Potential AK therapy: Ingenor mebutate demonstrates significant clearance rates

May 1, 2009

The mainstay of treatment for actinic keratoses (AKs) is liquid nitrogen, but the therapy has several disadvantages. Ingenor mebutate, a topical gel, is being investigated for its efficacy and safety as a therapy, with the most recent findings showing a significant difference in the clearance rate of AKs with the use of this gel, as well as good tolerability.

Key Points

The results point to a potential alternative to standard therapy with liquid nitrogen to treat AKs, according to Brian Berman, M.D., Ph.D.

"Our reliance on liquid nitrogen as a highly effective treatment was not borne out in more recent studies," says Dr. Berman, professor of dermatology and internal medicine, department of dermatology and cutaneous surgery, University of Miami Miller School of Medicine, Miami. "It is, however, still the mainstay for lesion-targeted therapy."

However, if clinicians opt to freeze with liquid nitrogen for a longer period of time, this can destroy other tissues, trigger pain and increase the chance of hypopigmentation, Dr. Berman says. Moreover, the use of liquid nitrogen targets specific lesions

"It is not a field therapy," he says. "You are not going to clear the sub-clinical lesions that you don't freeze."

There is a need for other AK therapies that would behave more as "field" therapies, detecting and treating subclinical AKs. "A field therapy gets rid of the AKs you see, and the ones you don't see," Dr. Berman tells Dermatology Times.

FDA approved

Topically applied imiquimod, fluorouracil and diclofenac have also been approved by the Food and Drug Administration (FDA) to treat AKs.

The disadvantage of these topical field therapies is that they require anywhere from weeks to months of therapy, Dr. Berman says.

Photodynamic therapy has been used to treat AKs, but it is not FDA-approved as field therapy for AKs. PEP005 has been shown to rapidly induce cell necrosis, as well as impact the immune system.

Recent data

The most recent data on PEP005 has demonstrated that a 0.015 percent concentration gel applied once daily for three consecutive days resulted in a total clearance rate in the intent-to-treat (ITT) population of 50.0 percent, p<0.001. There was a partial clearance rate of 71.9 percent, p<0.001. A total of 265 patients were initially randomized into the U.S.-Australian study and included in the ITT population.

The strongest concentration in this study produced a median reduction in overall lesion count of 84.5 percent.

Subjects in the study were randomized to receive three concentrations of the active compound, those being 0.005 percent, 0.010 percent, or 0.015 percent or vehicle.

There were two treatment regimens, with subjects receiving once-a-day treatment for either two or three consecutive days. The subjects in the study had AK lesions on the face and scalp.

The therapy was applied to a 25 cm2 contiguous AK treatment area containing four to eight clinically typical AK lesions. The primary objective was complete clearance of AK lesions, defined as the proportion of patients at day 57 who had no clinically visible AK lesions in the treated area.

Investigators also measured partial clearance of AK lesions as a secondary objective, which was defined as the proportion of patients at day 57 with a 75 percent or greater decrease in the number of AK lesions identified at baseline in the selected treatment area.

For all active treatment groups, local skin reactions peaked at day 4 and returned to vehicle treatment levels by day 15. Investigators assessed local skin reactions, such as erythema, flaking, crusting, swelling, vesiculation/pustulation and erosion/ulceration.

Indeed, a cosmetic benefit was noted. A total of 39 patients experienced an improvement in hyperpigmentation, and 19 experienced improvement in hypopigmentation. Three patients reported a mild increase in hyperpigmentation, and seven patients reported a mild increase in hypopigmentation. .

There were no further sequelae to treatment-related events, including application-site irritation and pruritus.

Ingenol mebutate 0.015 percent gel was rapid, effective and well-tolerated for the treatment of facial and scalp AKs. A phase 3 study is under way to examine the impact of ingenol mebutate on clearing AKs on sites other than the face and scalp, Dr. Berman says.

Disclosure: Dr. Berman is a member of the scientific advisory boards of Graceway and Peplin.

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