Actinic keratoses: Experimental topical gel offers effective short treatment regime

February 1, 2009

Ingenol mebutate is a novel approach for the treatment of actinic keratoses. This new topical approach successfully treats AKs in only two or three days, - a much shorter therapeutic regimen compared to the current readily used topical approaches, such as solaraze, 5-FU and imiquimod, and, therefore, also increases patient compliance.

Key Points

Researchers are currently fine-tuning the dosing regimens of the drug. According to a recent study, 0.025 percent of ingenol mebutate gel applied once a day for two consecutive days appears to be the optimal dose for the treatment of AK lesions of the face and scalp.

"I think the uniqueness of this drug is that we are able to achieve positive therapeutic results for AKs using a very short dosing regimen - only a two-day treatment," says Michael Freeman, M.B.B.S., of the Skin Centre, Gold Coast, Queensland, Australia.

Study parameters

Dr. Freeman headed a 57-day study in which six concentrations and two regimens of ingenol mebutate gel were evaluated for their effectiveness, tolerability and safety profile in 88 patients with facial and scalp AK lesions.

The patients included in the study had four to eight AK lesions in a contiguous 25 cm² area on the face or face and scalp, and they were treated with 0.0125 percent, 0.0175 percent, or 0.025 percent once daily (QD) for a maximum of two days, or with 0.0025 percent, 0.005 percent, 0.0075 percent, 0.0125 percent, 0.0175 percent, or 0.025 percent QD for a maximum of three days.

Results

The maximum tolerated dose based on local tolerability was 0.025 percent QD for two days, where complete clearance was 38.9 percent.

Dr. Freeman found that all concentrations produced partial clearance of AK lesions in at least some patients, ranging from 25 percent with 0.0025 percent for three days to 100 percent with 0.0125 percent and 0.0175 percent for two days, and 0.0125 percent and 0.025 percent for three days.

Patient satisfaction was recorded as very positive at all concentrations, with no adverse events. Tolerability was high, as 83 percent of patients managed to apply the drug for two days and approximately half of the patients for three days, reflecting a good treatment protocol adherence.

Advantages

Dr. Freeman says that a major advantage of ingenol mebutate is that in only two days, one can achieve comparable therapeutic results when compared to those achieved with 5-FU and imiquimod after weeks and months of treatment, respectively.

A strong inflammatory response is not expected with solaraze. The strong inflammatory responses seen with ingenol mebutate are comparable to those seen with 5-FU and imiquimod.

"The mechanism of action of ingenol mebutate has only been partially elucidated. This novel topical agent seems to augment the neutrophil-killing ability on abnormal cells through mitochondrial damage, making it a unique tool in the treatment of AKs," Dr. Freeman says.

Dr. Freeman says that the effectiveness of ingenol mebutate is histologically proven for superficial BCC and, currently, there is a debate as to whether this histological confirmation is needed or warranted for AKs.

"Clinically, one can be very sure that clinical clearance is enough for AKs, but certainly, we have histological proof for superficial BCC, and I think that is appropriate," Dr. Freeman says.

Finding its niche

According to Dr. Freeman, ingenol mebutate could also find its niche as an alternate therapy to photodynamic therapy (PDT) for the treatment of BCCs and superficial SCCs.

He says first, all of the nodular components of the tumor could be curetted, and then ingenol mebutate could be applied to the lesion for two or three days after the wound heals.

"The short application time is what is unique with this topical agent, and I believe it will prove to be very useful in the dermatologist's armamentarium.

"Currently, this brand-new topical therapy promises rapid treatment of actinic keratoses and BCCs with a two-day regimen.

"Ongoing studies are aimed at assessing the efficacy of ingenol mebutate for actinic keratoses allowing for a FDA submission mid-2010," Dr. Freeman says.