Expert Opinion on Emerging Drugs
ISSN: 1472-8214 (Print) 1744-7623 (Online) Journal homepage: http://www.tandfonline.com/loi/iemd20
Emerging topical treatments for psoriasis Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter To cite this article: Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter (2013) Emerging topical treatments for psoriasis, Expert Opinion on Emerging Drugs, 18:4, 523-532, DOI: 10.1517/14728214.2013.861418 To link to this article: http://dx.doi.org/10.1517/14728214.2013.861418
Published online: 26 Nov 2013.
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Review
Emerging topical treatments for psoriasis
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Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter† 1.
Background
Baylor University Medical Center, Department of Dermatology, Dallas, TX, USA
2.
Medical need
3.
Existing treatments
4.
Current research goals
5.
Scientific rationale
6.
Competitive environment
7.
Potential development issues
8.
Conclusion
9.
Expert opinion
Introduction: Psoriasis is an immune-mediated chronic inflammatory skin disease which classically presents as erythematous, scaly plaques affecting extensor surfaces of the limbs, scalp and trunk. Approximately 80% of patients have a mild-to-moderate form routinely treated with topical medications, whereas phototherapy, systemic and biological therapies are typically reserved for treatment of moderate-to-severe psoriasis. Areas covered: The major advances in psoriasis therapy in the past 15 years have been in new immunomodulatory and biological molecules, with a significant unmet need to have new, efficient and safe topical treatment options for the large percentage of patients for whom systemic therapy is not indicated. The available topical therapies (corticosteroids and vitamin D3 analogs) have remained relatively unchanged over the past several decades. This article reviews emerging topical drugs and formulations currently under evaluation in clinical trials. Expert opinion: The time is right for a revolution in our topical therapy armamentarium. It has lagged significantly behind the systemic biological evolution of new drug development. Our large psoriasis population with mild-to-moderate psoriasis certainly deserves potent but safe and innovative topical agents with a new mode of action as well as with long-lasting clinical efficacy. Keywords: psoriasis, therapeutics, topical administration Expert Opin. Emerging Drugs (2013) 18(4):523-532
1.
Background
Psoriasis is a chronic inflammatory disease affecting 1 -- 2% of the population worldwide [1]. Clinically, psoriasis presents as well-demarcated, raised, erythematous, scaly plaques predominantly affecting the scalp, trunk and extensor surfaces; however, any body site can also be involved. Psoriasis is a psychologically debilitating disease and can have profound impact on patients’ quality of life regardless of the degree of body surface area (BSA) involvement. Mild-to-moderate psoriasis affects ~ 80% of the total psoriasis population worldwide [2]. Topical medication is typically used as first line of treatment in mild psoriasis but can also be used concomitantly with phototherapy, systemic or biological therapies for moderate-to-severe psoriasis. This article will review emerging topical treatments for psoriasis which include Janus-associated kinase (JAK) and other kinase inhibitors, signal transducers and activators of transcription (STAT) and pan-selectin inhibitors, phosphodiesterase-4 (PDE4) inhibitors, nonsteroidal anti-inflammatories and vitamin D analogs. We based our search on information released by the National Psoriasis Foundation about clinical trials of new topical agents for psoriasis.
10.1517/14728214.2013.861418 © 2013 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted
523
D. N. Kivelevitch et al.
5.
Scientific rationale
Article highlights. .
. .
Moderate to severe psoriasis affects 80% of the psoriasis population. Topical therapies are the first line of treatment for this group of patients. There is an unmet need for more effective and safer topical agents. New therapeutic groups are being studied for topical therapy (i.e., JAK, PDE4 and STAT inhibitors, pan-selectin antagonists and other new anti-inflammatory agents).
This box summarizes key points contained in the article.
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2.
Medical need
In the past decade, increasing insight into the immunopathogenesis of psoriasis has led to the development of a multitude of targeted biological therapies which have revolutionized treatment for moderate-to-severe psoriasis, including interleukin (IL)-17 and IL-12/23 inhibitors [3-6]. While extensive research has been performed for new biological therapies for moderate-to-severe psoriasis, new therapeutic class of agents for milder disease have remained relatively stagnant over the past 20 years. Topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis but are not without side effects [7,8]. Thus, there is fertile ground for further research into new topical agents that have the potential to be safer and more effective short-term and long-term alternatives to our current therapies.
3.
Existing treatments
Since its appearance > 35 years ago, high potency topical steroids have been the most efficacious topical therapy available. Side effects of topical corticosteroid preparations include cutaneous atrophy, hypopigmentation, tachyphylaxis and hypothalamic-pituitary-adrenal axis suppression with more widespread body surface usage (Table 1) [9]. Vitamin D derivatives are often utilized as a steroid-sparing alternative but are also not without side effects, among which include skin irritation (e.g., in folds and on the face) and hypercalcemia (Table 2) [10]. In addition, other topical treatments, including tar, dithranol, calcineurin inhibitors and retinoids, are available as therapeutic options. Concerns regarding side effects and loss of efficacy with prolonged use make it important to look for new treatment alternatives.
4.
Current research goals
This article reviews ongoing clinical research trials in topical treatments for psoriasis providing an update to the healthcare community regarding the upcoming developments in this area. 524
Psoriasis is an immune-mediated chronic inflammatory disease in which inflammation and cell proliferation can occur in excess. The immunopathogenesis encompasses a multitude of signaling steps that can be targeted in order to exert a specific therapeutic effect [11,12]. The kinase/ STAT pathway and PDE4 involve intracellular signal transduction necessary for inflammation to develop [13-16]. Pan-selectin antagonists inhibit leukocyte extravasation by affecting the ability of immune cells to roll and migrate, thereby reducing inflammation [17,18]. Finally, the mechanism of action of nonsteroidal anti-inflammatory agents mentioned in this article are as yet not completely known but have been shown to decrease cytokine production and cellular proliferation -- the two major aspects of psoriasis immunopathogenesis. 6.
Competitive environment (Table 3)
JAK inhibitors JAKs play an integral role in signal transduction from several cytokines implicated in the physiopathology of psoriasis, including IL-12, IL-23, and interferon gamma (IFN-g). JAKs, a form of tyrosine kinase, target signal transducers and activators of transcription (STAT) and regulate proliferation, inflammation, cell activation and survival [13]. Specifically, by suppressing IL-23 receptor expression, these agents inhibit IL-23 signaling and thus reduce T-helper (TH17) cell differentiation. Inhibition of JAK1 also weakens signaling via IL-6, IFN-g, and type 1 IFN [19]. Thus, by targeting JAKs, investigative treatments may elicit both anti-inflammatory and antiproliferative properties. 6.1
Ruxolitinib (INCB018424, Incyte Pharmaceuticals and Novartis)
6.1.1
INCB018424, a novel JAK1/2 inhibitor was tested topically for psoriasis in a double-blind and vehicle or active comparator-controlled study [20]. Twenty-seven adult patients with stable chronic plaque psoriasis were enrolled in the trial. Two similar psoriatic plaques were selected for treatment in each patient with one treated with INCB018424 creams and a matching plaque with vehicle cream or active comparator (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream once or twice daily [q.d. or b.i.d.]) and followed weekly for 28 days. A greater reduction in lesion area was observed in plaques treated with higher concentrations (1 and 1.5%) and increased frequency of application (b.i.d. vs q.d.) of INCB018424, whereas little change in mean lesion area was seen for vehicle-treated lesions. Mean total lesion score (scaling, redness and thickness) decreased by 53% with 1% INCB018424 cream q.d. (p = 0.033) and 54% (p = 0.056) with 1.5% b.i.d., compared to a 32% reduction in the vehicle arm. Response to the 0.5% cream was similar
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Emerging topical treatments for psoriasis
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Table 1. Reported AEs in pediatric patients, according to the FDA report. Event
Frequency (n = 202)
Local irritation Skin depigmentation or discoloration Striae or skin atrophy Cushing syndrome Growth retardation Hyperglycemia (diabetes) Scarring Staphylococcal infection Genital hypertrichosis Hirsutism Rosacea Acne Glaucoma Hypersensitivity reaction Adrenal insufficiency Bruising Fungal infection Gynecomastia Perioral dermatitis Mental status or mood change
66 30 30 6 5 5 5 4 4 4 3 3 3 3 2 2 2 2 2 2
6.2
Other kinase inhibitors CT327 (Creabilis SA)
6.2.1
AEs that occurred in fewer than two reports are not listed.
to that of the vehicle arm. After 30 days of INCB018424 1.5% cream b.i.d., the reduction in mean lesion area was slightly better than that of calcipotriene 0.005% cream but not as good as the effect seen with betamethasone dipropionate 0.05% cream b.i.d. The mean plasma concentrations of INCB018424 were < 1% of the concentrations required for systemic activity; therefore, systemic adverse events (AEs) were unlikely drug-related. There were no serious AEs (SAEs) or discontinuations due to AEs reported during the study. Local AEs included stinging, itching, irritation, pain, dryness, exfoliation and/or redness at the application site and were all mild or moderate in severity [20]. More studies with a larger population are needed to clearly establish the efficacy of INCB018424. Nevertheless, despite the limited sample of patients, this study suggests that topical JAK inhibitors may have a potential role in the dermatological topical therapeutic arsenal for psoriasis. Tofacitinib, (Pfizer, Inc.) Tofacitinib, a novel, small-molecule JAK inhibitor, acts by selectively inhibiting signaling by heterodimers containing JAK3 and/or JAK1. It has been developed as an oral agent to treat rheumatoid arthritis, ulcerative colitis, Crohn’s disease and psoriasis, in addition to preventing transplant rejection [21]. It is currently approved for rheumatoid arthritis in the United States, and oral tofacitinib is in late stage development for the systemic treatment of psoriasis. A Phase IIa, randomized, double-blind, parallel-group, vehicle-controlled trial of topical tofacitinib was conducted in 71 patients who were randomized to 2% tofacitinib or placebo in two different vehicles for twice daily application to a target plaque area for 4 weeks [19]. The 6.1.2
primary end point of percentage change from baseline in target plaque severity score (TPSS) at week 4 revealed a difference of -12.87% between ointment 1 (-54.4%) and vehicle 1 (-41.5%), but no significant difference for ointment 2 (-24.2%) and vehicle 2 (-17.2%), where negative values represent a reduction in TPSS and a favorable treatment effect. No SAEs were reported and the only AEs to occur in more than one patient were nasopharyngitis (n = 4) and urinary tract infection (n = 3). The number of patients who reported burning or stinging at the treatment site was small and occurred with similar frequency across all groups [19].
CT327 reduces inflammation via the inhibition of tyrosine kinase receptor type 1, a high-affinity nerve growth factor receptor. Additionally, it also targets sensory neurons implicated in chronic pruritus [22]. A recent Phase IIa study assessed the safety and efficacy of 0.1% CT 327 cream in 48 patients who were treated topically with study drug twice daily and 9 patients who were treated with matching placebo [23]. Using the Physician’s Global Assessment as primary end point, 33% of patients had controlled disease at the end of week 8 compared to only 8% at the study start. The number of severe or very severe patients was reduced by 50% over the course of the study. For placebo patients, 7% of patients had controlled disease at the end of week 8 compared to 6% at the start. Creabilis Therapeutics conducted a randomized, placebo-controlled, Phase IIb study in 2012 to evaluate the safety and efficacy of three dose strengths of CT327 ointment (0.05, 0.1 and 0.05% w/w) compared to a placebo in 160 patients with mild-to-moderate psoriasis [24]. The drug was applied to plaques twice daily for up to 8 weeks. The study end points were Investigator’s Global Assessment (IGA), pruritus improvement in visual analog scale, modified psoriasis area and severity index (mPASI) and AE reports. The results are currently unpublished. E6201 (Eisai Co., Ltd) E6201 is a molecule known for its capacity to inhibit mitogenactivated protein kinase/extracellular signal-regulated kinase kinase-1 and suppression of the activation of NF-kB and AP-1 in various cells. Therefore, it suppresses the production of various proinflammatory cytokines in human monocytes and lymphocytes and inhibits cell proliferation and IL-8 production in human keratinocytes [25]. A preclinical trial was performed on mice to determine the anti-inflammatory effect of a topical compound utilizing E6201 [26]. In this preclinical study, E6201 demonstrated an anti-inflammatory effect similar to that of betamethasone dipropionate ointment by inhibiting lymphocyte response and neutrophil migration. It also attenuated epidermal hyperplasia induced by IL-23, and when tested in vitro, E6201 inhibited IL-17 production in human lymphocytes [26]. In addition to its promising anti-inflammatory properties in vitro, two Phase II 6.2.2
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Table 2. Reported AEs in patients using calcipotriol. Event
Frequency (%)
Skin irritation Rash Pruritus Dermatitis Worsening of psoriasis
10 -- 15 1 -- 10 1 -- 10 1 -- 10 1 -- 10
randomized controlled trials (RCT) with E6201 have been completed with > 100 patients recruited with no results yet published [27,28]. STAT inhibitors STAT proteins are intracellular signal transducers involved in several processes, including growth, survival, inflammation and differentiation. Specifically, STAT1/2 are involved in signaling transduction in immune cells and STAT3 plays a key role in keratinocyte proliferation, differentiation and migration induced by several cytokines [15].
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6.3
STA-21 (Kochi University) STA-21 (ochromycinone) is a known antibiotic and was identified as a STAT3 inhibitor. STA-21 efficiently inhibits STAT3 signaling in normal human keratinocytes as well as in cancer cell lines [17]. A Phase II non-randomized trial on eight patients assessed the objective clinical scores of erythema, induration and scaling. Five patients showed > 30% improvement in the score after 2 weeks of treatment with STA-21 compared to vehicle control [18]. 6.3.1
Topical PDE4 inhibitors PDE4 acts via degradation of cAMP, a key second messenger involved in signal transduction. The four subfamilies of PDE4 have been observed to have a fundamental role in tissue inflammation [14]. The role of cAMP-specific PDE4 inhibitors in psoriasis has been evaluated due to their broad antiinflammatory properties and potent inhibition of cytokine release from T-helper cells (Th1 and Th2), known to play an integral role in psoriatic disease [16]. 6.4
An-2728 (Anacor Pharmaceuticals, Inc.) AN-2728, a phenoxy-2,1-benzoxaborole derivative has been investigated in Phase I and Phase II clinical trials in patients with plaque-type psoriasis [29]. Three Phase Ib, randomized, double-blind, active- and placebo-controlled, single-center clinical trials assessed AN-2728 in male patients with plaque-type psoriasis. During these trials, psoriatic lesions were divided into six areas, each receiving treatment 10 times over the course of 12 days. The first Phase Ib trial compared AN-2728 (5% ointment or cream), betamethasone valerate (0.1%) and tacrolimus (0.1%) and vehicle cream or ointment in 12 patients. At day 12, there was significant reduction in the thickness of psoriatic lesions that had been treated with AN-2728 (54% for both formulations; p < 0.025), compared
to no change observed in the vehicle. This mean reduction in lesion thickness for AN-2728 was greater than that of tacrolimus (48%), but less than that of betamethasone valerate (72%). The second Phase Ib clinical trial evaluated AN-2728 ointment (0.5, 2 and 5%) in 12 patients with stable plaque psoriasis. The mean reduction in psoriatic lesion thickness for the 0.5, 2 and 5% ointments were 26, 35 and 36%, respectively (p < 0.002 for all concentrations versus vehicle), compared with 59 and 34% for betamethasone valerate and tacrolimus, respectively. The third Phase Ib clinical trial assessed AN-2728 cream (0.3, 1 and 2%) in 12 male patients with stable plaque psoriasis and all arms demonstrated significant improvement in lesion thickness compared with vehicle (p < 0.053, p = 0.0002 and p = 0.0002, respectively). A Phase IIa, randomized, double-blind, placebo-controlled, clinical trial assessed the self-application of AN-2728 5% ointment twice a day for 4 weeks in larger cohort of patients (n = 35) with stable plaque psoriasis. Two psoriatic plaques of comparable size and overall severity were selected: one lesion was treated with AN-2728, while the other was treated with vehicle. Twenty-four patients (68.6%) showed a significant improvement in the overall TPSS, compared with two patients (5.7%) in the vehicle-treated group (p < 0.001); in 9 patients (25.7%), plaques showed no change in the severity score. The mean reduction in the secondary end points of erythema, scaling and plaque elevation were also greater for patients treated with AN-2728 compared to vehicle, with statistically significant results noted at days 14, 21 and 28. A Phase IIb, randomized, double-blind, placebo-controlled, single-center, safety and efficacy clinical trial assessed AN-2728 5% ointment twice a day for 12 weeks in 30 patients with stable plaque psoriasis. Preliminary data revealed that psoriatic plaques treated with AN-2728 had improved severity scores compared to plaques treated with vehicle (p < 0.001 and p < 0.01 at 6 and 8 weeks, respectively). In this trial, 13% of the plaques treated with AN-2728 cleared completely, with 43% being clear or almost clear. There were no severe AEs, application site reactions, other treatment-related AEs or laboratory abnormalities [29]. The company is currently focusing AN-2728 development activities on atopic dermatitis and will defer the start of Phase III trials in psoriasis [30].
6.4.1
526
PAN-selectin antagonists Selectins (CD62) are a family of cell adhesion molecules, that play a fundamental part in leukocyte extravasation through cellular rolling and migration; thus, selectin antagonists can decrease immune cell migration and inflammation [31]. 6.5
Bimosiamose (TBC1269) (Revotar Biopharmaceuticals AG)
6.5.1
Bimosiamose is a pan-selectin antagonist that has shown to be effective in both preclinical [31] and clinical studies. In an open-labelled, clinical trial of five patients with moderate-tosevere psoriasis treated with bimosiamose by intralesional, injection (600 mg/day injection) for 2 weeks, a 43%
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Emerging topical treatments for psoriasis
Table 3. Emerging topical compounds.
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Drug name
Sponsoring company
Efficacy
Ruxolitinib (INCB018424)
Incyte Pharmaceuticals and Novartis
Tofacitinib
Pfizer, Inc.
CT 327
Creabilis Therapeutics
E6201
Eisai Co., Ltd.
Improvement in erythema, induration and scaling in 53% of patients using 1% cream q.d. and 54% of patients using 1.5% b.i.d., compared to a 32% vehicle at 28 days TPSS improved for ointment 1 compared to vehicle (-54.4 and -41.5%) at week 4 33% of patients had a controlled disease (PGA) at week 8 compared to 7% of patients in placebo group. Unknown
STA-21
Kochi University
An-2728
Anacor Pharmaceuticals, Inc.
Bimosiamose/ TBC1269 LEO 80185
Revotar Biopharmaceuticals AG LEO Pharma
Calcipotriene Calcitriol LEO 90100
GlaxoSmithKline Galderma LEO Pharma
M518101 WBI-1001
Maruho Co., Ltd. Welichem Biotech, Inc.
LAS 41004 PH-10
Almirall, S.A. Provectus Pharmaceuticals
> 30% improvement in erythema, induration and scaling after 2 weeks in 5 of 8 patients Overall TPSS improved compared with plaques treated with vehicle at 8 weeks (p < 0.01); 13% of the plaques cleared completely, and 43% were clear or almost clear Unpublished
85% of patients achieved a PASI 50 and 52% of patients achieved a PASI 75 at week 4; 61% of patients were clear or almost clear according to the IGA at week 4 (adolescents) Unpublished (pediatric patients) Unpublished (pediatric patients) Unpublished Unpublished 50% of patients achieved PASI 75 after 12 weeks Unknown 23 -- 29% of patients achieved complete or almost complete resolution of PSI components (erythema, induration and scaling)
Current Phase
Mechanism of action
II
JAK inhibitor
IIa
JAK inhibitor
IIb
TrK Inhibitor Type 1
Preclinical II
MEK1 and MEKK1 inhibitor STAT3 inhibitor
IIb
PDE4 inhibitor
II
Pan-selectin inhibitor
II
Vitamin D3 analog + corticosteroid
III IV III
Vitamin D3 analog Vitamin D3 analog Vitamin D3 analog + corticosteroid Vitamin D3 analog Nonsteroidal, anti-inflammatory Anti-inflammatoryunclear Unclear
III IIa II II
IGA: Investigator’s Global Assessment; MEKK1: Activated protein kinase/extracellular signal-regulated kinase kinase-1; PASI: Psoriasis Area and Severity Index; PGA: Physician’s Global Assessment; TPSS: Target plaque severity score; TrK: Tyrosine kinase receptor; PSI: Psoriasis Severity Index.
attenuation of epidermal thickness in four out of five patients was observed in addition to reductions in lymphocyte infiltration. PASI scores also showed significant improvement [32]. A multicenter Phase II RCT has been completed to evaluate the safety and efficacy of bimosiamose 5% cream in 107 patients with chronic plaque-type psoriasis. The results have yet to be published [33]. Vitamin D3 analogs in the pediatric population Vitamin D3 analogs activate inhibitory genes on cell replication and stimulate cell differentiation [34], while also suppressing the production of proinflammatory cytokines [35]. 6.6
Calcipotriene/betamethasone dipropionate 0.005%/0.064% in adolescents (LEO Pharma)
6.6.1
Calcipotriene/betamethasone dipropionate is an established topical treatment for adult psoriasis, but not currently FDA-indicated for adolescent psoriasis [36-38]. A Phase II, non-randomized, single-group, open-label study was undertaken to evaluate the safety and efficacy of calcipotriene/ betamethasone dipropionate ointment in patients 12 to 17 years old with at least moderate psoriasis and a total BSA of 5 to 30%. The primary end point measured was the number of adverse drug reactions and only 2 of the 33 patients
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experienced an AE, both of which were upper respiratory tract infections. The secondary end point assessed efficacy of the drug using IGA at week 4. Of the 33 patients, 20 patients (61%) demonstrated an IGA of clear or almost clear at week 4. Using Patient’s Global Assessment of Disease Severity, 23 of the 33 patients (70%) were clear or very mild at week 4 [39]. Calcipotriene foam 0.005% (GlaxoSmithKline plc.)
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6.6.2
A multicenter, randomized, double-blind, Phase III study comparing calcipotriene foam 0.005% with vehicle foam in pediatric subjects, aged 2 to 11 years with mild-to-moderate plaque psoriasis is currently underway. Patients with at least 5% BSA involvement on the body and at least 5% scalp involvement (excluding the face) with an Investigator’s Static Global Assessment score of mild-to-moderate (score of 2 or 3) at baseline are eligible to participate in the study. Approximately 180 subjects will be enrolled and dosed twice daily for 8 weeks. Subjects will be randomly assigned to one of two treatment groups in a 2:1 ratio (calcipotriene foam 0.005%: vehicle foam) [40]. Calcitriol 3 mg/g ointment (Galderma SA) Calcitriol is also being studied for use in the pediatric population; a new open-label study is currently recruiting patients to evaluate pharmacokinetics and pharmacodynamics of calcitriol 3 µg/g ointment applied twice daily for 14 days in pediatric subjects (2 to 12 years of age) with plaque psoriasis (BSA = 5 -- 35%). No results have been reported to date [41]. 6.6.3
LEO 90100 (LEO Pharma) LEO 90100 is a new aerosol formulation which contains calcipotriene 0.064% and betamethasone 0.005%, the same active ingredients in the same concentration as the already available products combining these agents, with the potential for increased absorption. Four clinical RCT were completed in the past 2 years, but results are currently unpublished. A 4-week, double-blind, Phase II study by LEO Pharma in 2012 determined the safety and efficacy of LEO 90100 cutaneous spray versus betamethasone plus calcipotriol, LEO 90100 vehicle, and ointment vehicle for psoriasis vulgaris. A new Phase III RCT is currently enrolling with an expected goal of 400 patients [42]. 6.6.4
M518101 (Maruho Co., Ltd.) M518101 is a vitamin D derivative currently being studied by Maruho Co., Ltd. One Phase I [43] and two Phase II [44,45] RCTs have been completed, and two Phase III RCTs [46,47] and one Phase III open-label trial [48] are underway. The trials will continue evaluating efficacy and safety in adult patients (> 18 years old) with plaquetype psoriasis and a BSA < 20%. Results of these trials have not yet been released. 6.6.5
528
6.7
Nonsteroidal anti-inflammatories WBI-1001, (Welichem Biotech, Inc.)
6.7.1
WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene1,3-diol) is a novel nonsteroidal anti-inflammatory molecule. WBI-1001 affects T cells through inhibition of multiple proinflammatory cytokines including tumor necrosis factor-a and IFN-g and by inhibiting both T-cell viability and infiltration processes. A randomized, double-blinded, placebo-controlled, single-center, Phase IIa study evaluated the efficacy and safety of this investigative agent [49]. Sixtyone patients with plaque psoriasis were randomized in a 2:1 ratio to either 1% WBI-1001 cream or placebo cream twice daily for 12 weeks. The proportion of patients who achieved PASI 50 or PASI 75 at 12 weeks for the intention-to-treat population was significantly higher (p < 0.0001 and p = 0.0004, respectively) for the WBI-1001 group (72.5 and 50%, respectively) compared to the placebo group (9.5 and 4.8% respectively). There was a decrease of 79.1% in BSA at 12 weeks for patients randomized to WBI-1001 compared with an increase of 9.4% for patients randomized to placebo (p < 0.0001). The difference between the two groups became significant as early as day 14. The main AEs included hyperpigmentation, dermatitis, folliculitis, papules, pain and pruritus. There were no clinically significant abnormal laboratory values or ECG changes noted during the study [49]. LAS 41004 (Almirall, S.A.) LAS 41004 inhibits cellular proliferation and reduces inflammation, although the precise mechanism of action is unclear. To date, a total of four Phase II RCTs with approximately 84 patients enrolled have been completed to assess the safety and efficacy of different concentrations of LAS 41004 compared to placebo or comparators for mild-to-moderate plaque psoriasis [50-53]. The results are currently unpublished. 6.7.2
PH-10 (Provectus Pharmaceuticals) PH-10 is a Rose Bengal 0.001% formulation developed for the treatment of inflammatory skin disorders, including psoriasis and atopic dermatitis. Its mechanism of action is poorly understood but it is known to photosensitize with possible phototoxic effects in addition to intrinsic cytotoxic properties. In 2010, Provectus Pharmaceuticals conducted a Phase IIc 8-week RCT to assess the safety and efficacy of PH-10 in plaque psoriasis. The study utilized three different concentrations of PH-10 (0.002, 0.005 and 0.01%) versus vehicle [54]. The primary efficacy end point was treatment success, defined as a 0 or 1 on all Psoriasis Severity Index (PSI) components and a 0 or 1 on the Plaque Response Scale at day 29. Secondary end points were PSI and Plaque Response, and Pruritus Self-Assessment Score changes at each visit from day 1 pretreatment for the duration of the study. Ninety-nine patients were randomized to each of the 6.7.3
Expert Opin. Emerging Drugs (2013) 18(4)
Emerging topical treatments for psoriasis
four arms. All three PH-10 drug concentrations showed improvement over the vehicle with the lowest dose providing consistent improvement for all PSI parameters. About 23 to 29% of subjects in all drug concentrations achieved complete or nearly complete resolution of all PSI components (erythema, induration and scaling) compared to 0% of subjects in the vehicle arm [55].
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7.
9.
Potential development issues
Given the early developmental phase and limited number of subjects in many of the clinical trials presented, it is still too early to predict which of the aforementioned agents will make it to the market for the treatment of mild-to-moderate psoriasis in adults and/or the pediatric population. Topical therapies have the ability to produce skin irritation and other side effects that might prevent further development. Another critical issue to be considered on continuing development is efficacy not only within class but also against comparators, such as the currently available corticosteroids and vitamin D derivatives. This would allow a better understanding of the potential advantage these investigative topical agents may have over our currently available therapies. 8.
reviewed have been shown to be efficacious for mild-tomoderate psoriasis, with some showing efficacy comparable or better than our currently available therapies. Further studies with different vehicles and larger population groups are essential to evaluate safety and efficacy profiles to confirm whether they will meet the current need for novel topical treatments.
Conclusion
The multiple new agents introduced in this review have shown limited results and side-effects profile to date. For use as first-line of therapy for patients with mild--tomoderate psoriasis, development of effective, safe and fast-acting topical medication is essential. Adherence to treatment can be used as an indirect marker of treatment success and has always been problematic in psoriasis patients [56]. The rate of nonadherence to topical treatments is not uniform with rates, up to 40 -- 50% being noted in studies. The main reasons behind this conduct are low efficacy, time consumption, poor cosmetic characteristics of preparations and doctor--patient relationship [57-59]. Patient education is an essential issue regarding correct topical therapy use and outcomes [60]. We believe there is an important need for new products and formulations that can help address this particular problem. The more effective a product is, the more likely the patients will adhere to treatment. Further, different vehicles for different body areas as well as for patient preferences can aid physicians in finding the most appropriate topical treatment for each individual patient. Dosing is another factor to be considered, once a day or twice a day regime may be of substantial difference for patients, considering time consumption is an important factor leading to nonadherence. The new drugs presented in this article have the potential to provide clinicians with a range of treatments either as monotherapy or in combination to meet each patient’s needs. A number of the drugs
Expert opinion
Topical therapies remain the treatment of choice for the majority of patients with psoriasis, that is, a total of 120 million worldwide, either as monotherapy for those with the milder form of the disease or in combination with phototherapy, systemic and biological therapies for those with more extensive disease. The development of new drugs for psoriasis over the past decade has been predominantly in the biological treatment category, thus, stressing the important need for new topical agents. For instance, the most potent of new topical agents, clobetasol propionate, was first made available over 40 years ago with the vitamin D3 compounds having been available for over 20 years. Where then are we heading with the new topical agents, as discussed in this article, and what is the ultimate goal? Ideally, a new mechanism of action, separate from that of topical steroids and vitamin D3 agents is preferred, one that has equal effectiveness to the more potent steroids, which is as effective once daily as twice and has a vehicle base applicable to patients for use in various affected anatomical areas. Will this also include the scalp, face, and intertriginous areas which traditionally require their own specific class and formulation of topical agents? The whole issue of patient adherence to topical therapy is of vital importance. As discussed in this article, expecting a patient to treat even as little as 5% of their BSA, that is, 10 -- 20 plaques of psoriasis, on a daily basis for a long term without evident significant improvement is asking too much of our patients. Yes, a rapid response is appreciated by each patient, but long-term maintenance of response with say pulse therapy, that is, 2 days a week, is the ultimate goal for optimal adherence and clinical response for this lifelong condition. Investigation into topical therapy has certainly expanded over the past 5 years with exciting new drugs under development, as discussed, with different methods of action and cytokine targets. The authors do believe that it is imperative that we concentrate more as clinicians and researchers on optimizing the design of new clinical trials with this large range of topical agents (Table 1). Thus, a 6- to 12-week study period for a topical agent is satisfactory to gauge initial improvement but longer periods of study, that is, up to 1 year is essential to measure response, side effects and, indeed, adherence over this period. Very few clinical studies over the past four decades have been designed to achieve this longer-term, high-quality goal. Another
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important aspect is obviously the mode of action of each agent. Our three currently approved oral systemic agents, methotrexate, cyclosporine and acitretin, outside of tazarotene, have to date failed to show efficacy as topical agents. Thus, having high-quality systemic agents does not necessarily transfer to equivalent potent topical agents. An important question is whether any of the agents listed in the table have sufficient promise to date to make their approval and acceptance likely in the years ahead? Several groups of topical agents, for example, JAK, PDE4 and other antiinflammatory topical agents are all in various clinical stages of development with encouraging responses in the majority. The time is indeed ripe for a revolution in our topical therapy armamentarium, which, as previously stated, has so lagged behind the systemic biological evolution of new drug development over the past decade. Our psoriasis population with mild-to-moderate psoriasis, 80% of the total psoriasis population, that is, close to 100 million patients worldwide, certainly deserve potent but safe new topical Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest D Kivelevitch has been a speaker for Abbott and has received compensation and honoraria from Abbott. A Menter has been on the advisory board for Abbott, Amgen, Galderma, Janssen and Wyeth. He has been a consultant for Abbott, Amgen, Eli Lilly, Galderma, Janssen, LEO Pharma, Stiefel and Wyeth. He has been an investigator for Abbott, Allergan, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer, Stiefel, Syntrix Biosystems and Wyeth. He has been a speaker for Abbott, Amgen, Galderma, Janssen, LEO Pharma and Wyeth. He has received grants from Abbott, Allergan, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer, Stiefel and Syntrix Biosystems. He has received honoraria from Abbott, Amgen, Galderma, Janssen, LEO Pharma, Stiefel and Wyeth. M Patel and K Hebeler have no conflicts of interest.
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Affiliation Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter† MD † Author for correspondence Baylor University Medical Center, Department of Dermatology, 3900 Junius Street, Suite 125, Dallas, TX 75246, USA Tel: +1972 354 7988; Fax: +1 972 715 1460; E-mail: [email protected]
ISSN: 1472-8214 (Print) 1744-7623 (Online) Journal homepage: http://www.tandfonline.com/loi/iemd20
Emerging topical treatments for psoriasis Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter To cite this article: Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter (2013) Emerging topical treatments for psoriasis, Expert Opinion on Emerging Drugs, 18:4, 523-532, DOI: 10.1517/14728214.2013.861418 To link to this article: http://dx.doi.org/10.1517/14728214.2013.861418
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Review
Emerging topical treatments for psoriasis
Downloaded by [Southern Cross University] at 12:51 06 November 2017
Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter† 1.
Background
Baylor University Medical Center, Department of Dermatology, Dallas, TX, USA
2.
Medical need
3.
Existing treatments
4.
Current research goals
5.
Scientific rationale
6.
Competitive environment
7.
Potential development issues
8.
Conclusion
9.
Expert opinion
Introduction: Psoriasis is an immune-mediated chronic inflammatory skin disease which classically presents as erythematous, scaly plaques affecting extensor surfaces of the limbs, scalp and trunk. Approximately 80% of patients have a mild-to-moderate form routinely treated with topical medications, whereas phototherapy, systemic and biological therapies are typically reserved for treatment of moderate-to-severe psoriasis. Areas covered: The major advances in psoriasis therapy in the past 15 years have been in new immunomodulatory and biological molecules, with a significant unmet need to have new, efficient and safe topical treatment options for the large percentage of patients for whom systemic therapy is not indicated. The available topical therapies (corticosteroids and vitamin D3 analogs) have remained relatively unchanged over the past several decades. This article reviews emerging topical drugs and formulations currently under evaluation in clinical trials. Expert opinion: The time is right for a revolution in our topical therapy armamentarium. It has lagged significantly behind the systemic biological evolution of new drug development. Our large psoriasis population with mild-to-moderate psoriasis certainly deserves potent but safe and innovative topical agents with a new mode of action as well as with long-lasting clinical efficacy. Keywords: psoriasis, therapeutics, topical administration Expert Opin. Emerging Drugs (2013) 18(4):523-532
1.
Background
Psoriasis is a chronic inflammatory disease affecting 1 -- 2% of the population worldwide [1]. Clinically, psoriasis presents as well-demarcated, raised, erythematous, scaly plaques predominantly affecting the scalp, trunk and extensor surfaces; however, any body site can also be involved. Psoriasis is a psychologically debilitating disease and can have profound impact on patients’ quality of life regardless of the degree of body surface area (BSA) involvement. Mild-to-moderate psoriasis affects ~ 80% of the total psoriasis population worldwide [2]. Topical medication is typically used as first line of treatment in mild psoriasis but can also be used concomitantly with phototherapy, systemic or biological therapies for moderate-to-severe psoriasis. This article will review emerging topical treatments for psoriasis which include Janus-associated kinase (JAK) and other kinase inhibitors, signal transducers and activators of transcription (STAT) and pan-selectin inhibitors, phosphodiesterase-4 (PDE4) inhibitors, nonsteroidal anti-inflammatories and vitamin D analogs. We based our search on information released by the National Psoriasis Foundation about clinical trials of new topical agents for psoriasis.
10.1517/14728214.2013.861418 © 2013 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted
523
D. N. Kivelevitch et al.
5.
Scientific rationale
Article highlights. .
. .
Moderate to severe psoriasis affects 80% of the psoriasis population. Topical therapies are the first line of treatment for this group of patients. There is an unmet need for more effective and safer topical agents. New therapeutic groups are being studied for topical therapy (i.e., JAK, PDE4 and STAT inhibitors, pan-selectin antagonists and other new anti-inflammatory agents).
This box summarizes key points contained in the article.
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2.
Medical need
In the past decade, increasing insight into the immunopathogenesis of psoriasis has led to the development of a multitude of targeted biological therapies which have revolutionized treatment for moderate-to-severe psoriasis, including interleukin (IL)-17 and IL-12/23 inhibitors [3-6]. While extensive research has been performed for new biological therapies for moderate-to-severe psoriasis, new therapeutic class of agents for milder disease have remained relatively stagnant over the past 20 years. Topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis but are not without side effects [7,8]. Thus, there is fertile ground for further research into new topical agents that have the potential to be safer and more effective short-term and long-term alternatives to our current therapies.
3.
Existing treatments
Since its appearance > 35 years ago, high potency topical steroids have been the most efficacious topical therapy available. Side effects of topical corticosteroid preparations include cutaneous atrophy, hypopigmentation, tachyphylaxis and hypothalamic-pituitary-adrenal axis suppression with more widespread body surface usage (Table 1) [9]. Vitamin D derivatives are often utilized as a steroid-sparing alternative but are also not without side effects, among which include skin irritation (e.g., in folds and on the face) and hypercalcemia (Table 2) [10]. In addition, other topical treatments, including tar, dithranol, calcineurin inhibitors and retinoids, are available as therapeutic options. Concerns regarding side effects and loss of efficacy with prolonged use make it important to look for new treatment alternatives.
4.
Current research goals
This article reviews ongoing clinical research trials in topical treatments for psoriasis providing an update to the healthcare community regarding the upcoming developments in this area. 524
Psoriasis is an immune-mediated chronic inflammatory disease in which inflammation and cell proliferation can occur in excess. The immunopathogenesis encompasses a multitude of signaling steps that can be targeted in order to exert a specific therapeutic effect [11,12]. The kinase/ STAT pathway and PDE4 involve intracellular signal transduction necessary for inflammation to develop [13-16]. Pan-selectin antagonists inhibit leukocyte extravasation by affecting the ability of immune cells to roll and migrate, thereby reducing inflammation [17,18]. Finally, the mechanism of action of nonsteroidal anti-inflammatory agents mentioned in this article are as yet not completely known but have been shown to decrease cytokine production and cellular proliferation -- the two major aspects of psoriasis immunopathogenesis. 6.
Competitive environment (Table 3)
JAK inhibitors JAKs play an integral role in signal transduction from several cytokines implicated in the physiopathology of psoriasis, including IL-12, IL-23, and interferon gamma (IFN-g). JAKs, a form of tyrosine kinase, target signal transducers and activators of transcription (STAT) and regulate proliferation, inflammation, cell activation and survival [13]. Specifically, by suppressing IL-23 receptor expression, these agents inhibit IL-23 signaling and thus reduce T-helper (TH17) cell differentiation. Inhibition of JAK1 also weakens signaling via IL-6, IFN-g, and type 1 IFN [19]. Thus, by targeting JAKs, investigative treatments may elicit both anti-inflammatory and antiproliferative properties. 6.1
Ruxolitinib (INCB018424, Incyte Pharmaceuticals and Novartis)
6.1.1
INCB018424, a novel JAK1/2 inhibitor was tested topically for psoriasis in a double-blind and vehicle or active comparator-controlled study [20]. Twenty-seven adult patients with stable chronic plaque psoriasis were enrolled in the trial. Two similar psoriatic plaques were selected for treatment in each patient with one treated with INCB018424 creams and a matching plaque with vehicle cream or active comparator (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream once or twice daily [q.d. or b.i.d.]) and followed weekly for 28 days. A greater reduction in lesion area was observed in plaques treated with higher concentrations (1 and 1.5%) and increased frequency of application (b.i.d. vs q.d.) of INCB018424, whereas little change in mean lesion area was seen for vehicle-treated lesions. Mean total lesion score (scaling, redness and thickness) decreased by 53% with 1% INCB018424 cream q.d. (p = 0.033) and 54% (p = 0.056) with 1.5% b.i.d., compared to a 32% reduction in the vehicle arm. Response to the 0.5% cream was similar
Expert Opin. Emerging Drugs (2013) 18(4)
Emerging topical treatments for psoriasis
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Table 1. Reported AEs in pediatric patients, according to the FDA report. Event
Frequency (n = 202)
Local irritation Skin depigmentation or discoloration Striae or skin atrophy Cushing syndrome Growth retardation Hyperglycemia (diabetes) Scarring Staphylococcal infection Genital hypertrichosis Hirsutism Rosacea Acne Glaucoma Hypersensitivity reaction Adrenal insufficiency Bruising Fungal infection Gynecomastia Perioral dermatitis Mental status or mood change
66 30 30 6 5 5 5 4 4 4 3 3 3 3 2 2 2 2 2 2
6.2
Other kinase inhibitors CT327 (Creabilis SA)
6.2.1
AEs that occurred in fewer than two reports are not listed.
to that of the vehicle arm. After 30 days of INCB018424 1.5% cream b.i.d., the reduction in mean lesion area was slightly better than that of calcipotriene 0.005% cream but not as good as the effect seen with betamethasone dipropionate 0.05% cream b.i.d. The mean plasma concentrations of INCB018424 were < 1% of the concentrations required for systemic activity; therefore, systemic adverse events (AEs) were unlikely drug-related. There were no serious AEs (SAEs) or discontinuations due to AEs reported during the study. Local AEs included stinging, itching, irritation, pain, dryness, exfoliation and/or redness at the application site and were all mild or moderate in severity [20]. More studies with a larger population are needed to clearly establish the efficacy of INCB018424. Nevertheless, despite the limited sample of patients, this study suggests that topical JAK inhibitors may have a potential role in the dermatological topical therapeutic arsenal for psoriasis. Tofacitinib, (Pfizer, Inc.) Tofacitinib, a novel, small-molecule JAK inhibitor, acts by selectively inhibiting signaling by heterodimers containing JAK3 and/or JAK1. It has been developed as an oral agent to treat rheumatoid arthritis, ulcerative colitis, Crohn’s disease and psoriasis, in addition to preventing transplant rejection [21]. It is currently approved for rheumatoid arthritis in the United States, and oral tofacitinib is in late stage development for the systemic treatment of psoriasis. A Phase IIa, randomized, double-blind, parallel-group, vehicle-controlled trial of topical tofacitinib was conducted in 71 patients who were randomized to 2% tofacitinib or placebo in two different vehicles for twice daily application to a target plaque area for 4 weeks [19]. The 6.1.2
primary end point of percentage change from baseline in target plaque severity score (TPSS) at week 4 revealed a difference of -12.87% between ointment 1 (-54.4%) and vehicle 1 (-41.5%), but no significant difference for ointment 2 (-24.2%) and vehicle 2 (-17.2%), where negative values represent a reduction in TPSS and a favorable treatment effect. No SAEs were reported and the only AEs to occur in more than one patient were nasopharyngitis (n = 4) and urinary tract infection (n = 3). The number of patients who reported burning or stinging at the treatment site was small and occurred with similar frequency across all groups [19].
CT327 reduces inflammation via the inhibition of tyrosine kinase receptor type 1, a high-affinity nerve growth factor receptor. Additionally, it also targets sensory neurons implicated in chronic pruritus [22]. A recent Phase IIa study assessed the safety and efficacy of 0.1% CT 327 cream in 48 patients who were treated topically with study drug twice daily and 9 patients who were treated with matching placebo [23]. Using the Physician’s Global Assessment as primary end point, 33% of patients had controlled disease at the end of week 8 compared to only 8% at the study start. The number of severe or very severe patients was reduced by 50% over the course of the study. For placebo patients, 7% of patients had controlled disease at the end of week 8 compared to 6% at the start. Creabilis Therapeutics conducted a randomized, placebo-controlled, Phase IIb study in 2012 to evaluate the safety and efficacy of three dose strengths of CT327 ointment (0.05, 0.1 and 0.05% w/w) compared to a placebo in 160 patients with mild-to-moderate psoriasis [24]. The drug was applied to plaques twice daily for up to 8 weeks. The study end points were Investigator’s Global Assessment (IGA), pruritus improvement in visual analog scale, modified psoriasis area and severity index (mPASI) and AE reports. The results are currently unpublished. E6201 (Eisai Co., Ltd) E6201 is a molecule known for its capacity to inhibit mitogenactivated protein kinase/extracellular signal-regulated kinase kinase-1 and suppression of the activation of NF-kB and AP-1 in various cells. Therefore, it suppresses the production of various proinflammatory cytokines in human monocytes and lymphocytes and inhibits cell proliferation and IL-8 production in human keratinocytes [25]. A preclinical trial was performed on mice to determine the anti-inflammatory effect of a topical compound utilizing E6201 [26]. In this preclinical study, E6201 demonstrated an anti-inflammatory effect similar to that of betamethasone dipropionate ointment by inhibiting lymphocyte response and neutrophil migration. It also attenuated epidermal hyperplasia induced by IL-23, and when tested in vitro, E6201 inhibited IL-17 production in human lymphocytes [26]. In addition to its promising anti-inflammatory properties in vitro, two Phase II 6.2.2
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Table 2. Reported AEs in patients using calcipotriol. Event
Frequency (%)
Skin irritation Rash Pruritus Dermatitis Worsening of psoriasis
10 -- 15 1 -- 10 1 -- 10 1 -- 10 1 -- 10
randomized controlled trials (RCT) with E6201 have been completed with > 100 patients recruited with no results yet published [27,28]. STAT inhibitors STAT proteins are intracellular signal transducers involved in several processes, including growth, survival, inflammation and differentiation. Specifically, STAT1/2 are involved in signaling transduction in immune cells and STAT3 plays a key role in keratinocyte proliferation, differentiation and migration induced by several cytokines [15].
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6.3
STA-21 (Kochi University) STA-21 (ochromycinone) is a known antibiotic and was identified as a STAT3 inhibitor. STA-21 efficiently inhibits STAT3 signaling in normal human keratinocytes as well as in cancer cell lines [17]. A Phase II non-randomized trial on eight patients assessed the objective clinical scores of erythema, induration and scaling. Five patients showed > 30% improvement in the score after 2 weeks of treatment with STA-21 compared to vehicle control [18]. 6.3.1
Topical PDE4 inhibitors PDE4 acts via degradation of cAMP, a key second messenger involved in signal transduction. The four subfamilies of PDE4 have been observed to have a fundamental role in tissue inflammation [14]. The role of cAMP-specific PDE4 inhibitors in psoriasis has been evaluated due to their broad antiinflammatory properties and potent inhibition of cytokine release from T-helper cells (Th1 and Th2), known to play an integral role in psoriatic disease [16]. 6.4
An-2728 (Anacor Pharmaceuticals, Inc.) AN-2728, a phenoxy-2,1-benzoxaborole derivative has been investigated in Phase I and Phase II clinical trials in patients with plaque-type psoriasis [29]. Three Phase Ib, randomized, double-blind, active- and placebo-controlled, single-center clinical trials assessed AN-2728 in male patients with plaque-type psoriasis. During these trials, psoriatic lesions were divided into six areas, each receiving treatment 10 times over the course of 12 days. The first Phase Ib trial compared AN-2728 (5% ointment or cream), betamethasone valerate (0.1%) and tacrolimus (0.1%) and vehicle cream or ointment in 12 patients. At day 12, there was significant reduction in the thickness of psoriatic lesions that had been treated with AN-2728 (54% for both formulations; p < 0.025), compared
to no change observed in the vehicle. This mean reduction in lesion thickness for AN-2728 was greater than that of tacrolimus (48%), but less than that of betamethasone valerate (72%). The second Phase Ib clinical trial evaluated AN-2728 ointment (0.5, 2 and 5%) in 12 patients with stable plaque psoriasis. The mean reduction in psoriatic lesion thickness for the 0.5, 2 and 5% ointments were 26, 35 and 36%, respectively (p < 0.002 for all concentrations versus vehicle), compared with 59 and 34% for betamethasone valerate and tacrolimus, respectively. The third Phase Ib clinical trial assessed AN-2728 cream (0.3, 1 and 2%) in 12 male patients with stable plaque psoriasis and all arms demonstrated significant improvement in lesion thickness compared with vehicle (p < 0.053, p = 0.0002 and p = 0.0002, respectively). A Phase IIa, randomized, double-blind, placebo-controlled, clinical trial assessed the self-application of AN-2728 5% ointment twice a day for 4 weeks in larger cohort of patients (n = 35) with stable plaque psoriasis. Two psoriatic plaques of comparable size and overall severity were selected: one lesion was treated with AN-2728, while the other was treated with vehicle. Twenty-four patients (68.6%) showed a significant improvement in the overall TPSS, compared with two patients (5.7%) in the vehicle-treated group (p < 0.001); in 9 patients (25.7%), plaques showed no change in the severity score. The mean reduction in the secondary end points of erythema, scaling and plaque elevation were also greater for patients treated with AN-2728 compared to vehicle, with statistically significant results noted at days 14, 21 and 28. A Phase IIb, randomized, double-blind, placebo-controlled, single-center, safety and efficacy clinical trial assessed AN-2728 5% ointment twice a day for 12 weeks in 30 patients with stable plaque psoriasis. Preliminary data revealed that psoriatic plaques treated with AN-2728 had improved severity scores compared to plaques treated with vehicle (p < 0.001 and p < 0.01 at 6 and 8 weeks, respectively). In this trial, 13% of the plaques treated with AN-2728 cleared completely, with 43% being clear or almost clear. There were no severe AEs, application site reactions, other treatment-related AEs or laboratory abnormalities [29]. The company is currently focusing AN-2728 development activities on atopic dermatitis and will defer the start of Phase III trials in psoriasis [30].
6.4.1
526
PAN-selectin antagonists Selectins (CD62) are a family of cell adhesion molecules, that play a fundamental part in leukocyte extravasation through cellular rolling and migration; thus, selectin antagonists can decrease immune cell migration and inflammation [31]. 6.5
Bimosiamose (TBC1269) (Revotar Biopharmaceuticals AG)
6.5.1
Bimosiamose is a pan-selectin antagonist that has shown to be effective in both preclinical [31] and clinical studies. In an open-labelled, clinical trial of five patients with moderate-tosevere psoriasis treated with bimosiamose by intralesional, injection (600 mg/day injection) for 2 weeks, a 43%
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Emerging topical treatments for psoriasis
Table 3. Emerging topical compounds.
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Drug name
Sponsoring company
Efficacy
Ruxolitinib (INCB018424)
Incyte Pharmaceuticals and Novartis
Tofacitinib
Pfizer, Inc.
CT 327
Creabilis Therapeutics
E6201
Eisai Co., Ltd.
Improvement in erythema, induration and scaling in 53% of patients using 1% cream q.d. and 54% of patients using 1.5% b.i.d., compared to a 32% vehicle at 28 days TPSS improved for ointment 1 compared to vehicle (-54.4 and -41.5%) at week 4 33% of patients had a controlled disease (PGA) at week 8 compared to 7% of patients in placebo group. Unknown
STA-21
Kochi University
An-2728
Anacor Pharmaceuticals, Inc.
Bimosiamose/ TBC1269 LEO 80185
Revotar Biopharmaceuticals AG LEO Pharma
Calcipotriene Calcitriol LEO 90100
GlaxoSmithKline Galderma LEO Pharma
M518101 WBI-1001
Maruho Co., Ltd. Welichem Biotech, Inc.
LAS 41004 PH-10
Almirall, S.A. Provectus Pharmaceuticals
> 30% improvement in erythema, induration and scaling after 2 weeks in 5 of 8 patients Overall TPSS improved compared with plaques treated with vehicle at 8 weeks (p < 0.01); 13% of the plaques cleared completely, and 43% were clear or almost clear Unpublished
85% of patients achieved a PASI 50 and 52% of patients achieved a PASI 75 at week 4; 61% of patients were clear or almost clear according to the IGA at week 4 (adolescents) Unpublished (pediatric patients) Unpublished (pediatric patients) Unpublished Unpublished 50% of patients achieved PASI 75 after 12 weeks Unknown 23 -- 29% of patients achieved complete or almost complete resolution of PSI components (erythema, induration and scaling)
Current Phase
Mechanism of action
II
JAK inhibitor
IIa
JAK inhibitor
IIb
TrK Inhibitor Type 1
Preclinical II
MEK1 and MEKK1 inhibitor STAT3 inhibitor
IIb
PDE4 inhibitor
II
Pan-selectin inhibitor
II
Vitamin D3 analog + corticosteroid
III IV III
Vitamin D3 analog Vitamin D3 analog Vitamin D3 analog + corticosteroid Vitamin D3 analog Nonsteroidal, anti-inflammatory Anti-inflammatoryunclear Unclear
III IIa II II
IGA: Investigator’s Global Assessment; MEKK1: Activated protein kinase/extracellular signal-regulated kinase kinase-1; PASI: Psoriasis Area and Severity Index; PGA: Physician’s Global Assessment; TPSS: Target plaque severity score; TrK: Tyrosine kinase receptor; PSI: Psoriasis Severity Index.
attenuation of epidermal thickness in four out of five patients was observed in addition to reductions in lymphocyte infiltration. PASI scores also showed significant improvement [32]. A multicenter Phase II RCT has been completed to evaluate the safety and efficacy of bimosiamose 5% cream in 107 patients with chronic plaque-type psoriasis. The results have yet to be published [33]. Vitamin D3 analogs in the pediatric population Vitamin D3 analogs activate inhibitory genes on cell replication and stimulate cell differentiation [34], while also suppressing the production of proinflammatory cytokines [35]. 6.6
Calcipotriene/betamethasone dipropionate 0.005%/0.064% in adolescents (LEO Pharma)
6.6.1
Calcipotriene/betamethasone dipropionate is an established topical treatment for adult psoriasis, but not currently FDA-indicated for adolescent psoriasis [36-38]. A Phase II, non-randomized, single-group, open-label study was undertaken to evaluate the safety and efficacy of calcipotriene/ betamethasone dipropionate ointment in patients 12 to 17 years old with at least moderate psoriasis and a total BSA of 5 to 30%. The primary end point measured was the number of adverse drug reactions and only 2 of the 33 patients
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experienced an AE, both of which were upper respiratory tract infections. The secondary end point assessed efficacy of the drug using IGA at week 4. Of the 33 patients, 20 patients (61%) demonstrated an IGA of clear or almost clear at week 4. Using Patient’s Global Assessment of Disease Severity, 23 of the 33 patients (70%) were clear or very mild at week 4 [39]. Calcipotriene foam 0.005% (GlaxoSmithKline plc.)
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6.6.2
A multicenter, randomized, double-blind, Phase III study comparing calcipotriene foam 0.005% with vehicle foam in pediatric subjects, aged 2 to 11 years with mild-to-moderate plaque psoriasis is currently underway. Patients with at least 5% BSA involvement on the body and at least 5% scalp involvement (excluding the face) with an Investigator’s Static Global Assessment score of mild-to-moderate (score of 2 or 3) at baseline are eligible to participate in the study. Approximately 180 subjects will be enrolled and dosed twice daily for 8 weeks. Subjects will be randomly assigned to one of two treatment groups in a 2:1 ratio (calcipotriene foam 0.005%: vehicle foam) [40]. Calcitriol 3 mg/g ointment (Galderma SA) Calcitriol is also being studied for use in the pediatric population; a new open-label study is currently recruiting patients to evaluate pharmacokinetics and pharmacodynamics of calcitriol 3 µg/g ointment applied twice daily for 14 days in pediatric subjects (2 to 12 years of age) with plaque psoriasis (BSA = 5 -- 35%). No results have been reported to date [41]. 6.6.3
LEO 90100 (LEO Pharma) LEO 90100 is a new aerosol formulation which contains calcipotriene 0.064% and betamethasone 0.005%, the same active ingredients in the same concentration as the already available products combining these agents, with the potential for increased absorption. Four clinical RCT were completed in the past 2 years, but results are currently unpublished. A 4-week, double-blind, Phase II study by LEO Pharma in 2012 determined the safety and efficacy of LEO 90100 cutaneous spray versus betamethasone plus calcipotriol, LEO 90100 vehicle, and ointment vehicle for psoriasis vulgaris. A new Phase III RCT is currently enrolling with an expected goal of 400 patients [42]. 6.6.4
M518101 (Maruho Co., Ltd.) M518101 is a vitamin D derivative currently being studied by Maruho Co., Ltd. One Phase I [43] and two Phase II [44,45] RCTs have been completed, and two Phase III RCTs [46,47] and one Phase III open-label trial [48] are underway. The trials will continue evaluating efficacy and safety in adult patients (> 18 years old) with plaquetype psoriasis and a BSA < 20%. Results of these trials have not yet been released. 6.6.5
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6.7
Nonsteroidal anti-inflammatories WBI-1001, (Welichem Biotech, Inc.)
6.7.1
WBI-1001 (2-isopropyl-5-[(E)-2-phenylethenyl] benzene1,3-diol) is a novel nonsteroidal anti-inflammatory molecule. WBI-1001 affects T cells through inhibition of multiple proinflammatory cytokines including tumor necrosis factor-a and IFN-g and by inhibiting both T-cell viability and infiltration processes. A randomized, double-blinded, placebo-controlled, single-center, Phase IIa study evaluated the efficacy and safety of this investigative agent [49]. Sixtyone patients with plaque psoriasis were randomized in a 2:1 ratio to either 1% WBI-1001 cream or placebo cream twice daily for 12 weeks. The proportion of patients who achieved PASI 50 or PASI 75 at 12 weeks for the intention-to-treat population was significantly higher (p < 0.0001 and p = 0.0004, respectively) for the WBI-1001 group (72.5 and 50%, respectively) compared to the placebo group (9.5 and 4.8% respectively). There was a decrease of 79.1% in BSA at 12 weeks for patients randomized to WBI-1001 compared with an increase of 9.4% for patients randomized to placebo (p < 0.0001). The difference between the two groups became significant as early as day 14. The main AEs included hyperpigmentation, dermatitis, folliculitis, papules, pain and pruritus. There were no clinically significant abnormal laboratory values or ECG changes noted during the study [49]. LAS 41004 (Almirall, S.A.) LAS 41004 inhibits cellular proliferation and reduces inflammation, although the precise mechanism of action is unclear. To date, a total of four Phase II RCTs with approximately 84 patients enrolled have been completed to assess the safety and efficacy of different concentrations of LAS 41004 compared to placebo or comparators for mild-to-moderate plaque psoriasis [50-53]. The results are currently unpublished. 6.7.2
PH-10 (Provectus Pharmaceuticals) PH-10 is a Rose Bengal 0.001% formulation developed for the treatment of inflammatory skin disorders, including psoriasis and atopic dermatitis. Its mechanism of action is poorly understood but it is known to photosensitize with possible phototoxic effects in addition to intrinsic cytotoxic properties. In 2010, Provectus Pharmaceuticals conducted a Phase IIc 8-week RCT to assess the safety and efficacy of PH-10 in plaque psoriasis. The study utilized three different concentrations of PH-10 (0.002, 0.005 and 0.01%) versus vehicle [54]. The primary efficacy end point was treatment success, defined as a 0 or 1 on all Psoriasis Severity Index (PSI) components and a 0 or 1 on the Plaque Response Scale at day 29. Secondary end points were PSI and Plaque Response, and Pruritus Self-Assessment Score changes at each visit from day 1 pretreatment for the duration of the study. Ninety-nine patients were randomized to each of the 6.7.3
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Emerging topical treatments for psoriasis
four arms. All three PH-10 drug concentrations showed improvement over the vehicle with the lowest dose providing consistent improvement for all PSI parameters. About 23 to 29% of subjects in all drug concentrations achieved complete or nearly complete resolution of all PSI components (erythema, induration and scaling) compared to 0% of subjects in the vehicle arm [55].
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7.
9.
Potential development issues
Given the early developmental phase and limited number of subjects in many of the clinical trials presented, it is still too early to predict which of the aforementioned agents will make it to the market for the treatment of mild-to-moderate psoriasis in adults and/or the pediatric population. Topical therapies have the ability to produce skin irritation and other side effects that might prevent further development. Another critical issue to be considered on continuing development is efficacy not only within class but also against comparators, such as the currently available corticosteroids and vitamin D derivatives. This would allow a better understanding of the potential advantage these investigative topical agents may have over our currently available therapies. 8.
reviewed have been shown to be efficacious for mild-tomoderate psoriasis, with some showing efficacy comparable or better than our currently available therapies. Further studies with different vehicles and larger population groups are essential to evaluate safety and efficacy profiles to confirm whether they will meet the current need for novel topical treatments.
Conclusion
The multiple new agents introduced in this review have shown limited results and side-effects profile to date. For use as first-line of therapy for patients with mild--tomoderate psoriasis, development of effective, safe and fast-acting topical medication is essential. Adherence to treatment can be used as an indirect marker of treatment success and has always been problematic in psoriasis patients [56]. The rate of nonadherence to topical treatments is not uniform with rates, up to 40 -- 50% being noted in studies. The main reasons behind this conduct are low efficacy, time consumption, poor cosmetic characteristics of preparations and doctor--patient relationship [57-59]. Patient education is an essential issue regarding correct topical therapy use and outcomes [60]. We believe there is an important need for new products and formulations that can help address this particular problem. The more effective a product is, the more likely the patients will adhere to treatment. Further, different vehicles for different body areas as well as for patient preferences can aid physicians in finding the most appropriate topical treatment for each individual patient. Dosing is another factor to be considered, once a day or twice a day regime may be of substantial difference for patients, considering time consumption is an important factor leading to nonadherence. The new drugs presented in this article have the potential to provide clinicians with a range of treatments either as monotherapy or in combination to meet each patient’s needs. A number of the drugs
Expert opinion
Topical therapies remain the treatment of choice for the majority of patients with psoriasis, that is, a total of 120 million worldwide, either as monotherapy for those with the milder form of the disease or in combination with phototherapy, systemic and biological therapies for those with more extensive disease. The development of new drugs for psoriasis over the past decade has been predominantly in the biological treatment category, thus, stressing the important need for new topical agents. For instance, the most potent of new topical agents, clobetasol propionate, was first made available over 40 years ago with the vitamin D3 compounds having been available for over 20 years. Where then are we heading with the new topical agents, as discussed in this article, and what is the ultimate goal? Ideally, a new mechanism of action, separate from that of topical steroids and vitamin D3 agents is preferred, one that has equal effectiveness to the more potent steroids, which is as effective once daily as twice and has a vehicle base applicable to patients for use in various affected anatomical areas. Will this also include the scalp, face, and intertriginous areas which traditionally require their own specific class and formulation of topical agents? The whole issue of patient adherence to topical therapy is of vital importance. As discussed in this article, expecting a patient to treat even as little as 5% of their BSA, that is, 10 -- 20 plaques of psoriasis, on a daily basis for a long term without evident significant improvement is asking too much of our patients. Yes, a rapid response is appreciated by each patient, but long-term maintenance of response with say pulse therapy, that is, 2 days a week, is the ultimate goal for optimal adherence and clinical response for this lifelong condition. Investigation into topical therapy has certainly expanded over the past 5 years with exciting new drugs under development, as discussed, with different methods of action and cytokine targets. The authors do believe that it is imperative that we concentrate more as clinicians and researchers on optimizing the design of new clinical trials with this large range of topical agents (Table 1). Thus, a 6- to 12-week study period for a topical agent is satisfactory to gauge initial improvement but longer periods of study, that is, up to 1 year is essential to measure response, side effects and, indeed, adherence over this period. Very few clinical studies over the past four decades have been designed to achieve this longer-term, high-quality goal. Another
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important aspect is obviously the mode of action of each agent. Our three currently approved oral systemic agents, methotrexate, cyclosporine and acitretin, outside of tazarotene, have to date failed to show efficacy as topical agents. Thus, having high-quality systemic agents does not necessarily transfer to equivalent potent topical agents. An important question is whether any of the agents listed in the table have sufficient promise to date to make their approval and acceptance likely in the years ahead? Several groups of topical agents, for example, JAK, PDE4 and other antiinflammatory topical agents are all in various clinical stages of development with encouraging responses in the majority. The time is indeed ripe for a revolution in our topical therapy armamentarium, which, as previously stated, has so lagged behind the systemic biological evolution of new drug development over the past decade. Our psoriasis population with mild-to-moderate psoriasis, 80% of the total psoriasis population, that is, close to 100 million patients worldwide, certainly deserve potent but safe new topical Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest D Kivelevitch has been a speaker for Abbott and has received compensation and honoraria from Abbott. A Menter has been on the advisory board for Abbott, Amgen, Galderma, Janssen and Wyeth. He has been a consultant for Abbott, Amgen, Eli Lilly, Galderma, Janssen, LEO Pharma, Stiefel and Wyeth. He has been an investigator for Abbott, Allergan, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer, Stiefel, Syntrix Biosystems and Wyeth. He has been a speaker for Abbott, Amgen, Galderma, Janssen, LEO Pharma and Wyeth. He has received grants from Abbott, Allergan, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Novo Nordisk, Pfizer, Stiefel and Syntrix Biosystems. He has received honoraria from Abbott, Amgen, Galderma, Janssen, LEO Pharma, Stiefel and Wyeth. M Patel and K Hebeler have no conflicts of interest.
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Affiliation Dario N Kivelevitch, Katherine R Hebeler, Mahir Patel & Alan Menter† MD † Author for correspondence Baylor University Medical Center, Department of Dermatology, 3900 Junius Street, Suite 125, Dallas, TX 75246, USA Tel: +1972 354 7988; Fax: +1 972 715 1460; E-mail: [email protected]
