Biological Effects of LEO 43204 in Actinic Keratosis

Inclusion Criteria:

- 1. Signed and dated informed consent has been obtained.

- 2. Subjects with at least 5 non-keratotic, clinically typical, visible and discrete
AK lesions within a contiguous 250 cm2 area (AK Treatment Area) on the upper
extremity,

- 3. Subjects with one additional AK lesion located on the contralateral arm.

- 4. Subjects with an area of normal skin in close proximity to the AK Treatment Area
or on the contralateral arm.

- 5. Male and female subjects, 18 years or older.

- 6. Agreement from the patient to allow photographs of the selected treatment area to
be taken and used as part of the study data package

- 7. Ability to follow study instructions and likely to complete all study requirements

- 8. Female Subjects must be of either

- non-childbearing potential, i.e. post-menopausal or have a confirmed clinical
history of sterility (e.g. the subject is without a uterus or has tubal
litigation) or,

- child-bearing potential* provided there is a confirmed negative pregnancy test
prior to trial treatment to rule out pregnancy.

- Female subjects are considered of child-bearing potential unless they have
had a hysterectomy or have undergone tubal litigation or have been
post-menopausal for at least one year prior to first visit.

- 9. Female subjects of child-bearing potential must be willing to use effective
contraception at trial entry and until completion.

Effective contraception is defined as follows:

- Abstinence (when this is in line with the preferred and usual life style of the
subject).

- Vasectomised partner (given that the subject is monogamous).

- An intrauterine device.

- Double barrier method defined as two distinct methods (two actual barrier methods).

- Hormonal contraceptive (oral hormonal birth control, oestrogenic vaginal ring,
percutaneous contraceptive patches, implants and injectables) for at least one
menstrual cycle prior to enrolment.

Exclusion Criteria:

- 1. Prior treatment with ingenol mebutate gel in the treatment area within the last 12
months.

- 2. Previously assigned treatment in this clinical trial or previously participated in
a clinical trial in the LEO 43204 programme (presently LP0084-68, LP0084-1013,
LP0084-1014, LP0084-1015, LP0084-1148, LP0084-1077, LP0084-1193, LP0084-1194,
LP0084-1195, LP0084-1196).

- 3. Location of the selected treatment area within 5 cm of an incompletely healed
wound or infected area of the skin (excl. study related biopsies) or within 5 cm of a
suspected basal cell carcinoma (BCC) or SCC.

- 4. History or evidence of skin conditions other than the study indication that would
interfere with the histologically- or biomarker evaluation of the study medication
(e.g. eczema, unstable psoriasis, xeroderma pigmentosum).

- 5. Treatment area lesions that have an atypical clinical appearance (e.g.
hypertrophic, hyperkeratotic, recalcitrant disease [had cryosurgery on two previous
occasions] and/or cutaneous horns).

- 6. Known sensitivity or allergy to any of the ingredients of LEO 43204 Gel (e.g.
citric acid)

- 7. Clinical diagnosis/history or evidence of any medical condition that would expose
a subject to an undue risk of a significant AE or interfere with assessments of
safety during the course of the study, as determined by Investigator clinical
judgment.

- 8. Anticipated need for in-patient hospitalisation or in-patient surgery during the
study period. Note that cosmetic/therapeutic procedures are not excluded if they fall
outside of the criteria detailed in the Prohibited Therapies or Medications (listed
below).

- 9. Anticipated excessive or prolonged exposure to ultraviolet light (e.g. sunlight)
or use of tanning beds for the duration of the study

- 10. Current participation in any other interventional clinical trial

- 11. Subjects who have received treatment with any non-marketed drug product (i.e. an
agent which has not yet been made available for clinical use following registration)
within the last two months.

- 12. Subjects known to be infected with Human Immunodeficiency Virus (HIV).

- 13. Subject known or, in the opinion of the investigator, is unlikely to comply with
the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state).

- 14. Females who are pregnant, of child-bearing potential and wishing to become
pregnant during the trial, or are breast feeding.

- 15. Females of child-bearing potential with positive pregnancy test at [screening or
visit 1].

- 16. Previous enrolment in this clinical trial. Prohibited Therapies and/or
Medications: within 2 weeks prior to the Screening visit

- 17. Cosmetic or therapeutic procedures (e.g. use of liquid nitrogen, surgical
excision, curettage, dermabrasion, medium or greater depth chemical peel, laser
resurfacing): within 2 cm of the selected treatment areas and within 2 cm of the
selected AK lesion outside the treatment area

- 18. Use of acid-containing therapeutic products (e.g. salicylic acid or fruit acids,
such as alpha and beta hydroxy acids and glycolic acids), topical retinoids or light
chemical peels: within 2 cm of the selected treatment areas and within 2 cm of the
selected AK lesion outside the treatment area

- 19. Use of topical salves (non-medicated/non-irritant lotion/cream are acceptable) or
topical steroids: within 2 cm of the selected treatment areas and within 2 cm of the
selected AK lesion outside the treatment area; artificial tanners: within 5 cm of the
selected treatment areas and within 5 cm of the selected AK lesion outside the
treatment area Prohibited Therapies and/or Medications: within 4 weeks prior to the
Screening visit

- 20. Treatment with immunomodulators (e.g. azathioprine), cytotoxic drugs (e.g.
cyclophosphamide, vinblastine, chlorambucil, methotrexate, podophyllin, camptothecin)
or interferon/interferon inducers.

- 21. Treatment with systemic medications that suppress the immune system (e.g.
cyclosporine, prednisone, methotrexate, infliximab).

- 22. Treatment/therapy with UVB

Prohibited Therapies and/or Medications: within 8 weeks prior to the Screening visit

- 23. Treatment with 5-FU, imiquimod, diclofenac, or photodynamic therapy: within 2 cm
of the selected treatment areas and within 2 cm of the selected AK lesion outside the
treatment area Prohibited Therapies and/or Medications: within 6 months prior to the
Screening visit

- 24. Use of systemic retinoids (e.g. isotretinoin, acitretin, bexarotene)