Topical NanoDox® for Atopic Dermatitis

Atopic Dermatitis (AD) is the most common inflammatory skin disease, affecting about 17% of
children and 6% adults in the USA , . AD is characterized by skin barrier disruption, an
aberrant adaptive immune response (i.e., Th2 polarized) to environmental allergens,
susceptibility to cutaneous bacterial infections and intractable itch , . The intense
pruritus and cutaneous infections contribute to the morbidity of AD and are major drivers of
the reduced quality-of-life associated with this disease , . In the World Health Organization
2010 Global Burden of Disease survey, AD has ranked first among common skin diseases . So
far, AD treatments have targeted inflammation with the widespread use of topical and more
intermittent use of systemic corticosteroids. In summary, despite its high prevalence,
effects on quality-of-life and economic burden - there are few effective treatments for AD.

Doxycycline are tetracycline antibiotics broadly used systemically to treat
inflammatory-dermatologic conditions. Several studies in human and animal models have shown
doxycycline have anti-inflammatory and pro-healing properties, mainly by blocking tissue
proteolytic activity. Doxycycline have been reported to nonselectively inhibit members of the
metalloproteinases (MMP) superfamily [reviewed in , ]. In addition to this direct inhibitory
activity, doxycycline indirectly prevents tryptic kallikreins activation by MMPs . Growing
body of evidence suggests that the tetracycline might also directly downregulate Protease
Activator receptor (PAR)-2 expression and function, which was also found to play a role in
induction of local inflammatory mediators . Importantly, the doxycycline antimicrobial
activity could lead to reduced Staphylococcus infection/colonization in AD skin, a known
trigger of AD flares

Inclusion Criteria:

- Male or female, 18 through 65 years of age, inclusive who are generally healthy except
for active atopic dermatitis diagnosed by the following criteria.

- Active Atopic Dermatitis: Subjects must have within the last 3 months according to
medical records, patient account or by medical exam of the investigator:

- Pruritus

- Eczema (acute, subacute, chronic)

- Chronic or relapsing history

Most subjects will have (seen in most cases, adding support to the diagnosis):

- Early age at onset

- Atopy

- Personal and/or family history

- Xerosis

Subjects may have (these clinical associations help to suggest the diagnosis of AD but are
too nonspecific for defining or detecting AD for research or epidemiological studies):

1. Atypical vascular responses (e.g., facial pallor, white dermographism, delayed blanch
response)

2. Keratosis pilaris/hyperlinear palms/ichthyosis

3. Ocular/periorbital changes

4. Other regional findings (e.g., perioral changes/periauricular lesions)

5. Perifollicular accentuation/lichenification/prurigo lesions

- Moderate to Severe AD: clinical score based on Eczema Area and Severity Score
(EASI) ≥ 10

- If receiving antihistamines, are on a stabilized dose, and expect to maintain
this dose throughout the study

- All female subjects of childbearing potential must have a negative pregnancy test
at screening visit and must be on an acceptable methods of contraception from the
Screening Visit continuously until 30 days after stopping study drug.

Exclusion Criteria:

- As determined by the study doctor, a medical history that may interfere with study
objectives (cancer, chronic illness)

- Known allergy to tetracycline

- Subjects with a systemic infection requiring a course of systemic antibiotics or
antivirals within the last 2 weeks

- Unstable AD or any consistent requirement for systemic immune-modulant Rx (e.g.
systemic steroids, phototherapy, Cyclosporine)

- History of use of biologic therapy (including intravenous immunoglobulin)

- Recent or anticipated concomitant use of systemic therapies that might alter the
course of AD

- Recent or current participation in another research study

- Females who are breastfeeding, pregnant, or with plans to get pregnant during the
participation in the study

- Subjects with a history of keloid formation

- History of lidocaine, epinephrine or Novocain allergy

- History of allergy to tape or other adhesive materials

- Hand eczema only (no body involvement).