Ingenol Mebutate Gel Clears Actinic Keratosis Lesions

March 9, 2010 (Miami Beach, Florida) — The new 0.05% ingenol mebutate gel (currently called PEP005) is effective and well tolerated when used to treat actinic keratoses (AK) on sites such as the chest and arms, according to a phase 3 study presented here at the American Academy of Dermatology (AAD) 68th Annual Meeting.

In fact, more than 27% of patients showed complete clearance of AK lesions after 2 days of treatment, and more than 44% had partial clearance.

"With no topical agents currently approved for the treatment of nonhead AK lesions, ingenol mebutate gel 0.05% could provide an attractive alternate therapy choice that offers few adverse events, [with] well-tolerated [local skin responses] LSRs and a convenient short course of therapy," principle investigator Neil Swanson, MD, professor and chair of dermatology at Oregon Health and Science University in Portland, told meeting attendees.

He noted that AK is starting to become more prevalent in younger patients and that prompt diagnosis and treatment are critical because this condition can progress to invasive squamous cell carcinoma.

"An unmet medical need exists for a safe and efficacious agent that can be used in a simple and reliable manner on difficult-to-treat areas," said Dr. Swanson.

An Australian Extract for AK Treatment

Ingenol mebutate is the active agent in the sap of the Australian plant Euphorbia peplus, "a traditional remedy for skin lesions," reported Dr. Swanson. A gel containing this ingredient is being developed for topical treatment of both AK and nonmelanoma skin cancers, and was shown in phase 2 trials to be effective in treating the scalp.

For this study, the investigators sought to evaluate the gel's overall effictiveness and safety parameters. They enrolled 255 patients at centers in the United States and Australia and randomized them to receive self-applied home treatment with either ingenol mebutate gel 0.05% or a vehicle gel once daily for 2 consecutive days. The patients were directed to apply the treatment to areas containing 4 to 8 lesions on the arm (n = 84 of patients receiving active treatment), back of hand (n = 25), chest (n = 9), leg (n = 6), and back (n = 2).

"The overwhelming majority of AK lesions were located on the arms or back of hands, which tend to take the longest to respond," said Dr. Swanson. "We were hoping to show that this agent would work in the difficult spots."

Effictiveness and safety evaluations were conducted on days 3, 8, 15, 29, and 57. The primary end point was complete clearance of lesion lesions at day 57; partial clearance (a 75% or greater reduction) was a secondary end point.

In addition, the patients filled out the Skindex-16 dermatological survey for quality-of-life issues and the Treatment Satisfaction Questionnaire for Medication (TSQM).

Increased Lesion Clearance

Results showed that 27.8% of patients treated with ingenol mebutate gel had complete lesion clearance across all application sites at day 57, compared with just 4.7% of those treated with the vehicle (P < .0001).

When evaluating the individual sites in the active treatment group, the investigators found complete clearance rates of 88.9% for the chest, 25.3% for arms, 16.7% for legs, and 16% for the back of the hand. However, complete clearance was not achieved in the 2 patients who applied the gel to their backs.

Partial clearance across all sites was achieved in 44.4% of the treatment group and in 7% of the vehicle group (P < .0001).

In addition, the patients treated with ingenol mebutate gel had a 69.1% median reduction in baseline lesions across all application sites, compared with 0% in the vehicle group (P < .0001).

TSQM scores were also significantly higher in the treatment group for effectiveness and for global satisfaction than in the vehicle group (P < .0001 for both).

Overall adverse events (AEs) "were generally mild to moderate and resolved by day 57, and the most common treatment emergent AEs were application-site reactions and pruritus," reported Dr. Swanson. There were no drug-related serious AEs.

The most frequent LSRs reported in the treatment group were erythema (92% at day 8) and flaking/scaling (90.4% at day 8).

"By day 57, the frequency of most of these LSRs had returned to or was below baseline level," said Dr. Swanson.

Although 3 patients who received active treatment reported increased pigmentation, 4 others reported a pigmentation improvement. None reported increased scarring. Skindex-16 scores for symptoms were higher for the treatment group than for the vehicle group at day 8 (P < .0001), but these scores were similar to baseline scores in both groups by day 57.

"Our findings show that 0.05% ingenol mebutate gel applied for 2 consecutive days was significantly more effective than the vehicle with respect to complete and partial clearance of AK lesions, and it was also well tolerated," explained Dr. Swanson. "It's an exciting new product coming down the pipeline."

Preliminary but Promising Findings

"This was a fairly large study for an AK trial and was well done, although the results are preliminary," said Darrell Rigel, MD, clinical professor of dermatology at New York University in New York City, and a past president of the AAD.

"This is a very new product that's awaiting approval, and it appears that 1 or 2 applications may be effective in long-term treatment, as opposed to other topical agents that require 4 weeks, 6 weeks, or longer. The hope is that compliance will also be better," said Dr. Rigel, who was not involved with this study. "I'd say that, at least preliminarily, this looks promising."

He cautioned that in some of the original trials, "there were some brisk reactions, as there are with many of these topical agents, but I think they will be titrated to the right doses before they come to the final use."

"We're always looking for new ways to treat AK and although this one is not [approved by the US Food and Drug Administration] yet, it looks like it may have some value in the future," concluded Dr. Rigel.

This study was sponsored by Peplin Ltd, a wholly owned subsidiary of LEO Pharma. Dr. Swanson reports being on Peplin's advisory board. Dr. Rigel reports consulting for LEO in the past, although he's had no involvement with the study of ingenol mebutate.

American Academy of Dermatology (AAD) 68th Annual Meeting: Abstract P105. Presented March 6, 2010.