1. Susman, Ed

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WASHINGTON, DC-A new topical agent appears to reduce actinic keratoses on the scalp of balding individuals far better than placebo gels, and reduces those pre-cancerous lesions without serious adverse events, researchers reported at the 74th annual meeting of the American Academy of Dermatology.

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For both doses of ingenol disoxate (Leo 43204 GEL), the reduction in the actinic keratosis count at week eight compared to baseline was significantly greater, said Jonathan Weiss, MD, co-owner of the Gwinnett Clinical Research Center, Inc., Snellville, Ga. The reduction was 73 percent with the 0.037 percent dose of ingenol disoxate among the 67 patients assigned to that dose, and was 79 percent with the 0.05 percent dose of the gel among the 64 patients assigned to the higher dose compared with a 13 percent reduction in lesions among the 32 placebo vehicle patients (p<0.001), Weiss reported. He noted that most of the effect-91 percent with low-dose ingenol disoxate and 97 percent with the high-dose gel-was observed by week four in the early phase I/phase II trial.


"Ingenol disoxate is a novel ingenol derivative developed for improved thermostability and biologic properties for the field treatment of actinic keratosis treatment," Weiss said.


The 0.05 percent low-dose ingenol disoxate gel was administered at the start of the trial and then daily for eight weeks to 67 patients, he explained. Actinic keratoses lesion counts were taken at baseline and at Day 29 and Day 57.


The same protocol was followed for 64 patients who were assigned to the 0.03 percent high-dose treatment. There were 32 patients assigned to receive a placebo vehicle who also followed the same application treatment and actinic keratosis counts.


Patients were treated for two days and then were assessed for adverse events; they were also seen at Day 8, Day 15, Day 29, and Day 57. In each treatment group, at least 95 percent of patients completed all treatments, Weiss reported.


Results for Ingenol Disoxate

In commenting on the study, Doris Day, MD, a board-certified dermatologist and attending physician at Lenox Hill Hospital, New York, told Oncology Times, "This was interesting because at least 95 percent of the patients completed all the treatments, and that is pretty impressive.


"Current ingenol treatments are not very well-tolerated so this new product is impressive in that regard," Day said. "With the current ingenol, treatment is just 1-3 days, but there are a lot of side effects. The novel thing with ingenol mebutate was that the course of treatment was short, but the price one paid in adverse events was not so short, as it turned out. So it did not pick up much popularity among doctors.


"What they are doing with this new drug is to find a version of ingenol that works, but is tolerable," she said. "This new version appears to have a better side effect profile than ingenol mebutate."


Weiss and colleagues enrolled white male patients with skin type I-III, while the majority were elderly who had previously been treated for actinic keratoses. Patients in the study were about 74 years of age and had been diagnosed with actinic keratoses for a median of seven years. The median actinic keratoses lesion count was 13, and about 64 percent of the patients in the study had 200-250 cm2 of the scalp treated.


Weiss said the safety profile was acceptable. The most common treatment-related adverse events were application-site pain including burning among 48 percent of the patients on low-dose ingenol disoxate and among 57 percent of the high-dose patients, while 6 percent of those patients taking placebo reported application site discomfort. Application-site pruritus was observed in 25 percent of patients on the low dose and in 27 percent of those on the high dose of the gel. About 3 percent of placebo patients experienced pruritus at the application site, Weiss reported. However, no serious adverse events were related to treatment, he said.


"For all active doses, the composite local skin reaction score peaked at day three, rapidly declined, and reached mild levels at week two," he said.


Actinic keratoses are very common, Day said. "It is what we see every day as dermatologists. Actinic keratoses are sun-damaged skin that is dysplastic, and if you leave them long enough they are going to evolve into a true squamous cell carcinoma and then that is a problem. We like to treat them when they are at the actinic keratosis stage.


"Generally, we use cryotherapy as a mainstay of treatment for actinic keratoses; then we use imiquimod or 5-fluorouracil in a topical form and also photodynamic therapy," she said. "When these researchers talk about coming up with a better ingenol, they are comparing it to ingenol mebutate but ingenol is not the gold standard for treatment of actinic keratosis."


Day said that, when actinic keratoses are treated, there is a field treatment plan-treating an area of the face or scalp rather than just spots. "We believe that in this manner we can help get rid of the actinic keratoses and prevent true skin cancers from arising,"


The reduction in actinic keratoses in the study of 73 percent to 79 percent compared with 13 percent reduction with vehicle "was acceptable," Day said. "This will be an option for some people," she said. "Cost will be an issue, of course."


She said she awaits the outcome of further trials. "It's always good to have another weapon in our holster against this disease," she said.


Ed Susman is a contributing writer.