Addressing treatment challenges in atopic dermatitis with novel topical therapies

Figures & data

Figure 1. Effects of atopic dermatitis on patients and their caregivers. Effects have been categorized into eight health- and function-related domains. Figure adapted with permission from Chamlin et al. (11).

Table 1. Summary of topical treatment for AD (8,20,23,26–28).

Treatment	Usage	Mechanism of action	Adverse effects
Moisturizers and emollients	All patients	Increase the hydration of the epidermis, primarily by acting as an occlusive layer preventing transepidermal evaporation	Greasy texture Can cause folliculitis and sweat retention Preservatives and fragrances may cause contact dermatitis
Topical corticosteroids (TCSs)	Low potency is recommended to treat AD of the face, groin, and axillae Only low-potency agents should be used to treat infants Once control is attained, TCSs should only be used intermittently	Activate nuclear glucocorticoid receptors to alter cytokine expression	Local: cutaneous atrophy, striae distensae, stellate pseudoscars telangiectasia, purpura milia, erythema, perioral dermatitis, rosacea, hyperpigmentation, hypopigmentation, tachyphylaxis, hypertrichosis, etc Systemic: HPA axis suppression, Cushing disease, glaucoma, decreased growth rate, hypertension, hypercalcemia, hyperglycemia, cataracts, femoral head osteonecrosis
Topical calcineurin inhibitors (TCIs)	Indicated for children <2 years of age Patients with facial or eyelid dermatitis Patients with extensive AD not controlled with mild TCSs	Calcineurin inhibition blocks early T-cell activation and the release of cytokines	Transient burning, pruritus, and erythema Boxed warning regarding carcinogenesis with long-term use Allergic contact dermatitis

AD: atopic dermatitis; HPA: hypothalamic–pituitary–adrenal.

Table 2. Joint AAAAI and ACAAI, and AAD guidelines for the use of topical treatments for AD (2,29).

	AAAAI/ACAAI	AAD
Moisturizers and emollients	Moisturizers should be recommended as first-line therapy	Moisturizers should be an integral part of treatment
Topical corticosteroids (TCSs)	TCSs should be recommended if AD is not controlled with moisturizers alone Low-potency TCSs TCSs are recommended for maintenance therapy Intermediate and high-potency TCSs are recommended for short-term exacerbation Potent corticosteroids should not be prescribed for use on the face, eyelids, genitalia, and intertriginous areas or in young infants The risk for systemic adverse events should be considered	TCSs are recommended for AD-affected individuals who have failed to respond to good skin care and regular emollient use Patient age, areas of the body affected, degree of xerosis, patient preference, and cost of medication should be considered Twice-daily application of TCSs is recommended, although once daily may be sufficient Proactive, intermittent use of TCSs is recommended on areas that commonly flare The potential for side effects should be considered Monitoring for cutaneous side effects during long-term, potent TCS use is recommended
Topical calcineurin inhibitors (TCIs)	TCIs can be considered for the management of AD TCIs should be considered for delicate areas that are unresponsive to low-potency TCSs because, unlike TCSs, TCIs do not cause skin atrophy Patients should be counseled regarding the potential for localized burning and itching during the first week of TCI use	TCIs are recommended for short-term, long-term, and maintenance treatment of AD in adults and children TCIs are preferable in situations that include recalcitrance to steroids, sensitive areas, steroid-induced atrophy, and long-term uninterrupted topical steroid use TCIs are recommended for use as steroid-sparing agents For patients <2 years of age with mild-to-severe disease, off-label use of TCIs can be recommended Side effects, including skin burning and pruritus, should be considered and patients should be informed Proactive intermittent use with TCIs is recommended on areas that commonly flare Clinicians should be aware of the boxed warning on the use of TCIs
Concomitant use of TCSs and TCIs	No recommendations	TCSs and TCIs can be used sequentially and concomitantly

AAAAI: American Academy of Allergy, Asthma & Immunology; AAD: American Academy of Dermatology; ACAAI: American College of Allergy, Asthma and Immunology; AD: atopic dermatitis.

Table 3. Key phase 1, 2 and phase 3 interventional trials for emerging topical therapies for AD.

Topical therapy	Mechanism of action	Trial	Phase	Patients	Primary outcome measure	Estimated completion date
Crisaborole/AN2728	PDE4 inhibitor	AD-303 (long-term safety extension study)		Enrollment: TBD from AD-301 and AD-302 Patients ≥2 years of age AD involvement ≥5% treatable BSA ISGA score of mild (2) or moderate (3)	Disease severity (ISGA), local tolerability, QoL (CDLQI, DLQI, or DFI), concomitant medication use, vital signs, AEs, or SAEs	November 2015
		NCT02118792 (AD-302)	3	Enrollment: 750 Patients ≥2 years of age AD involvement ≥5% treatable BSA ISGA score of mild (2) or moderate (3)	Proportion of patients achieving success in ISGA at day 29 in the AN2728-treated group compared with the vehicle-treated group	July 2015
		NCT02118766 (AD-301)	3	Enrollment: 750 Patients ≥2 years of age AD involvement ≥5% treatable BSA ISGA score of mild (2) or moderate (3)	Proportion of patients achieving success in ISGA at day 29 in the AN2728-treated group compared with the vehicle-treated group	July 2015
		NCT01602341 (AD-204)	2	Enrollment: 86 Male and female patients between 12 and 17 years of age BSA ≤35% Presence of 2 comparable lesions	Change from baseline in ADSI score between 0.5% and 2% ointment applied QD or BID (29 days)	January 2013
		NCT01301508 (AD-202)	II	Enrollment: 46 Male and female patients between 18 and 75 years of age AD clinically stable for ≥1 month 2 or more comparable lesions	Percentage of patients in whom test article performed better than vehicle (greater decrease in ADSI score; day 28)	December 2011
		NCT01652885 (AD-203)	1 & 2	Enrollment: 23 Male and female patients between 12 and 17 years of age AD involvement ≥10% and ≤35% treatable BSA	Assessment of safety and tolerability (up to 28 days)	November 2012
		MUSE Trial (AD-102)	1b	Enrollment: 34 Male and female patients between 2 and 17 years of age ISGA score of mild (2) or moderate (3) at baseline	PK and safety under maximal use conditions	November 2013
DRM02	PDE4 inhibitor	NCT01993420	2	Estimated enrollment: 21 Male and female patients between 18 and 70 years of age Stable AD 2 lesions of similar size with an identical EASI score of ≥5 and ≤9	Change in Physician's Lesion Assessment (over 6 weeks)	February 2014
E6005	PDE4 inhibitor	NCT01461941	2	Enrollment: 78 Male and female patients between 20 and 64 years of age Outpatients diagnosed with AD	Changes of pruritus score, and changes of eczema area and severity from baseline (12 weeks)	January 2013
		NCT02094235	1 & 2	Enrollment: 62 Male and female patients between 2 and 15 years of age Mild-to-moderate symptoms of AD at baseline with evaluable skin lesions	PK of E6005 (21 days) and the number of participants with AEs	January 2015
		NCT01179880	1 & 2	Enrollment: 76 Male patients between 20 and 65 years of age Evaluable typical eczema on the back	PK of E6005 (13 days)	December 2012
LEO 29102	PDE4 inhibitor	NCT01037881	2	Enrollment: 183 Male and female patients between 18 and 65 years of age AD classified as mild (2) or moderate (3) according to IGA Lesions located on the trunk and limbs Treatment lesions involving 3% to 10% of BSA	Change in EASI score from baseline to end of treatment (4 weeks)	June 2010
OPA-15406	PDE4 inhibitor	NCT02068352	2	Enrollment: 94 Male and female patients between 10 and 70 years of age History of AD for >3 years AD affecting ≥5% and ≤40% of BSA at baseline IGA score of 2 (mild) or 3 (moderate) in the selected treatment area	Safety as assessed by incidence and severity of AEs, and incidence of success (defined as an ISGA score of clear [0] or almost clear [1] with >2-grade reduction from baseline)	February 2015
GSK2894512	Non-steroidal anti-inflammatory	NCT02564055	2	Enrollment: 258 Male and female patients between 12 and 65 years of age AD affecting ≥5% and ≤35% of BSA at baseline An IGA score of ≥3 at baseline At least 1 target lesion of >3 cm ×3 cm at baseline, but not located on the hands, feet, or genitalia	Proportion of patients with an IGA score of clear (0) or almost clear (1) at week 12 and a minimum 2-grade improvement from baseline	August 2016
MRX-6	Multifunctional anti-inflammatory	NCT02031445	2	Enrollment: 80 Male and female patients between 2 and 17 years of age AD as defined by an IGA score of mild (2) or moderate (3) AD affecting ≥5% of BSA at baseline AD for >3 months prior to baseline	IGA (4 weeks)	July 2014
SB011	GATA-3–specific DNAzyme	NCT02079688	2	Enrollment: 26 Male and female patients between 18 and 60 years of age SCORAD between 20 and 50 2 comparable lesions Increased IgE	Change of local SCORAD from baseline to day 15	December 2015
Q301	Unknown	NCT02426359	2	Enrollment: 60 Males or females ≥18 years of age AD as defined by an IGA score of moderate (3) or severe (4)	Score change from baseline on SCORAD (2, 4, 6, and 8 weeks)	April 2016

AD: atopic dermatitis; AE: adverse event; BSA: body surface area; CDLQI: Children’s Dermatology Quality of Life Index; DFI: Dermatitis Family Impact; DLQI: Dermatology Quality of Life Index; EASI: Eczema Area and Severity Index; IGA: Investigator’s Global Assessment; IgE: immunoglobulin E; ISGA: Investigator’s Static Global Assessment; PDE4: phosphodiesterase 4; PK: pharmacokinetics; QD: once daily; QOL: quality of life; SCORAD: scoring atopic dermatitis. With the exception of the AD-303 trial and the MUSE trial, all information was obtained from ClinicalTrials.gov.

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