Safety and Efficacy of Ingenol Mebutate Gel 0.015% for Treatment of AK on the Face in Solid Organ Transplant Recipients

Actinic keratoses (AK) are patches of dysplastic keratinocytes arising in sun-damaged skin.
These lesions are precursors to cutaneous squamous cell carcinoma (SCC), and are treated to
prevent progression to SCC. First-line therapy for AK include cryotherapy and curettage,
which target clinically visible lesions but do not address the subclinical lesions in the
field of ultraviolet radiation damage. Field therapy includes topical chemotherapy,
immunotherapy, and photodynamic therapy. Ingenol mebutate is the active compound found in
Euphorbia peplus sap, and has been approved for treatment of AK in immunocompetent patients.
Ingenol mebutate 0.015% is favored over other topical treatments for treatment of AK on the
face due to the brief treatment course, high clearance rate, and resolution without sequelae.

Solid organ transplant recipients (OTR) have a high incidence of AK and high risk of
developing SCC, and require frequent field therapy. In addition, OTR generally have a higher
burden of AK and require treatment of a larger surface area than the 25 cm2 area labeled for
ingenol mebutate 0.015%. The investigators plan to investigate the safety and efficacy of
ingenol mebutate 0.015% in OTR, with a treatment area up to 100cm2.

This is a single arm, open-label interventional study of ingenol mebutate 0.015% in solid
organ transplant recipients. The investigators plan to treat 20 subjects, 10 kidney
transplant recipients and 10 lung transplant recipients. The investigators have selected
these two populations as the represent the spectrum of solid organ transplantation: kidney
transplant recipients are the largest transplant population, but have lower levels of
immunosuppression and skin cancer risk. Lung transplant recipients have the highest burden of
skin cancer and actinic keratoses.

Inclusion Criteria:

1. Adults at least 18 years old.

2. Subject must be a solid organ transplant recipient at least one year from the date of
transplantation.

3. Subjects must be in stable health as confirmed by medical history, per investigator
judgement.

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

5. Subjects have at least 4 and no more than 20 clinically typical
(non-hyperkeratotic/hypertrophic), visible actinic keratoses in a treatment area of
approximately 100cm2 on the face. Treatment areas will include a single cheek
(nasofacial sulcus to tragus, malar cheekbone to jawline and avoiding the lower eyelid
and mouth); the forehead (hairline to eyebrows, extending laterally to the root of the
helix).

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

7. Subject is willing and able to participate in the study and to comply with all study
requirements including concomitant medication and other treatment restrictions.

8. 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:

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

2. Subjects with a history of bone marrow or stem cell transplantation.

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

4. Subjects with hyperkeratotic or hypertrophic AKs.

5. 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.

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

7. Subjects who have previously been treated with ingenol mebutate in study area within
the past 8 weeks.

8. Subjects who have used any topical prescription medications for actinic keratosis on
the study area within 8 weeks prior to study treatment initiation.

9. Subjects who have used any topical prescription medications for other reason on the
study area within 4 weeks prior to study treatment initiation.

10. 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.

11. Subjects with known hypersensitivity to Picato gel or any of the inactive ingredients:
isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, or
benzyl alcohol.