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BLOCK DRUG’s ACTINEX LABELING SUGGESTS MILDER SIDE EFFECTS

Executive Summary

BLOCK DRUG's ACTINEX LABELING SUGGESTS MILDER SIDE EFFECTS for the prescription actinic keratoses treatment compared to existing drug therapies, which are fluorouracil-based. Fluorouracil requires treatments to continue until the inflammatory response to the drug causes skin erosion, necrosis and ulceration. Actinex labeling notes that "no necrosis, scarring or ulceration was observed during the initial course of therapy." Actinex (masoprocol topical cream, 10%), developed by Fort Lee, N.J.-based Chemex, was approved Sept. 4 for actinic keratoses, sun-related precancerous skin lesions. Actinex labeling adds that "the presence or absence of local skin reactions does not correlate with successful ultimate therapeutic outcome." In fluorouracil therapy, the time of treatment cessation is determined by the appearance of necrosis, erosion and ulceration. Pain associated with Actinex treatment also apparently is less severe. Fluorouracil is marketed domestically by Roche as Efudex (fluorouracil 2% or 5%) and by Allergan Herbert as Fluoroplex (fluorouracil 1%). Efudex labeling notes in reference to treatment-related lesions that "complete healing of the lesions may not be evident for one to two months following cessation of Efudex therapy." Fluoroplex gives no specific healing time. Actinex labeling notes that "while local skin reactions are frequent, they usually resolve within two weeks of discontinuation." The most frequent adverse reactions to Actinex are erythema (46%), flaking (46%), itching (32%), dryness (27%), edema (14%), burning (12%) and soreness (5%), labeling states. Actinex labeling continues: "Reactions reported in 1% to 5% of patients include: bleeding, crusting, eye irritation, oozing, rash, skin irritation, soreness, stinging, tightness and tingling." Reported adverse reactions to Fluoroplex are pain, pruritis, burning, irritation, inflammation, allergic contact dermatitis and telangiectasia (inflammation of the capillaries). Fluoroplex labeling adds that "occasionally, hyperpigmentation and scarring have also been reported." Similarly, Efudex labeling lists the most frequent local reactions as "pain, pruritis, hyperpigmentation and burning." In addition, "other local reactions include allergic contact dermatitis, scarring, soreness, tenderness, suppuration, scaling and swelling. Also reported are alopecia, insomnia, stomatitis, irritability, medicinal taste, photosensitivity, lacrimation, telangiectasia and urticaria [hives], although a causal relationship is remote." Block Drug's Reed & Carnrick ethical pharmaceutical division is "creating a dedicated dermatological sales force" to launch Actinex. The market for Actinex is defined by the estimated 5.5 mil. annual cases of actinic keratoses. Block Drug purchased the worldwide marketing rights to Actinex for actinic keratoses from Chemex in 1990. Under the licensing agreement, Chemex is due a $3 mil. milestone payment from Block on approval of the drug and will get an additional $2 mil. and royalties, respectively, on initial and continuing sales of Actinex. If worldwide sales of Actinex meet "target goals" two years from sell-in, Chemex will receive an additional $2 mil. Chemex filed an NDA for Actinex, the firm's first NDA submission, in December 1988. Chemex described the efficacy of fluorouracil and masoprocol in treating actinic keratoses as "similar." In Phase III Actinex trials, 72% of the 308 patients treated with masoprocol experienced "clinically significant improvement," measured subjectively by the clinician. The treatment duration of Actinex for actinic keratoses is twice daily for 28 days. Fluoroplex labeling estimates treatment duration at two to six weeks, with increased frequency or longer duration possibly required for areas other than the head and neck; Efudex treatment time is estimated at two to four weeks. Actinex is supplied in a 30 gm tube. FDA is requesting in its approval letter that Block submit Segment I (fertility and general reproductive performance) animal studies to the agency within one year of the approval date. The approved labeling cites animal teratology studies in which "no adverse fetal effects were observed." Chemex retains the rights to masoprocol for applications other than actinic keratoses and is finishing antitumor studies of the chemical in human tumors transplanted in mice. The firm hopes to file an IND for an antitumor application in the first quarter of 1993, and is looking at lung, breast, ovarian and colon cancer, as well as leukemia, as possible areas of application. Masoprocol, a new chemical entity, is extracted from the creosote bush. Other Chemex dermatological products in the pipeline, which are being developed under a 1991 joint venture agreement with Block ("The Pink Sheet" April 29, 1991, In Brief), include topical anti-allergic/anti-inflammatory amlexanox, for the treatment of recurrent apthous ulcers, or canker sores. Chemex plans to complete Phase II studies for the application in January. Amlexanox, licensed from Takeda Chemical, is marketed in Japan for asthma. The nonsteroidal topical anti-inflammatory EPC-K is being developed by Chemex for dermatological applications. Phase II studies could start early next year with an NDA filing in 1994. EPC-K is being developed by licenser Senju Pharmaceuticals in Japan for ophthalmic applications. In addition, Chemex plans to file INDs by the end of 1992 for CHX-3309, a topical platelet activating factor (PAF) antagonist licensed from Takeda, for immune diseases of the skin; and methotrezate for epicutaneous treatment of severe psoriasis. Methotrezate is a zinc salt of methotrexate. Chemex believes the salt form may increase the residence time of the substance in the skin. Chemex also plans to file an IND by the end of the year for cytarabine, licensed from Upjohn, as a genital warts treatment. Cytarabine is not included in the Block/Chemex joint venture.
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