Imiquimod 3.75% Cream in Combination With Cryotherapy in the Treatment of Hypertrophic Actinic Keratoses

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 multplie 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,
electrodessication and curettage, topical chemotherapy and light therapies. With
provider-administered devices, temperature utilized, times of contact, and other variations
in administration, influence efficacy of treatment. Efficacy can be improved by increasing
the freeze time, but this is often associated with greater discomfort, more severe skin
necrosis, and increased risk of post-treatment hypopigmentation. In addition, 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%. There is limited
information on long-term AK clearance rates after cryosurgery and those reports differ in
their methods of calculation. In a study comparing cyrotherapy, imiquimod and
5-fluorouracil, at 12 months post cryotherapy 28% (7/25) had complete clearance of baseline
lesions that had undergone cryotherapy, but only 4% (1/25) had complete clearance of the
treatment field.

Imiquimod is a topical immune response modifier that activates the innate immune system via
Toll-like receptor 7, as well as enhances the acquired immune system. A 5% topical
formulation has been approved for the treatment of AKs in the US as a 2x/week for 16 week
regimen and in Europe as a 3x/week for 4 week regimen for 1 or 2 courses of therapy. Topical
imiquimod 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. In a comparison of cryosurgery versus imiquimod for the treatment of AKs,
Krawtchenko et al reported initial complete clearance rates of 68 and 85% by clinical
assessment, respectively. However, the treatment field sustained clearance rate was 4%
versus 73%, respectively. Tan et al reported that while application of imiquimod or vehicle
following cryosurgery resulted in comparable target AK clearance rates at 12 weeks of 79%
versus 76%, respectively, the imiquimod group had fewer total AKs and fewer subclinical AKs.

The imiquimod 5% formulation has limitations for the treatment of AKs. It is approved for
the treatment of a small area of skin (25 cm2), uses a less than intuitive 2 times per week
(2x/week) dosing schedule, and has a prolonged treatment period (16 weeks). Dosing more
frequently than 3x/week with imiquimod 5% cream was not well tolerated in subjects with AK.
Imiquimod cream at a concentration of 3.75% has been found in Phase 3 studies to be superior
to placebo cream with respect to clearance of AKs using a regimen of up to 2 packets (250 mg
of cream per packet, 500 mg total) applied daily to the entire face (approximately 200 cm2)
for two 2-week treatment cycles separated by a 2-week no-treatment period.

Inclusion Criteria:

1. Adults at least 18 years old.

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

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

4. Prior to cryosurgery, subjects have at least 3 hypertrophic actinic keratoses on each
dorsal hand/forearm.

5. Subject must be willing to forego any other treatments on the dorsum of the hands and
or/forearms, including tanning bed use and excessive sun exposure while in the study.

6. 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.

7. 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 a history of melanoma anywhere on the body.

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

3. Subjects with non-melanoma skin cancer on the dorsum of the hands or forearms.

4. 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.

5. Subjects who have previously been treated with imiquimod: on the dorsum of the hands
or forearms in the past 6 months; or outside of the study area within the past 30
days.

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

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

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

9. Subjects who have known allergies to any excipient in the study cream.

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 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)

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