Treatment of Actinic Keratoses (AK) on the Face

Actinic keratoses (AK) are common cutaneous lesions associate with chronic ultraviolet
radiation exposure. Ultraviolet radiation produces local and systemic immunosuppression,
mutations in the p53 tumor suppressor gene, and deoxyribonucleic acid pyrimidine covalent
dimmers, each of which is believed to contribute to the dysplasia seen in AK. While most
authorities consider AK as a pre-malignant lesion, some consider it as an incipient squamous
cell carcinoma (SCC). The risk for progression to SCC for an individual AK is reportedly low
but highly variable; however, as patients often have multiple AKs, the overall risk for
progression over a lifetime can be significant; thus treatment of AKs is warranted. In
addition, the skin around clinically obvious AK lesions has been subject to the same chronic
ultraviolet exposure, resulting in genetic damage and mutations, resulting in "field
cancerization." Subclinical AKs may progress to clinical AKs, or even de novo invasive SCCs.

Among the current therapies for the treatment of AK are excisional surgery, cryosurgery,
electrodesiccation and curettage, topical chemotherapy and light therapies. Cryosurgery is
considered the gold standard for therapy, however as with other lesion-directed therapies,
cryosurgery does not treat subclinical lesions in the surrounding skin. Treated lesion
clearance rates at 3 months post-treatment after double-freeze thaw cryotherapy has been
reported to be around 76-88%; however, new lesions in the treatment field were not included.
Overall lesion clearance rate, including new subclinical lesions, at approximately 5 months
post-cryosurgery has been reported to be 35-51%. The inability to treat subclinical lesions
with lesion-directed cryosurgery, has spurred the emergence of topical medications such as
ingenol mebutate for field-directed therapy.

Ingenol mebutate is the active compound in the sap from Euphorbia peplus L. (E. peplus). The
sap from E. peplus has a long history of community use for the topical treatment of various
skin conditions, including AKs. Ingenol mebutate, in a gel formulation referred to as PEP005
(ingenol mebutate) Gel or PEP005 Gel, has been evaluated in clinical trials as field therapy
for the topical treatment of AK and photo damaged skin and as lesion-specific treatment for
seborrheic keratosis and non-melanoma skin cancer (NMSC). The mechanism of action of ingenol
mebutate in AK therapy is not yet fully understood. In vivo and in vitro models have
demonstrated both an induction of local lesion cell death and promotion of lesion-specific
inflammatory response. A 0.015% topical formulation has been approved for the treatment of
AKs in the US as a once a day for three consecutive days regimen. Topical ingenol mebutate
treatment may also reduce subclinical lesions in the treatment area, resulting in fewer
"new" AK lesions developing over the same period of time when compared to focal treatment.

Phase III data demonstrated complete field clearance of AKs in 37-47% on the face as well as
sustained clearance of approximately 50% twelve months post treatment. Similarly a
randomized controlled study found a mean reduction of 83% in AK lesions on the face. 87.2%
of AK's in the treatment area at baseline were still clear 12 months later. Previous
clinical studies report mild to moderate local adverse events (AE) such as pruritus, pain,
irritation and local skin response (LSR) (eg erythema, flaking, scaling). The unpleasant and
often unsightly localized skin irritation can be emotionally difficulty for patients and
provoke anxiety. It is unknown whether a large inflammatory reaction is necessary for
successful treatment of actinic keratosis with ingenol mebutate 0.015%. Currently, there are
no clinical studies evaluating combination therapies (eg topical steroids, barrier creams,
etc.) with ingenol mebutate 0.015% that would decrease irritation while maintaining
efficacy.

Inclusion Criteria:

- Adults at least 18 years old.

- Subjects must be in good general health as confirmed by the medical history.

- Subjects must be able to read, sign, and understand the informed consent

- Subjects must have two separate, relatively symmetrical 25 cm2 treatment areas on the
face with at least 3-8 non-hypertrophic AKs.

- Subject must be willing to forego any other treatments on the face, including tanning
bed use and excessive sun exposure while in the study.

- Subject is willing and able to participate in the study as an outpatient, making
frequent visits to the study center during the treatment and follow-up periods and to
comply with all study requirements including concomitant medication and other
treatment restrictions.

- If subject is a female of childbearing potential she must have a negative urine
pregnancy test result prior to study treatment initiation and must agree to use an
approved method of birth control while enrolled in the study.

Exclusion Criteria:

- Subjects with a history of melanoma anywhere on the body.

- Subjects with an unstable medical condition as deemed by the clinical investigator.

- Subjects with current non-melanoma skin cancer on the face.

- Subjects with any dermatologic disease in the treatment area that may be exacerbated
by the treatment proposed or that might impair the evaluation of AKs.

- Subjects who have previously been treated with ingenol mebutate: on the face in the
past 6 months; or outside of the study area within the past 30 days.

- Women who are pregnant, lactating, or planning to become pregnant during the study
period.

- Subjects who have experienced a clinically important medical event within 90 days of
the visit (e.g., stroke, myocardial infarction, etc).

- Subjects who have active chemical dependency or alcoholism as assessed by the
investigator.

- Subjects who have known allergies to any excipient in the ingenol mebutate 0.015% gel
and/or dermasil lotion.

- Subjects who are currently participating in another clinical study or have completed
another clinical study with an investigational drug or device on the study area
within 30 days prior to study treatment initiation.

- Subjects who have received any of the following within 90 days prior to study
treatment initiation:

- interferon or interferon inducers

- cytotoxic drugs

- immunomodulators or immunosuppressive therapies (inhaled/ intranasal steroids
are permitted)

- oral or parenteral corticosteroids

- topical corticosteroids if greater than 2 gm/day

- any dermatologic procedures or surgeries on the study area (including any AK
treatments)

- Subjects who have used any topical prescription medications on the study area within
30 days prior to study treatment initiation.