FDA Approves Revisions for Botulinum Toxin Products

Recently, the FDA, under the authorities granted by the Food and Drug Administration Amendments Act (FDAAA) of 2007, approved the following revisions to the prescribing information for Botox/Botox Cosmetic and Myobloc:

• A Boxed Warning highlighting the possibility of experiencing potentially life-threatening distant spread of toxin effect from the injection site after local injection.

• A Risk Evaluation and Mitigation Strategy (REMS) that includes a Medication Guide to help patients understand the risks and benefits of botulinum toxin products.

• Changes to the established drug names to reinforce individual potencies and prevent medication errors. The potency units are specific to each botulinum toxin product, and the doses or units of biological activity cannot be compared or converted from one product to any other botulinum toxin product. The new established names reinforce these differences and the lack of interchangeability among products. (See Table 1 for name changes and indications).

AbobotulinumtoxinA (Dysport), which was approved earlier this year, already included the Boxed Warning, REMS, and new established name at the time of approval.

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Other Drug News

The Medicines Company Withdraws MMA For 3-7 Day Daily-Dose Oritavancin

The Medicines Company has withdrawn its European marketing authorization application (MAA) for the 200 mg 3-7 day daily dose therapy of oritavancin, its investigational antibiotic drug candidate for the treatment of complicated skin and skin structure infections (cSSSI) caused by Gram-positive-pathogens.

The MAA had been filed in Europe in June 2008, by Targanta Therapeutics Corp., which was acquired by the Medicines Company in February 2009. During their review of the MAA this year, the European Medicines Agency (EMEA) had expressed concerns similar to those raised by the FDA in its December 2008 complete response letter to Targanta’s new drug application for oritavancin. As both the FDA and EMEA indicated that another trial would be required before approval could be considered, Medicines is now in dialogue with the FDA regarding plans for a global Phase III program.

The Company also intends to work with the European regulators to ascertain their support for the program design. The Company expects to begin the program in late 2009, with an expected enrollment period of 1 to 2 years.

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S&A News

Mount Sinai Medical School to Join Provectus Trial for PH-10 for Psoriasis

Provectus Pharmaceuticals, Inc., has added Mount Sinai School of Medicine as its second and final site for its expanded Phase II clinical trial of the Company’s lead dermatology agent PH-10 for psoriasis. Jason Emer, MD, will serve as principal investigator of the trial; he is also the lead investigator for the Phase II clinical trial of PH-10 for atopic dermatitis, for which patient enrollment was completed in June.

The Phase II psoriasis trial, which began in July, has an expected enrollment of 30 patients. It is a non-randomized, open-label, single-group assignment trial that is designed to measure safety and efficacy of PH-10, an aqueous hydrogel formulation of rose bengal disodium for topical administration to the skin; it is being studied for the treatment of cutaneous skin disorders, specifically psoriasis and atopic dermatitis. The estimated primary completion date for final data collection is February 2010, with the study estimated to be completed by April 2010.

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Antioxidants Not Associated With Increased Melanoma Risk

Contradicting findings were found in the Supplementation in Vitamins and Mineral Antioxidants (SUVIMAX), a major French study, which reported a 4-fold higher melanoma risk in women randomized to receive a supplement with nutritionally appropriate doses of antioxidants, and a report in the August issue of Archives of Dermatology, which concluded that antioxidant supplements do not appear to be associated with an increased risk of melanoma.

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SUVIMAX Study

The French study, reported in the Journal of Nutrition in September 2007, was a randomized trial of antioxidants for cancer prevention. It found that daily supplementation with nutritionally appropriate doses of vitamins C and E, beta carotene, selenium and zinc appeared to increase the risk of melanoma in women 4-fold. (Hercberg S. Antioxidant supplementation increases the risk of skin cancers in women but not in men. J. Nutr. 2007;137:2098-2105.)

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VITAL Study

The newly reported study examined the association between antioxidants and melanoma among 69,671 women and men who were participating in the Vitamins and Lifestyle (VITAL) study, led by Maryam M. Asgari, MD, MPH, of Kaiser Permanente Northern California, Oakland.

Based on that data, the authors of the report concluded that intake of multivitamins and supplements during the previous 10 years, including selenium and beta carotene, was not associated with melanoma risk in either women or men. They also examined the risk of melanoma associated with long-term use of supplemental beta carotene and selenium at doses comparable to the previous study and found no association. (Asgari, MM, Maruti SS, Kushi LH, White E. Antioxidant supplementation and risk of incident melanomas: Results of a large prospective cohort study. Arch Dermatol. 2009;145(8):879-882.)

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Study Identifies Seven Risk Factors For Transformation Of Eye Growths Into Melanoma

Seven factors — two of which were newly identified — may predict whether a choroidal nevus develops into melanoma, according to a report in the August issue of Archives of Ophthalmology. (Shields CL et al. Choroidal nevus transformation into melanoma: Analysis of 2514 consecutive cases. Arch Ophthalmol. 2009;127(8):981-987.)

This conclusion was based on the findings of a group of investigators led by Carol L. Shields, MD, at Wills Eye Institute, Thomas Jefferson University, Philadelphia. They studied the medical records of 2,514 consecutive eyes of patients with choroidal nevi between 1974 and 2006, using Kaplan-Meier estimates and Cox regression analyses. The tumors had a median diameter of 5 mm and a median thickness of 1.5 mm at the beginning of the study. Choroidal nevi grew into melanoma in a total of 180 eyes (7%) over an average follow-up of 53 months, including 2% after 1 year, 9% after 5 years and 13% after 10 years.

The factors that predicted growth into melanoma included five previously identified factors: tumor thickness greater than 2 mm, fluid beneath the retina, symptoms such as decreased vision or flashes and floaters, orange pigment and a tumor edge within 3 mm of the optic disc. Two newly identified factors included hollowness of the growth on ultrasound and the absence of a surrounding halo, or circular band of depigmentation.

With these features in mind, authors made these recommendations for patient monitoring. Patients with choroidal nevi that do not display any of the seven features of disease should be monitored twice yearly at first and then followed up yearly if their condition remains stable; those with one or two features should be monitored every 4 to 6 months; and those with three or more features should be evaluated at an experienced center for possible treatment.

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New Approach to Wound Healing With Silver

In a presentation to the American Chemical Society meeting, Ankit Agarwal, a postdoctoral researcher at the University of Wisconsin-Madison, described an experimental approach to wound healing that could take advantage of silver’s antibacterial properties while avoiding the damage silver can cause to fibroblasts.

Silver is widely used to prevent bacterial contamination in wound dressings, says Agarwal, “but these dressings deliver a very large load of silver, and that can kill a lot of cells in the wound.”

In her experiment, Agarwal crafted a “sandwich” of ultra-thin polymers that adhere through electrical attraction. To make the sandwich, Agarwal alternately dips a glass plate in two solutions of oppositely charged polymers, and adds a precise dose of silver, with 1 square inch containing just 0.4% of the silver that is found in the silver-treated antibacterial bandages now used in medicine.

In tests in lab dishes, the low concentration of silver killed 99.9999% of the bacteria but did not damage fibroblasts needed to repair a wound.

Details of Agarwal’s experiment were provided in a press release from the University of Wisconsin – Madison.

“This architecture is very easily tuned to different applications,” Agarwal says, because it allows exact control of such factors as thickness, porosity and silver content. The final sandwich may range from a few nanometers to several hundred nanometers in thickness. (One nanometer is one-billionth of a meter; a human hair is about 60,000 nanometers in diameter.)

In tests using mouse cells and sample bacteria, Agarwal has tuned the dose to find the “sweet spot” where the silver bullet destroys 99.9999% of the bacteria, but does not harm fibroblasts.

To kill bacteria, silver must take the form of charged particles, or ions, and the tiny silver nanoparticles that Agarwal embeds in the sandwich can be designed to release ions for days or weeks as needed. In contrast, Agarwal says, commercial wound dressings contain a large dose of silver ions, which are released faster and with less control.

The required dose of silver can also be reduced because the new material would be designed to stay in close contact with the wound, says Nicholas Abbott, a professor of chemical and biological engineering who advises Agarwal. “In a commercial dressing, the silver is part of the bandage that is placed on the wound surface. We envision this material becoming incorporated into the wound; the cells will grow over it and it will eventually decay and be absorbed into the body, much like an absorbable suture.”

Tests on animals will be needed to before the new material can be tested on humans, says Abbott. “A commercial dressing needs to have a large quantity of silver so it can diffuse to the wound bed, and that quantity turns out to be toxic to mammalian cells in lab dishes. We are putting the silver where we need it, so we can use a small loading of silver, which does not exhibit toxicity to mammalian cells because the silver is precisely targeted.”

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Study Links Merkel Cell Polyomavirus to Squamous Cell Carcinoma

A virus discovered last year in Merkel cell carcinoma (MCC) has now been found in people with squamous cell carcinoma (SCC) with healthy immune systems, according to researchers at the Ohio State University Comprehensive Cancer Center — James Cancer Hospital and Solove Research Institute.

Findings, which were made public ahead of publication in the June 25th online Journal of Investigative Dermatology described the study based on tumors and tissue samples of 58 people with SCC. Among them, the Merkel cell polyomavirus was detected in more than a third of the patients and in 15 % of the tumors tested. In addition, all of the virus found in tumor cells had a mutation that could enable the viral DNA to integrate into the DNA of the host cell. (Dworkin AM. Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals. J Investig Dermatol. 2009.)

“Originally it was thought that this virus caused only this rare skin cancer, but our findings indicate that it is a lot more prevalent than we initially thought.” said principal investigator Amanda E. Toland, assistant professor of molecular virology, immunology and medical genetics and a researcher with the Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

To learn if people with SCC harbored the virus, Toland, working closely with first author and graduate research associate Amy Dworkin and Ohio State pathologists O. Hans Iwenofu and Sara B. Peters, examined DNA samples from SCC tumors, from normal-appearing skin adjacent to the tumor, when available; from white blood cells, and from cells washed from the mouth.

The investigators detected the virus in 26 of 177 SCC samples, 11 of 63 adjacent-skin samples, and one sample from a mouthwash. They found no viral DNA in any of the blood samples from 57 patients. In all, 21 of 58 SCC patients, or 36%, tested positive for the virus.

By sequencing the viral DNA from 31 normal and tumor samples, the researchers showed that the same mutation was present in all the viruses tested from tumors, and in 60% of the viruses tested from adjacent healthy-looking tissue.

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Sun Exposure May Trigger Autoimmune Diseases

Ultraviolet (UV) radiation from sunlight may be associated with the development of certain autoimmune diseases, particularly in women, according to a study by researchers at the National Institute of Environmental Health Sciences (NIEHS), which was published in the August issue of Arthritis & Rheumatism. The study was the first to evaluate and find a possible UV radiation association in autoimmune diseases in women. (Love LA et al. Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women. Arthritis Rheum. 2009; Aug;60(8):2499-504. ).

The study was designed to determine if there was a relationship between the level of UV exposure at the onset of the disease and the type of myositis and autoantibodies that people developed.

To conduct the study, the NIEHS researchers collaborated with myositis centers across the country that had seen 380 patients who had been diagnosed with dermatomyositis or polymyositis and determined their autoantibodies.

In addition to finding an association between the level of UV radiation and the proportion of women who developed dermatomyositis compared to polymyositis, the researchers found an association between UV levels and the proportion of women with the anti-Mi-2 autoantibody.

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In Brief…

Bayer Healthcare Announced… that Intendis, which is part of Bayer, has acquired two prescription dermatology products lines from SkinMedica, Inc. The company acquired Desonate and NeoBenz Micro. Under the transaction, which is still subject to the necessary regulatory approvals, Intendis will acquire all commercial rights, including assigned contracts and intellectual property related to the two product lines.

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Tribute to our Founding Editor

We at Skin & Aging and HMP Communications regret the passing of Harry J. Hurley, Jr., MD, the pre-eminent dermatologist who founded The Journal of Geriatric Dermatology January 1993, which became Skin & Aging 5 years later in January 1998.

He was also clinical professor of dermatology at the University of Pennsylvania Medical School, where he researched the physiology and diseases of the sweat glands and granuloma formations with the Walter Shelley. The two developed the Hurley-Shelley axillary resection technique to surgically treat excessive underarm sweating. Dr. Hurley was the author or coauthor of many professional articles and books, including the textbook Dermatology.

In 1969 he was founding president of the Pennsylvania Academy of Dermatology. He was a past president of the American Dermatological Association and the American Board of Dermatology and was the board’s executive director for 7 years.