WAILEA, HAWAII – Physicians will likely gain a novel short-course field therapy for multiple actinic keratoses next year.
Ingenol mebutate (Leo Pharmaceuticals) hit all of its end points in two phase III clinical trials. One trial was conducted in patients treated for fields of multiple actinic keratoses (AKs) on the head and neck, the other in patients with clusters of AKs anywhere else, Dr. Theodore Rosen said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).
Dr. Theodore Rosen
Median reductions in AKs in these pivotal trials were comparable to results reported with other field therapies, such as imiquimod and 5-fluorouracil. What is remarkable about ingenol mebutate, however, is these outcomes were achieved with only 2 days of once-daily therapy for non–head and neck AKs and 3 days of therapy at a lower concentration for AKs on the head and neck, noted Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.
In contrast, the original regimen for the 5% imiquimod dermatologists have been using since its 2004 marketing approval for AKs entails a full 16 weeks of twice-weekly therapy. That being said, last year, the FDA approved a new, shorter-duration formulation of imiquimod which Dr. Rosen said was a better product than the traditional 5% version.
Ingenol mebutate is a diterpene ester derived from the sap of a plant, Euphorbia peplus, traditionally used by Australian aborigines for topical treatment of various skin ailments. Ingenol mebutate's mechanism of action is not fully understood, but involves initial cell necrosis because of mitochondrial disruption followed by granulocyte-dependent cytotoxicity. Immune upregulation also appears to be involved, Dr. Rosen explained.
Non–Head and Neck AK Study
The phase III non–head and neck AK study involved 256 patients randomized to 2 consecutive days of once-daily ingenol mebutate 0.05% gel or placebo applied to up to a 25-cm2 area of skin with four to eight visible AKs. The ingenol mebutate group showed a complete clearance rate at day 57 of 27.8%, compared with 4.7% for placebo, and a median 67% reduction in AKs.
The 27.8% complete clearance rate is nothing to write home about, but the 67% reduction in AKs is quite impressive, particularly for a 2-day therapy, according to Dr. Rosen, who was an investigator in these and other AK clinical trials.
"That 67% median reduction is very nice, and it’s really the most accurate measurement because it tells you how many of these things are going to go away by treating the field," Dr. Rosen said.
The complete clearance rate was highest on the chest, followed by the arms, legs, back of hand, and back.
Side effect rates were low at 1%-2%, and consisted of burning, irritation, pain, and other symptoms that are associated with most field therapies for AKs. Interestingly, the peak incidence of the skin side effects was not until day 8.
"You'll have to prepare patients for the fact that almost a week after they’re done with therapy, they may suddenly look worse," he noted.
The product labeling will limit treatment to areas of 25 cm2 or less because that is how the pivotal trials were done. "If you want to treat more than 25 cm2, you’ll probably be off-label, but we do that all the time," he said.
In an exploratory trial in which investigators treated AK fields of 25, 50, 75, and 100 cm2 on the dorsal arms using 0.05% ingenol mebutate applied once daily for 2 days, cumulative local skin reaction scores correlated with the size of the area treated. Even in patients who underwent treatment of 100 cm2 of involved skin, side-effect scores returned to baseline by 2 months. Most patients tolerated even the most severe reactions, he noted.
Head and Neck AK Study
The phase III head and neck AK trial involved treatment of areas up to 25 cm2 in 264 patients. This trial featured several drug concentrations and durations; the one that produced the best outcomes and will move forward to the marketplace is 0.015% once daily for 3 days. It yielded a complete clearance rate of 50% on day 57, and an 85% median reduction in AKs, according to Dr. Rosen.
With two different concentrations of ingenol mebutate likely to be approved for application at different sites, physicians will need to remain vigilant regarding possible dispensing errors or patient misuse, he said.
Imiquimod
While ingenol mebutate's duration of efficacy remains unknown, that is not the case with imiquimod.
The new imiquimod 3.75% cream (Zyclara), approved last year for treatment of AKs, provides clear benefits over the older 5% formulation in terms of convenience, and with comparable efficacy.