricozzi et al.
Because topical therapies are conventionally considered the first-line therapeutic approach, a broader array of compounds in different formulations is needed. Although it apparently seems that a large number of topical medications is available (active drugs, over-the-counter products), in daily clinical practice, it resulted smaller because of intolerability and inefficacy, thus, limiting the opportunity to ‘tailor’ the treatment on patient’s needs. Following the high interest in developing systemic drugs for the treatment of moderate-to-severe psoriasis, pharmaceutical companies are deeply committed to design new topical medications. Some of these new agents are constituted by innovative vehicles that may help to improve skin penetration, exploiting, for instance, the nanotechnology. In fact, traditional emollients or moisturizing cream are insufficient to deliver active ingredients in adequate amounts to active sites, conversely, nano-emulsions may increase drug delivery to the skin [77]. Oil/water nano-sized carriers are promising colloidal drug carrier systems for diverse therapeutic applications showing favorable properties as they become invisible with a good sensory texture and non-greasy feel. Furthermore some emerging topical agents selectively target disease-defining pathogenic pathways such as JAK/STAT signaling or PDE signaling. It is highly interesting the Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
8.
Scha¨fer T. Epidemiology of psoriasis. Review and the German perspective. Dermatology 2006;212:327-37 9.
development of topically delivered selective blockers targeting pathogenic aspects such as neurogenic inflammation, immune-mediated inflammation or epidermal hyperplasia. Preliminary clinical outcomes seem to be promising although there is a limited availability of long-term and large-scale studies assessing safety and efficacy of these new agents. Moreover, it is hard to predict their potentiality as head-to-head studies comparing them with approved therapeutics are lacking. Overall, we may hypothesize that the advantage of having new topical therapies is given by a larger array of topical options, allowing controlling the disease for longer periods, through rotational or combined schemes and thus, beneficially delaying the use of systemic therapies. Having some novel topical therapies in an advanced stage of development, broader therapeutic armamentarium will be possibly available, giving the chance to associate different medications and seek to personalize the topical treatment approach to each patient.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Walsh JA, McFadden M, Woodcock J, et al. Product of the Physician Global Assessment and body surface area: a simple static measure of psoriasis severity in a longitudinal cohort. J Am Acad Dermatol 2013;69:931-7 Gottlieb AB, Chaudhari U, Baker DG, et al. The National Psoriasis Foundation Psoriasis Score (NPF-PS) system versus the Psoriasis Area Severity Index (PASI) and Physician’s Global Assessment (PGA): a comparison. J Drugs Dermatol 2003;2:260-6
2.
Bowcock AM, Krueger JG. Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 2005;5:699-711
3.
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866-73
4.
Voorhees JJ. Pathophysiology of psoriasis. Annu Rev Med 1977;28:467-73
10.
5.
Barker JN, Karabin GD, Stoof TJ, et al. Detection of interferon-gamma mRNA in psoriatic epidermis by polymerase chain reaction. J Dermatol Sci 1991;2:106-11
Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol. Arch Dermatol 1989;125:1647-52
11.
Reichrath J, Perez A, Muller SM, et al. Topical calcitriol (1,25-dihydroxyvitamin D3) treatment of psoriasis: an immunohistological evaluation. Acta Derm Venereol 1997;77:268-72
6.
7.
..
468
Chiricozzi A, Zhang S, Dattola A, et al. Role of Th17 in the pathogenesis of cutaneous inflammatory diseases. J Biol Regul Homeost Agents 2012;26:313-18 Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis 2005;64:ii65-8; discussion ii69 Comprehensive overview on clinical severity assessment tools.
12.
O Neill JL, Feldman SR. Vitamin D analogue-based therapies for psoriasis. Drugs Today (Barc) 2010;46:351-60
13.
Tanghetti EA. The role of topical vitamin D modulators in psoriasis therapy. J Drugs Dermatol 2009;8:s4-8
14.
Feldman SR, Eastman WJ, Brundage T, et al. A multicenter, randomized, Expert Opin. Pharmacother. (2014) 15(4)
.
double-blind study of the efficacy and safety of calcipotriene foam, 0.005%, vs vehicle foam in the treatment of plaque-type psoriasis of the scalp. J Drugs Dermatol 2013;12:300-6 First publication on efficacy and safety of calcipotriene in foam formulation.
15.
Available from: http://clinicaltrials.gov/ ct2/results?term=calcipotriene+FOAM +0%2C005%25&Search=Search
16.
Barker JN, Ashton RE, Marks R, et al. Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study with active comparator. Br J Dermatol 1999;141:274-8 Relevant publication on efficacy and safety of maxacalcitol in treating psoriasis.
.
17.
.
18.
Helfrich YR, Kang S, Hamilton TA, et al. Topical becocalcidiol for the treatment of psoriasis vulgaris: a randomized, placebo-controlled, double-blind, multicentre study. Br J Dermatol 2007;157:369-74 Efficacy and safety of becocalcidiol in treating psoriasis. Anstey AV, Kragballe K. Retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/
New topical treatments for psoriasis
betamethasone dipropionate ointment. Int J Dermatol 2006;45:970-5 19.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
20.
21.
22.
23.
Papp KA, Guenther L, Boyden B, et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol 2003;48:48-54 Saraceno R, Gramiccia T, Frascione P, et al. Calcipotriene/betamethasone in the treatment of psoriasis: a review article. Expert Opin Pharmacother 2009;10:2357-65 Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002;82:131-5 Kragballe K, Austad J, Barnes L, et al. A 52 -week randomized safety study of calcipotriol/betamethasone dipropionate two compound product (Dovobet/ Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol 2006;154:1155-60 Saraceno R, Camplone G, D’Agostino M, et al. Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiol gel) in the treatment of scalp psoriasis: results from a study in 885 patients. J Dermatolog Treat 2013. [Epub ahead of print]
24.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01347255?term=LEO +90100+and+psoriasis&rank=1
25.
Fleming C, Ganslandt C, Guenther L, et al. Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol 2010;20:465-71
26.
Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol 1999;38:16-24
27.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01743118?term=SPS4251 +and+psoriasis&rank=1
28.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00557739?term=CRx-191 +and+psoriasis&rank=1
29.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00796211?term=CRx-197002&rank=1
30.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01610596? term=halobetasol+propionate+and +psoriasis&rank=3
31.
Saraceno R, Kleyn CE, Terenghi G, Griffiths CE. The role of neuropeptides in psoriasis. Br J Dermatol 2006;155:876-82
32.
Bernstein JE, Parish LC, Rapaport M, et al. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15:504-7
33.
Weber G, Klughardt G, Neidhart M, et al. Treatment of psoriasis with somatostatin. Arch Dermatol Res 1982;272:31-6
34.
Available from: http://www.creabilis-sa. com/ct-327/
35.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01465282?term=CT+327 +and+psoriasis&rank=2
36.
Available from: http://www.centerwatch. com/news-online/article/3070/creabilisbegins-phase-iib-trial-of-ct327-in-psoriasis
37.
Nazarin R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs 2009;10:1236-42 First publication on AN-2728 as potential therapeutic agents for the treatment of inflammatory skin disorders.
.
38.
Available from: http://www.anacor.com
39.
Available from: http://clinicaltrials.gov/ show/NCT00132730
40.
Available from: http://clinicaltrials.gov/ ct2/results?term=MK-0873+AND +PSORIASIS&Search=Search
41.
Cassano N, Vena GA. Janus kinase inhibition as a potential strategy for the treatment of psoriasis: state of the art and future perspectives. J Biol Regul Homeost Agents 2012;26:587-96
42.
Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol 2012;83:1136-45
43.
Mak RK, Hundhausen C, Nestle FO, et al. Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr 2009;100:2-13
44.
Jabbari A, Jhonson-Huang LM, Krueger JG. Role of the immune system and immunological circuits in psoriasis. G Ital Dermatol Venereol 2011;146:17-30
Expert Opin. Pharmacother. (2014) 15(4)
45.
.
Ports WC, Khan S, Lan S, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol 2013;169:137-45 First publication regarding the treatment of psoriasis with tofacitinib.
46.
Flagan ME, Blumenkopf TA, Brisette WH, et al. Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem 2010;53:8468-84
47.
Available from: http://clinicaltrials.gov/ct2/ show/NCT01831466?term=CP-690% 2C550%2CPfizer+and+psoriasis&rank=13
48.
Callis Duffin K, Luchi M, et al. Novel mechanism for topical treatment of plaque psoriasis - results of a randomized, double blind, concentration ranging, vehicle controlled 12 week study with JAK 1/2 inhibitor INCB018424 cream [abstract 261]. 2010 Annual Meeting of the Society for Investigative Dermatology, Hilton Atlanta, Atlanta, Georgia, May 5-8. J Invest Dermatol 2010;130:S44 Important clinical outcomes using INCB018424 cream.
.
49.
.
Punwani N, Scherle P, Flores R, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol 2012;67:658-64 Another relevant paper about the use of INCB018424 cream.
50.
Muramoto K, Goto M, Inoue Y, et al. E6201, a novel kinase inhibitor of mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase -1 and mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. J Pharmacol Exp Ther 2010;335:23-31
51.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00539929? term=E6201&rank=2
52.
Bissonnette R, Chen G, Bolduc C, et al. Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis: results from a phase 2 a, randomized, placebo-controlled clinical trial. Arch Dermatol 2010;146:446-9 Efficacy and safety of topical WBI-1001 in the treatment of atopic dermatitis.
.
469
A. Chiricozzi et al.
Bissonnette R, Bolduc C, Maari C, et al. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial. J Eur Acad Dermatol Venereol 2012;26:1516-21 Efficacy and safety of topical WBI-1001 in the treatment of psoriasis.
62.
Bissonette R, Nigen S, Bolduc C. Efficacy and tolerability of topical tacrolimus of male genital psoriasis. J Cutan Med Surg 2008;12:230-4
63.
Freeman AK, Linowski GJ, Brady C, et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 2003;48:564-8
54.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00941278?term=PH-10 +and+psoriasis&rank=2
64.
55.
Available from: http://www.centerwatch. com/news-online/article/3092/alerts.aspx
56.
Available from: http://clinicaltrials.gov/ ct2/show/NCT00823693? term=bimosiamose+AND+5+%25+cream +AND+psoriasi&rank=1
57.
Bodenlenz M, H€offerer C, Magnes C, et al. Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling. Eur J Pharm Biopharm 2012;81:635-41
53.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/18/14 For personal use only.
.
58.
59.
60.
61.
470
Chang HN, Pang JH, Yang SH, et al. Inhibitory effect of indigo naturalis on tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells. Molecules 2010;15:6423-35 Haider AS, Lowes MA, Suarez-Farinas M, et al. Identification of cellular pathways of “Type1”, Th17 cells, and TNF-and inducible nitril oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine a in psoriasis. J Immunol 2008;180:1913-20 Brune A, Miller DW, Lin P, et al. Tacrolimus ointment is effective for psoriasis on the face intertriginous areas in pediatrics patients. Pediatr Dermatol 2007;24:76-80 Steele JA, Choi C, Kwong PC. Topical tacrolimus in the treatment of inverse psoriasis in children. J Am Acad Dermatol 2005;53:713-16
Lebwohl M, Freeman AK, Chapman MS, et al. Tacrolimus ointment is effective for facial and intertriginous psoriasis. J Am Acad Dermatol 2004;51:723-30
65.
Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol 2004;51:731-8
66.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009;60:643-59
67.
68.
Kreuter A, Sommer A, Hyun J, et al. 1% pimecrolimus, 0.005% calcipotriol, and 0.1% bethamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study. Arch Dermatol 2006;142:1138-43 Ahn SJ, Oh SH, Chang SE, et al. A case of infantile psoriasis with pseudoainhum successfully treated with topical pimecrolimus and low-dose narrowband UVB phototherapy. J Eur Acad Dermatol Venereol 2006;20:1332-4
69.
Chiricozzi A, Chimenti S. Effective topical agents and emerging perspectives in the treatment of psoriasis. Expert Rev Dermatol 2012;7:283-93
70.
Holick MF, Chimeh FN, Ray S. Topical PTH (1-34) is a novel, safe and effective treatment for psoriasis: a randomized self-controlled trial an open trial. Br J Dermatol 2003;149:370-6
71.
Available from: http://clinicaltrials.gov/ ct2/show/NCT01873677?term=M518101 +and+psoriasis&rank=2
Expert Opin. Pharmacother. (2014) 15(4)
72.
Boisseau-Garsaud AM, Donatien P, Margerin C, et al. EGF Receptor expression and growth of psoriatic and normal human keratinocytes are modulated by 1,25 (OH)2-vitamin D3 ex vivo. Arch Dermatol Res 1996;288:453-7
73.
Keme´ny L, Michel G, Arenberger P, Ruzicka T. Down-regulation of epidermal growth factor receptors by dithranol. Acta Derm Venereol 1993;73:37-40
74.
Gilligan A, Bushmeyer S, Knowles BB. Variation in EGF-induced EGF receptor downregulation in human hepatomaderived cell lines expressing different amounts of EGF receptor. Exp Cell Res 1992;200:235-41
75.
Nanney LB, Yates RA, King LE Jr. Modulation of epidermal growth factor in psoriatic lesions during treatment with topical EGF. J Invest Dermatol 1992;98:296-301
76.
Roupe´ KM, Nybo M, Sj€obring U, et al. Injury is a major inducer of epidermal innate responses during wound healing. J Invest Dermatol 2010;130:1167-77
77.
Saraceno R, Chiricozzi A, Gabellini M, et al. Emerging applications of nanomedicine in dermatology. Skin Res Technol 2013;19:e13-19
Affiliation Andrea Chiricozzi1,2 MD, Rossella Pitocco1 MD, Rosita Saraceno1 MD, Steven Paul Nistico3 MD, Alessandro Giunta1 MD & Sergio Chimenti†1 MD † Author for correspondence 1 University of Rome Tor Vergata, Department of Dermatology, Via Montpellier 1, 00133 Rome, Italy Tel: +39 339 566 8320; Fax: +39 062 090 2742; E-mail: [email protected] 2 The Rockefeller University, Laboratory for Investigative Dermatology, 1230 York Avenue, 10065 New York, NY, USA 3 Magna Graecia University, Department of Health Sciences, Catanzaro, Italy
