An Equivalence Study of Generic Ingenol Mebutate Gel 0.015% and Picato Gel 0.015% in Subjects With Actinic Keratosis

Picato® (ingenol mebutate) gel is the first and only ingenol mebutate product approved by
the Food and Drug Administration (FDA) in 2012 for the topical treatment of AKs on the face
and scalp (0.015% formulation) and on the trunk and extremities (0.05% formulation). The FDA
approved regimen for ingenol mebutate gel, 0.015% for the treatment of AKs on the face and
scalp is once-daily application of one unit dose tube for three consecutive days applied to
one contiguous skin area of approximately 25 cm2 (e.g., 5 cm x 5 cm).

Inclusion Criteria:

- Subject was male or non-pregnant female 18 years of age or older.

- Females must have been post-menopausal, surgically sterile, or using an effective
method of birth control. Women of childbearing potential (WOCBP) must have had a
negative urine pregnancy test (UPT) at Visit 1/Baseline.

- Subject provided written informed consent.

- Subject had a clinical diagnosis of AK at Visit 1/Baseline with at least four, but no
more than eight visible and discrete non-hyperkeratotic, non-hypertrophic AK lesions,
each at least 4 mm in diameter, within a contiguous 25 cm2 treatment area ("the
Treatment Area") located on the face or scalp.

- Subject was willing and able to apply the test article as directed, comply with study
instructions, and commit to all follow-up visits for the duration of the study.

- Subject was in good general health and free of any disease state or physical
condition that might have impaired evaluation of AK lesions or which, in the
investigator's opinion, exposed the subject to an unacceptable risk by study
participation.

Exclusion Criteria:

- 1. Subject was pregnant, lactating, or was planning to become pregnant during the
study.

- Subject had a location of the selected contiguous 25 cm2 Treatment Area that (a) was
within 5 cm of an incompletely healed wound or (b) was in an area containing a lesion
that was previously treated with ingenol mebutate.

- Subject had hyperkeratotic, hypertrophic, or large mat-like AKs (e.g., AK >1 cm2 in
size) within the contiguous 25 cm2 Treatment Area.

- Subject had more than eight AKs, independent of size, within the selected contiguous
25 cm2 Treatment Area

- Subject had atopic dermatitis, basal cell carcinoma, eczema, psoriasis, rosacea,
squamous cell carcinoma, xeroderma pigmentosum, or any other possibly confounding
skin conditions within the region of the head that contained the selected Treatment
Area (i.e., face or scalp).

- Subject had any skin pathology or condition that, in the investigator's opinion,
could have interfered with the evaluation of the test article or required the use of
interfering topical, systemic, or surgical therapy.

- Subject was immunosuppressed (e.g., human immunodeficiency virus, systemic
malignancy, graft host disease, etc.).

- Subject experienced an unsuccessful outcome from previous ingenol mebutate therapy
(an unsuccessful outcome was defined as after a reasonable therapeutic trial with no
compliance issues and the topical drug did not work).

- Subject used topical creams, lotions, or gels of any kind within the selected
Treatment Area within one day prior to entry into the study.

- Subject had the need or planned to be exposed to artificial tanning devices or
excessive sunlight during the study or had used artificial tanners within two weeks
of Visit 1/Baseline.

- Subject had used any of the following topical medications on the face or scalp:

- Corticosteroids within two weeks of Visit 1/Baseline;

- Keratolytic-containing therapeutic products or medicated or irritant topical
salves within two weeks of Visit 1/Baseline, including, but not limited to,
alpha hydroxy acids (e.g., glycolic acid, lactic acid etc. >5%), beta hydroxy
acid (salicylic acid >2%), and urea >5%;

- Topical retinoids (e.g., tazarotene, adapalene, tretinoin) within two weeks of
Visit 1/Baseline;

- Light treatments (e.g., psoralen plus ultraviolet A therapy, ultraviolet B)
within four weeks of Visit 1/Baseline;

- Photodynamic therapy within eight weeks of Visit 1/Baseline;

- 5-fluorouracil, diclofenac, imiquimod, or ingenol mebutate within eight weeks of
Visit 1/Baseline; or

- Other topical therapy for actinic keratosis within 2 cm of the selected
contiguous 25 cm2 Treatment Area within eight weeks of Visit 1/Baseline.

- Subject had cryodestruction or chemodestruction, surgical excision, curettage,
dermabrasion, chemical peel, or laser resurfacing on the Treatment Area (i.e., face
or scalp) within two weeks prior to Visit 1/Baseline.

- Subject used any of the following systemic medications:

- Corticosteroid therapy within one month;

- Interferon/interferon inducers, cytotoxic drugs, immuno-modulators, or
immunosuppressive therapies within one month;

- Retinoid therapy within six months prior to Visit 1/Baseline.

- Subject had lesions suspicious for skin cancer (skin cancer not ruled out by biopsy)
or untreated skin cancers within the selected contiguous 25 cm2 Treatment Area on the
face or scalp.

- Subject was enrolled in an investigational drug or device study.

- Subject used an investigational drug or investigational device treatment within one
month prior to Visit 1/Baseline.

- Subject had a history of sensitivity to any of the ingredients in the test articles
(see Section 9.4.2).

- Subject had any condition which, in the investigator's opinion, would have made it
unsafe or precluded the subject's ability to fully participate in this research
study.

- Subject was unable to communicate or cooperate with the investigator due to language
problems, poor mental development, impaired cerebral function, or physical
limitations.

- Subject was known to be noncompliant or was unlikely to comply with the requirements
of the study protocol (e.g., due to alcoholism, drug dependency, mental incapacity)
in the opinion of the investigator.

- Subject was previously enrolled in the same study.