Editorial update on emerging treatments of atopic dermatitis

Abstract

Various new agents are in the research pipeline for atopic dermatitis. These include IL-4 receptor antagonist, cis-urocanic acid, κ-opiod receptor agonist, neurokinin receptor antagonist and antimicrobial peptide. The current review updates the status of these clinical trials and provides insight into other potential molecular targets including IL-22 and TLR-2.

Keywords::

• atopic dermatitis
• IL-22
• S. aureus
• therapy

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that affects both children and adults. The disease is characterized by itch, flexural distribution of eczema and staphylococcus aureus (S. aureus) colonization. It is associated with significant morbidity including sleep deprivation, anxiety, depression and social isolation. In addition, infectious complications including S. aureus and herpes simplex virus infections are common. The pathogenesis of AD involves an interaction between environment, skin barrier defects and immune response. More than 30% of AD patients are affected by asthma, allergic rhinitis and food allergy. Hereditary basis of both immune dysregulation (cytokine gene cluster at 5q31.1) and skin barrier defect (filaggrin mutations) has been confirmed in a recent genome-wide association meta-analysis [1]. The treatment of AD remains challenging due to potential adverse effects associated with the standard therapy, which consists of topical corticosteroids and topical calcineurin inhibitors. The advent of various barrier creams has generated excitement for alternative treatments of AD. However, a recent study has shown that two of the currently available barrier creams (Atopiclair^™ and EpiCeram®) are no more superior than the much less expensive over-the-counter petrolatum-based ointments for barrier replacement [2]. Nevertheless, barrier therapy remains conceptually to be a viable way to prevent AD. This hypothesis will be tested by The Barrier Enhancement for Eczema Prevention study (www.beepstudy.org). Meantime, newer therapeutic agents are needed for symptomatic management of AD. The current Editorial updates new AD medications that have been in clinical trials since the last review in this journal [3].

1. Anti-inflammatory therapy

Most of these medications target specific inflammatory pathways in AD. IL-4 and IL-13 play a central role in pathogenesis of Th2 inflammation. Targeting these cytokines will not only decrease the inflammation of AD, but may also lead to an improvement of barrier defects, since it has been shown that filaggrin is suppressed by IL-4/IL-13 (reviewed in ref. [4]). Of interest, two medications that are currently in AD clinical trials are directed against IL-4 receptor (Aeroderm and REGN-668) (Table 1). Urocanic acid (UCA) is one of the breakdown products of filaggrin and a major component of the natural moisturizing factor. The trans-isomer of UCA is a UV protector of the skin, whereas the cis-isomer is known to be immunosuppressive. One of the studies investigates the efficacy of cis-UCA in AD. The risk/benefit ratio of this medication would be of interest due to its immunosuppression. The role of UCA in AD is also interesting in that it decreases S. aureus survival via modulation of pH and iron-regulated surface determinant A (IsdA) in S. aureus [5].

Table 1. Atopic dermatitis medications in research pipeline*.

Compound	Mechanism of action	Route of administration	Study design	Status	Company
Anti-inflammatory
NF-κB decoy	NF-κB decoy is a oligodeoxynucleotide that mimics the NF-κB binding sequence on the chromosomal DNA, thereby inhibiting the inflammatory response triggered by NF-κB.	Topical	Data not available	Phase II	AnGes MG, Inc.
GW-870086X	Glucocorticoid agonist	Topical	Randomized, double blind, placebo and active controlled; compared with 0.05% fluticasone propionate cream	Phase II	GlaxoSmithKline
AN2728 and AN2898	Inhibitors of PDE4	Topical	Randomized, double blind placebo controlled.	Phase IIa	Anacor Pharmaceuticals
Miltefosine (TF-002)	A membrane lipid raft modulator	Topical	Randomized, double blind, active controlled; moderate-to-severe AD; compared with 1% hydrocortisone lotion	Phase IIa; results: improvement of AD severity (based on three-item severity score) and barrier function was comparable with 1% hydrocortisone; side effects included pruritus, burning, tingling and dry skin (Dolle et al. Allergy 2010; 65:1158-65)	JADO Technologies GmbH
WBI-1001	Inhibitor of T-cell cytokines	Topical	Multicenter randomized, parallel group, double blind, placebo controlled; included severe AD	Phase IIb; significant improvement in SCORAD, EASI, IGA; adverse effects were folliculitis, contact dermatitis and headache (Bissonnette R et al. Br J Dermatol. 2011 Dec 19, Epub ahead of print)	Welichem Biotech Inc.
PH-10	Formulation of rose bengal disodium, which is capable of undergoing photochemical reactions when activated by ambient light; may ameliorate inflammation of the skin when activated by ambient light.	Topical	Data not available	Phase II	Provectus Pharmaceuticals
ALK-depot	House dust mite allergen immunotherapy	Subcutaneous	Randomized parallel group, double blind, placebo controlled	Phase III	ALK-Abello
Aeroderm (AER-003)	A pegylated IL-4 variant that interferes with IL-4α receptor to block the action of both IL-4 and IL-13	Subcutaneous	Randomized, placebo controlled, parallel group; moderate to severe AD.	Phase II a	Aerovance
Adenosylcobalamin liposomal gel (HL009)	Inhibitor of nitric oxide synthase	Topical	Randomized, double blind, placebo controlled	Phase II	HanAll BioPharma
CD 2027 (Calcitriol)	Modulator of innate immunity	Topical	Randomized, double blind, placebo controlled.	Phase II	Galderma
ProtoCure (cis-urocanic acid)	Immunosuppressant	Topical	Randomized, double blind, placebo and active controlled, parallel assignment; compared with 0.1% Protopic ointment; moderate to severe AD.	Phase II	BioCis Pharma Ltd
Mapracorat (BOL-303242-X; ZK-245186)	Glucocorticoid agonist	Topical	Randomized, double blind, vehicle controlled.	Phase II	Bayer HealthCare
REGN-688 (SAR-231893)	Monoclonal against IL-4 receptor	Subcutaneous	Randomized, double blind, placebo controlled, sequential ascending, repeated dose; moderate to severe AD.	Phase I/II	Regeneron Pharmaceuticals Inc./Sanofi
Anti-itch
Nalfurafine hydrochloride (TRK-820; AC-820)	κ-Opiod receptor agonist	Oral	Data not available.	Phase II	Toray
DNK-333	Neurokinin-1 and -2 receptor antagonist	Oral	Multicenter, randomized, double blinded, placebo and active controlled; compared with betamethasone	Phase II	Novartis Pharmaceuticals
SUN-13834	Chymase inhibitor	Oral	Multicenter randomized, double blind, placebo controlled.	Phase II	Asubio Pharmaceuticals, Inc.
Antimicrobial
DPK-060	Antimicrobial peptide	Topical	Randomized, double blind, placebo controlled.	Phase II	Pergamum

*The information in the above Table was obtained from Pharmaprojects and ClinicalTrials.gov; the entry criteria were based on medications in which a mechanism of action is identified.

2. Anti-itch therapy

κ-Opiod receptors (KOR), which mediate anti-itch effects, have been found to be decreased in AD [3]. On the other hand, substance P, a neuropeptide, which mediates itch via neurokinin (NK) receptors, is increased in AD. Aprepitant is a selective high-affinity NK-1 receptor antagonist that has recently been found to significantly decrease itch in atopic patients [6]. Currently, two systemic agents, one KOR agonist and one NK receptor antagonist, are in Phase II trials for AD (Table 1).

3. Antimicrobial therapy

Natural antimicrobial peptides (AMPs) are relatively deficient in AD skin lesions [7]. This deficiency contributes to increased S. aureus and inflammation in AD. DPK-060 represents one of the first AMPs in randomized controlled trial for the treatment of AD (Table 1).

4. Perspectives and future directions

Since the last review of this journal [3], bleach bath has been in wider clinical use for AD. However, its efficacy is not without controversy [8]. In our clinical experience, bleach bath may be of benefits in select patients. Successful treatment for AD will continue to depend on specific targeting of molecular defects in order to minimize risk/benefit ratio. Most of the investigative medications described in this article are mechanism based. They represent some of the most exciting treatment modalities for AD to date. This is particularly true for anti-itch medications, in which the number of controlled trials has increased since the last review. While the clinical trials for AD are ongoing, progress in the study of AD pathogenesis continues to generate potential new molecular targets for the treatment of AD (Table 2). IL-22 expression is increased in AD lesions and contributes to the pathology of AD [9-11]. This cytokine, together with IL-17, upregulates AMPs to increase defense against microbial pathogens; however, it may also play a role in inflammation depending on the presence or absence of IL-17 [12]. The dual role of IL-22 presents a potential therapeutic target in AD. Th17 cells are crucial in the cellular immunity against mucosal fungal as well as S. aureus infections [13]. The homing of these cells to cutaneous sites can be controlled by AMPs. Therefore, topical AMPs that have both direct antimicrobial effects and modulatory effects on cellular immunity may be effective against S. aureus colonization in AD. Toll-like receptor-2 (TLR-2) is a host receptor for S. aureus. Increasing evidence suggests the presence of TLR-2 polymorphisms in AD keratinocytes [14]. These findings may have important implications in the clinical management of AD subgroups in terms of disease manifestation and preventive treatments. Of interest, genetic variations in innate immunity has been shown to play a role in the cutaneous immune response and severity of psoriasis, a chronic inflammatory skin disease that is frequently compared and contrasted with AD [15,16]. Midorikawa et al. have shown that different strains of S. aureus are capable of elicit variable AMP production by keratinocytes [17], suggesting the ability of different S. aureus strains in modifying the cutaneous innate immune response. This provides rationale for targeting specific strains of S. aureus (e.g., methicillin-resistant S. aureus) [18,19]. α-Toxin-producing strains of S. aureus contribute to increased host expression of IL-22 and IL-31 [20]. The latter cytokine plays a role in the pathogenesis of itch in AD. These strains of S. aureus may also represent a therapeutic target in AD. In summary, further studies are needed in the innate immune response of AD against microbial pathogens, particularly S. aureus. These studies may provide future insight in the treatment of AD.

Table 2. Potential molecular targets in atopic dermatitis (AD).

Molecule	Expression in AD	Mechanism of action
IL-22	Increased	Possibly increases inflammation in AD.
TLR-2	Genetic polymorphisms	Increases thymic stromal lymphopoietin expression (Vu et al. J. Allergy Clin. Immunol. 2010; 126:985-93).
Human β defensin-2 (hBD-2)	Decreased	Decreased level probably leads to decreased Th17 activity against Staphylococcus aureus.
α-toxin	Increased	Increases IL-22 and IL-31 production.
IL-31	Increased	Increases pruritus.
IL-25	Increased	Decreases filaggrin synthesis (Hvid et al. J. Invest. Dermatol. 2011; 131:150-7)

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.