Polyphenon E for warts by Ray Sahelian, M.D.
January 20 2016

The FDA approved a special extract of green tea as a prescription drug for the topical (external) treatment of genital warts caused by the human papilloma virus (HPV). The new drug, called Veregen (Polyphenon E) Ointment is the first prescription botanical (herbal) drug approved by FDA under the “new” drug amendments of 1962 that required drugs to be proven both safe and effective prior to being marketed in the U.S. The active drug ingredient, Polyphenon E, represents a proprietary mixture of phytochemicals produced from a partially purified water extract of green tea leaves. Green tea, brewed from the leaves of the tea plant (Camellia sinensis), is one of the most popular beverages worldwide. Unlike leaves used for black or oolong teas, leaves used to prepare “green” tea do not undergo a fermentation process. Therefore, green tea retains higher levels of highly antioxidant polyphenolic compounds known as catechins.

Research for warts
Polyphenon E has been shown to have significant pharmacological activities when tested both internally and externally in animals and humans. For FDA drug approval, the safety and efficacy of Polyphenon E Ointment were studied in two prospective, randomized, double-blind clinical studies in nearly 400 adults with external genital and anal warts ranging in number from 2 to 30. Test subjects applied the ointment three times daily until complete clearance of all warts. In each of these clinical trials, the median time to clear warts completely was 16 weeks and 10 weeks, respectively. Changes in the skin over the site of use were the most commonly reported side effects and included redness, itching, burning, pain/discomfort, ulceration, swelling, and local hardening of the skin.

FDA defines a “botanical” as a product that exclusively contains ingredients from plants, algae or fungi. In contrast to most conventional pharmaceutical drugs comprised of one single chemical, botanicals contain complex mixtures of naturally-occurring chemicals. In order to more appropriately evaluate herbal mixtures, in June 2004 the FDA published Guidance for Industry for Botanical Drugs, a new policy providing advice for potential botanical drug manufacturers, describing both the application process and providing recommendations as to how chemically complex products might satisfy the requirements of FDA’s rigorous “new drug” review process.

About Polyphenon E Ointment
Polyphenon E Ointment, 15% is a botanical drug approved as a topical treatment of external genital and anal warts in adults. External genital warts, caused by human papilloma viruses (HPV type 6 or 11), are one of the most common and fastest-spreading venereal diseases worldwide. Scientists estimate that as many as 1 million new cases of genital warts are diagnosed in the United States each year. Approximately 14 million people in the United States and 15 million people in Europe are infected with HPV.

Polyphenon E Ointment is a product of global development. In 1997, Epitome Pharmaceuticals Ltd., a privately owned Canadian company (Halifax, Nova Scotia) licensed from Mitsui Norin, Ltd. (Tokyo, Japan), a patented method of treating external genital warts through the topical application of Polyphenon E green tea extract, the patent for which extends through 2017. Epitome sublicensed the technology to MediGene AG of Munich, Germany, which collaborated in two multi-center Phase II clinical trials. In 2003 MediGene extended its license to include the treatment of hyperplasia caused by papilloma viruses. In 2004 MediGene conducted two Phase III trials, one in Europe and another in the Americas. Based on these trial results, MediGene submitted a New Drug Application (NDA) to the FDA Center for Drug Evaluation and Research in September 2005. FDA accepted the NDA for filing in early December 2005. MediGene reportedly plans to submit European marketing authorization applications for the drug before the end of 2006. MediGene is the first German biotech company to obtain marketing authorization for a drug in the United States.

Polyphenon E Ointment was developed by MediGene, a German company, and will be marketed in the United States by Bradley Pharmaceuticals of Fairfield, NJ. MediGene predicts peak sales potential of up to $100 million annually. The drug will be commercialized in the United States by MediGene’s marketing partner, Bradley Pharmaceuticals, Inc.  operating units will market Polyphenon E Ointment, 15%, with the Doak Dermatologics subsidiary promoting the drug to dermatologists, and Bradley's Kenwood Therapeutics division marketing this topical therapy to obstetric and gynecological physicians.

Am J Clin Dermatol. 2012. Polyphenon E 10% ointment in immunocompetent adults with external genital and perianal warts. Polyphenon E 10% ointment, which contains a mixture of green tea catechins, is indicated for the treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients aged ≥18 years. In two double-blind, multinational studies in adults with external genital and perianal warts, polyphenon E 10% ointment for up to 16 weeks was significantly more effective than vehicle with regard to the complete clearance of all warts (i.e. those at baseline and newly appearing during treatment) [primary endpoint]. In gender subgroup analyses, polyphenon E 10% ointment was more effective than vehicle in both men and women in one of two individual studies, and in pooled data from both studies. Polyphenon E 10% ointment was also significantly more effective than vehicle with regard to several secondary endpoints, including the complete clearance of baseline warts and partial clearance of at least 50% of all warts in both studies. Rates of recurrence of any warts or development of new warts were low (<9%) in both treatment arms during a 12-week follow-up period in both studies. Polyphenon E 10% ointment was generally well tolerated in adults with external genital and perianal warts. According to pooled data from the two clinical studies, the majority of adverse events associated with polyphenon E 10% ointment involved application site and local skin reactions at the treatment site.

Expert Opin Biol Ther. 2014. Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications. Sinecatechins was the first botanical drug licensed for treatment in humans in the US. It is approved for the topical treatment of external genital and perianal warts. Some properties of the polyphenolic components included in sinecatechins suggest additional therapeutic potential for other skin diseases. In addition to treatment of skin tumors, sinecatchins may also be used to protect against photocarcinogenesis. Considering antioxidative properties of polyphenols and the capability to enhance DNA repair, sinecatechins appears attractive for primary prevention of nonmelanoma skin cancer either as additive in sunscreens or as dietary supplement for oral administration.

Cervical cancer, conflicting results
Gynecol Oncol. 2014. Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia. In vitro data and pilot data suggest that green tea catechins may possess chemopreventive activity for cervical cancer and precursor lesions. We conducted a randomized, double-blind, placebo-controlled trial of Polyphenon E (decaffeinated and enriched green tea catechin extract) in women with persistent human papillomavirus (HPV) infection and low-grade cervical intraepithelial neoplasia (CIN1) to evaluate the potential of Polyphenon E for cervical cancer prevention. Ninety-eight eligible women were randomized to receive either Polyphenon E (containing 800 mg epigallocatechin gallate) or placebo once daily for 4 months. The primary study outcome was oncogenic HPV clearance and clearance of CIN1. Polyphenon E was shown to be acceptable, safe and well tolerated. There was no difference in the response rate by treatment allocation. Complete response, defined as negative for high-risk HPV and normal histopathology, was noted in 7 (17%) and 6 (14%) women in the Polyphenon E and placebo arms, respectively. Progression, defined as persistent oncogenic HPV with histopathologic evidence of progression, was more common in the Polyphenon E group than in the placebo group [6 (14%) vs. 3 (7%)]. Based on the largest randomized placebo-controlled trial of a green tea extract for HPV related cervical disease, we conclude that 4 months of Polyphenon E intervention did not promote the clearance of persistent high-risk HPV and related CIN1.

Eur J Cancer Prev. 2003. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. We investigated clinical efficacy of green tea extracts (polyphenon E; poly E and (-)-epigallocatechin-3-gallate [EGCG]) delivered in a form of ointment or capsule in patients with human papilloma virus (HPV) infected cervical lesions. Fifty-one patients with cervical lesions (chronic cervicitis, mild dysplasia, moderate dysplasia and severe dysplasia) were divided into four groups, as compared with 39 untreated patients as a control. Poly E ointment was applied locally to 27 patients twice a week. For oral delivery, a 200 mg of poly E or EGCG capsule was taken orally every day for eight to 12 weeks. In the study, 20 out of 27 patients (74%) under poly E ointment therapy showed a response. Six out of eight patients under poly E ointment plus poly E capsule therapy (75%) showed a response, and three out of six patients (50%) under poly E capsule therapy showed a response. Six out of 10 patients (60%) under EGCG capsule therapy showed a response. Overall, a 69% response rate (35/51) was noted for treatment with green tea extracts, as compared with a 10% response rate (4/39) in untreated controls. Thus, the data collected here demonstrated that green tea extracts in a form of ointment and capsule are effective for treating cervical lesions, suggesting that green tea extracts can be a potential therapy regimen for patients with HPV infected cervical lesions.