3M Submits Aldara For Actinic Keratosis, Plans Carcinoma Filing Mid-Year

3M could gain two new indications for its topical immune response modifier Aldara in 2004, with a recent submission for actinic keratosis and a filing for basal cell carcinoma planned for this summer.

The supplemental NDA for use of Aldara (imiquimod) for the treatment of actinic keratosis (AK) was submitted May 5 and is receiving a standard review, setting FDA's user fee deadline in March 2004 (see chart p. 17 for list of recent submissions and their user fee goals). 3M expects to follow the submission with an sNDA filing for the treatment of superficial basal cell carcinoma (BCC) in the next few months.

Both indications could substantially increase the potential market for Aldara. The product is the leading prescription treatment for external genital and perianal warts, with sales of "well over $100 mil. in 2002," 3M said.

According to the Skin Cancer Foundation, BCC is the most common form of skin cancer and affects 800,000 Americans each year.

3M estimates that as many as 10 mil. Americans are affected by AK each year. Approximately 60% of predisposed persons aged 40 years and older have at least one AK lesion, according to the American Academy of Dermatology.

The firm is stressing the importance of early treatment of AK, noting that it is a common precursor to squamous cell carcinoma. Estimates of the risk of progression of AK to invasive squamous cell carcinoma range from <1% to 16%.

Imiquimod, which is the first immune response modifier submitted for AK, acts by up-regulating interferon and other cytokines involved in the cell-mediated immune response at the application site. Aldara has both antiviral and antitumor activity, according to 3M.

The immune system has a recognized role in non-melanoma skin cancers - evidenced by the increased incidence of the disease in immunosuppressed patients. The immune system is also thought to contribute to the spontaneous regression of AK, which can occur in up to 25% of cases.

"Activation of the host's immune system could therefore be a potential method to combat different types of NMSC," Andrea Persaud, MD, Mount Sinai, et al., say in an October 2002 Journal of the American Academy of Dermatology article.

"This is substantiated by the successful treatment of AK, BCC and small SCCs by intralesionally administered interferon, which acts to stimulate an immune reaction at the tumor site."

AK is currently treated by surgical and nonsurgical methods. The most common surgical treatment in the U.S. is cryotherapy; nonsurgical therapies include 5-fluorouracil, trichloroacetic acid, and Dusa's topical photodynamic therapy Levulan Kerastick (aminolevulinic acid 20%), which was approved Dec. 3, 1999.

The Aldara sNDA is based on two double-blind, randomized, placebo-controlled clinical trials involving 436 patients with multiple AKs. Patients were treated with Aldara or placebo cream twice per week for 16 weeks.

"At eight-weeks post-treatment, half the patients treated with Aldara had at least an 83% reduction in the number of AK lesions counted at baseline versus 0% in the placebo group," 3M said. "Complete clearance of AKs was seen in 45% of patients treated with Aldara versus 3% in the placebo group."

In a Phase II study published in the October 2002 Journal of the American Academy of Dermatology, imiquimod was shown to cause a significant reduction in the average number of lesions per patient.

Patients in the study had at least six bilateral, discrete, visible and/or palpable actinic keratoses located on the face, arms or legs and had not been treated with 5FU, laser resurfacing, chemical peel or cryotherapy within 28 days before the trial.

Patients applied 5% imiquimod cream to lesions on one side of the body, and vehicle cream on the other side, one to three times a week. Seventeen out of 22 patients completed the eight-week treatment period and the subsequent eight-week observation period.

"On the imiquimod-treated side the average number of lesions per patient was reduced from 10.1, at the initial visit, to 6.2 at the end of the 8-week post-treatment period," the study states. "On the vehicle-treated side, the average number of lesions decreased from 8.1 to 7.6."

The reduction in the number of AK lesions from baseline to week 16 for imiquimod vs. vehicle was statistically significant (p<0.005). Additionally, a decrease in lesion size was detected after 16 weeks.

"Imiquimod treatment caused minimal adverse effects in contrast to currently prescribed treatments for AK including topically applied therapies and cryosurgery and other surgical techniques, which can cause pain, erythema, inflammation and erosion, and may result in scarring and skin pigmentation changes," Persaud et al. concluded.

The most frequently reported adverse reactions in the pivotal studies were local skin and application site reactions, including flaking/scaling, induration, edema, erythema and scabbing/crusting.

3M recently reported positive results from two double-blind, randomized, placebo-controlled clinical trials in 724 patients with superficial BCC. Aldara yielded a histological clearance rate of 82% compared to 3% for placebo.

Patients were treated with Aldara cream or vehicle cream once daily, five or seven times per week for six weeks. "The clinical studies showed the optimal dosing to be five times per week," 3M said.