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Sinecatechins 10% Ointment: A Green Tea Extract for the Treatment of External Genital Warts

Aditya K. Gupta, MD, PhD, FAAD, FRCPC1,2 and Deanne Daigle, MSc2
1Department of Medicine, University of Toronto, Toronto, ON, Canada
2Mediprobe Research Inc., London, ON, Canada

Conflict of Interest: None reported

ABSTRACT

External genital warts (EGWs) resulting from the human papilloma virus (HPV) are a common sexually transmitted infection and cause significant impairments in patient quality of life and sexual well-being. Therapeutic options for EGWs can be providerassisted, but many patients opt for treatment that can be applied at home. Sinecatechins 10% ointment is a new botanically based patient-administered therapy for EGWs. It is comprised of >85% catechins, green tea polyphenols that have been shown to possess antioxidant, antiproliferative, antiviral, and antitumor properties. Phase III trials of sinecatechins 10% ointment have demonstrated higher efficacy and lower recurrence rates compared to currently available patient-applied treatments. Therefore, sinecatechins 10% ointment presents an alternative self-administered topical treatment for EGWs.

Key Words: catechins, condylomata acuminata, EGCG, epigallocatechin-3-gallate, genital warts, green tea extract, human papillomavirus, HPV, sinecatechins, Veregen, Polyphenon E

Introduction

It is estimated that 10-30% of the adult population in Canada is infected with human papilloma virus (HPV).1 While high-risk strains of HPV cause various types of cancer, low-risk strains can cause condyloma acuminate, also known as external anogenital warts (EGWs). EGWs are highly contagious and are, therefore, one of the most common forms of sexually transmitted infections. The prevalence of EGWs in Canada is an estimated 1.8%, with an annual incidence rate of 154/100,000 for males and 120/100,000 for females.2 Patients with EGWs present with one or several cauliflower-like growths on the genitals and/or anal regions and clinical appearance is often sufficient for a diagnosis. EGWs are associated with a significant burden of illness and considerable impairment of patients’ emotional and sexual well-being.3 Although up to 50% of untreated cases spontaneously regress at 6 months4, it is impossible to predict which lesions will regress, remain unchanged, or proliferate5; therefore it is recommended that treatment be offered to all patients with EGWs.

EGW treatment includes provider-assisted and patient-applied therapies or a combination of these modalities. Treatment can be categorized as ablative, antiproliferative, or immunomodulatory.6 CO2 laser, trichloroacetic acid, excision, cryotherapy, and electrocautery are ablative therapies that necessitate the assistance of a trained healthcare professional. Until recently, patient-applied therapies were either antiproliferative or immunomodulatory in nature. Podophyllin 10-25% and podophyllotoxin 0.5% are patient-applied antiproliferative agents, while imiquimod is an immunomodulatory agent that is available in both 5% and 3.75% formulations. Podophyllotoxin and imiquimod are considered the first choice among patient-applied treatment options;7 however, despite the greater ease and autonomy offered by patient-applied therapy, clearance rates with these treatments are lower than those achieved with physician-assisted options.8 Furthermore, lesion reappearance is common regardless of treatment choice as there is no way to eradicate the underlying viral infection.6

Sinecatechins ointment 10% (Veregen®), a new patient-applied treatment formulated from green tea (Camellia sinensis) extracts, has recently been licensed in Canada for the treatment of EGWs.9 Sinecatechins 10% ointment is comprised of >85% catechins, which are flavonoids responsible for the antioxidant effects of green tea. Sinecatechins 10% ointment contains eight different catechins, of which >55% is epigallocatechin-3-gallate (EGCG), the most abundant and potent catechins.10 Although the exact mechanisms of action of sinecatechins 10% ointment in regression of EGWs are currently unknown, they are likely multimodal, consisting of antiviral, pro-apoptotic and antiinflammatory responses.11 The antiviral properties of EGCG may result from the inhibition of activator protein 1 (AP-1) transcriptional activity that effectively down-regulate expression of HPV genes. Transcription of anti-apoptotic HPV genes by the infected cell could be counteracted by EGCG directly activating pro-apoptotic proteins as well as upregulating and downregulating the expression of pro- and anti-apoptotic proteins, respectively, resulting in cell death.12 EGCG also possesses anti-inflammatory activity by inducing anti-inflammatory interleukin (IL)-12 and reducing pro-inflammatory IL-10 activity. This would shift towards a T helper cell type 1 (Th1)-mediated immune response promoting the elimination of HPV-infected cells by the immune system. The various catechins and other molecular constituents of sinecatechins ointment likely work synergistically to modulate these complex biologic pathways to promote the regression of EGWs.10 Therefore, although the exact mechanisms of action of sinecatchins 10% ointment have not been fully elucidated, its efficacy in treating EGWs may be attributable to its antioxidant, antiproliferative, antiviral, and antitumor properties.11

Clinical Efficacy

Gross et al. conducted a Phase II/III, randomized, double-blind trial to assess the efficacy and safety of two formulations of sinecatechins ointment for the treatment of EGW.13 Two hundred and forty-two participants (125 males, 117 females) with 2-30 warts (wart area of 12-600 mm2) were randomized to receive either sinecatechins 15% ointment, sinecatechins 10% cream, or placebo (two placebo arms pooled for analyses). Participants were instructed to apply their respective treatments three times a day for 12 weeks and those who achieved complete clearance at the end of 12 weeks were followed for an additional 12 weeks. Rates of complete clearance of baseline warts and of all warts (baseline and new) as well as recurrence rates for sinecatechins 10% cream and vehicle are displayed in Table 1. No significant differences between sinecatechins 10% cream and placebo groups were found.

The efficacy of sinecatechins 10% ointment in the treatment of EGWs was further assessed in two identically-designed, randomized, double-blind, Phase III trials,14,15 the pooled results were also reported.16 A total of 1,005 participants (535 men and 470 women) with 2-30 EGWs and a lesion area of 12-600 mm2 were allocated in a 2:2:1 ratio to receive sinecatechins 15% ointment, sinecatechins 10% ointment or vehicle. Treatment was applied at 8-hour intervals three times a day for 16 weeks or until complete resolution of all baseline warts was observed. Complete responders were followed for an additional 12 weeks. Phase III trial results are displayed in Table 1. Rates of complete clearance of all warts in both sinecatechins ointment groups were significantly superior to vehicle (Ps<0.001). Time to complete clearance was also shorter for participants treated with sinecatechins 15% and 10% ointment than those treated with vehicle (P<0.01). Median time to complete wart clearance in the two trials was 16 weeks and 10 weeks in the sinecatechins 15% and 10% ointment groups, respectively. In all studies, recurrence rates were low and complete clearance rates were higher in women than in men.

Phase II/III Phase III Pooled Analysis
Gross et al. 200713 Stockfleth et al. 200815 Tatti et al. 200814 Tatti et al. 200916
Sinecatechins
10% Cream
(N=79)
Vehicle
(N=83)
Sinecatechins
10% Ointment
(N=199)
Vehicle
(N=103)
Sinecatechins
10% Ointment
(N=202)
Vehicle
(N=104)
Sinecatechins
10% Ointment
(N=401)
Vehicle
(N=207)
Complete clearance of baseline warts (%) 46 37 51 39 55 34 - -
Complete clearance of all warts (%) 46 38 50 37 59 34 52 35
Recurrence after 12 weeks (%) 12 10 4 3 8 9 7 6
Table 1. Efficacy rates for sinecatechins 10% ointment vs. vehicle
N = sample size

Safety and Adverse Events

No serious adverse events (AEs) were reported in the Phase II/III study.13 Only two participants in the sinecatechins 10% group had AEs considered possibly or probably related to the study drug and these included hyperkeratosis and skin discoloration. A number of local skin reactions were reported, but no significant differences in severe local reactions between active treatment groups and placebo were found. AE rates were also similar between treatment groups and vehicle in the Phase III trials.16 One patient in the sinecatechins 10% group developed severe pustular vulvovaginitis, which was considered related to study drug.14 Three patients in the other Phase III trial developed moderate lymphadenitis, moderate rash, and moderate phimosis, all were considered possibly related to the study medication.15 The overall incidence of any local reaction during treatment was higher in active treatment groups than vehicle (85.9% and 82.9% vs. 60.4%).16 Incidence of most common application-site reactions are presented in Table 2. In all studies, application-site reactions declined over the study period regardless of initial intensity. It has been suggested that local reactions such as erythema are associated with the release of pro-inflammatory cytokines; thus, patients should be advised that these signs may be indicative of clinical response and are correlated with higher clearance rates.15 Sinecatechins 10% ointment is contraindicated in individuals with a history of hypersensitivity to any of its components and treatment should be discontinued if hypersensitivity occurs.

Adverse Events Sinecatechins 10% Ointment (N=401) Vehicle (N=207)
Erythema 67.3% 32.4%
Pruritus 65.0% 45.4%
Irritation 63.5% 31.9%
Pain 46.5% 14.5%
Ulceration 46.0% 9.7%
Edema 39.8% 11.1%
Induration 27.3% 11.1%
Vesicles 18.8% 6.3%
Table 2. Incidence of most common application-site reactions occurring in ≥5% of participants11

Discussion

Sinecatechins 10% ointment was the first botanical drug approved by the US FDA and is now available in Canada for the treatment of EGWs. Although provider-assisted therapies have higher efficacy rates than patient-applied therapies, they are subject to the patient’s pain tolerance and aesthetic concerns, as some can cause considerable discomfort and/or result in scarring. Provider-assisted therapies are also dependent upon the doctors’ and patients’ schedules and patients may be hesitant to comply with repeat clinic visits because of the sensitive nature of this condition. Consequently, many patients opt for more convenient treatment that can be self-administered in the privacy and comfort of their home. Efficacy rates from the Phase III trials of sinecatechins 10% ointment are higher than those achieved with podophyllotoxin 0.5% or imiquimod 5% and 3.75%. However, it is recommended that sinecatechins 10% ointment be applied three times a day in comparison to thrice weekly application with imiquimod 5% and once daily application with imiquimod 3.75%. Therefore, patient adherence to the dosing regimen may need to be considered, as compliance is an important factor in achieving treatment effectiveness. Unlike other at-home treatments, it is not necessary to wash off the ointment prior to the next application. Sinecatechins 10% ointment has lower recurrence rates relative to other patient-applied therapies and is also the first EGW treatment to possess several disease-fighting mechanisms, such as anti-inflammatory, antiviral, and antiproliferative properties. Therefore, sinecatechins 10% ointment presents a botanically based alternative to currently available treatments for EGWs that offers a satisfactory balance of clearance rates, reduced frequency of lesion recurrence after successful treatment, and favorable adverse event profile.

References

  1. The Society of Obstetricians and Gynaecologists of Canada (SOGC). Incidence and prevalence of HPV in Canada [Internet]. 2007. Available at: http://www.hpvinfo.ca/health-care-professionals/what-is-hpv/incidenceand-prevalence-of-hpv-in-canada/. Accessed November 24, 2014.
  2. Kliewer EV, Demers AA, Elliott L, et al. Twenty-year trends in the incidence and prevalence of diagnosed anogenital warts in Canada. Sex Transm Dis. 2009 Jun;36(6):380-6.
  3. Qi SZ, Wang SM, Shi JF, et al. Human papillomavirus-related psychosocial impact of patients with genital warts in China: a hospital-based crosssectional study. BMC Public Health. 2014 14:739.
  4. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis. 2005 Mar 1;191(5):731-8.
  5. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003 Sep;189(3 Suppl):S3-11.
  6. Vender R, Bourcier M, Bhatia N, et al. Therapeutic options for external genital warts. J Cutan Med Surg. 2013 Dec;17 Suppl 2:S61-7.
  7. Lopaschuk CC. New approach to managing genital warts. Can Fam Physician. 2013 Jul;59(7):731-6.
  8. Yanofsky VR, Patel RV, Goldenberg G. Genital warts: a comprehensive review. J Clin Aesthet Dermatol. 2012 Jun;5(6):25-36.
  9. Medigene press release. Medigene’s drug Veregen® receives market approval in Canada [Internet]. September 10, 2013. Available at: http://www.medigene.com/presse-investoren/news/pressemitteilungen/medigenes-drug-veregen-receives-market-approval-in-canada. Accessed November 24, 2014.
  10. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin- 3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011 Dec 15;82(12):1807-21.
  11. Veregren® (sinecatechins) ointment 10% [product monograph]. Paladin Labs Inc., St-Laurent, QC. Revised October 28, 2014. Available at: http://www.paladin-labs.com/our_products/Veregen-PM-En.pdf. Accessed November 24, 2014.
  12. Stockfleth E, Meyer T. The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts. Expert Opin Biol Ther. 2012 Jun;12(6):783-93.
  13. Gross G, Meyer KG, Pres H, et al. A randomized, double-blind, four-arm parallel-group, placebo-controlled Phase II/III study to investigate the clinical efficacy of two galenic formulations of Polyphenon E in the treatment of external genital warts. J Eur Acad Dermatol Venereol. 2007 Nov;21(10):1404-12.
  14. Tatti S, Swinehart JM, Thielert C, et al. Sinecatechins, a defined green tea extract, in the treatment of external anogenital warts: a randomized controlled trial. Obstet Gynecol. 2008 Jun;111(6):1371-9.
  15. Stockfleth E, Beti H, Orasan R, et al. Topical Polyphenon E in the treatment of external genital and perianal warts: a randomized controlled trial. Br J Dermatol. 2008 Jun;158(6):1329-38.
  16. Tatti S, Stockfleth E, Beutner KR, et al. Polyphenon E: a new treatment for external anogenital warts. Br J Dermatol. 2010 Jan;162(1):176-84.

In this issue:

  1. Interleukin-17 (IL-17) Inhibitors in the Treatment of Plaque Psoriasis: A Review
  2. Sinecatechins 10% Ointment: A Green Tea Extract for the Treatment of External Genital Warts
  3. Update on Drugs and Drug News - January-February 2015