Daigle Deanne – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Wed, 05 Feb 2020 20:37:45 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Nivolumab for Metastatic Melanoma https://www.skintherapyletter.com/melanoma/nivolumab/ Thu, 17 Mar 2016 18:09:43 +0000 https://www.skintherapyletter.com/?p=318
Aditya K. Gupta, MD, PhD, FRCPC1,2 and Deanne Daigle, MSc2


1Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
2Mediprobe Research Inc., London, ON, Canada

Conflict of interest: None Reported.

ABSTRACT
Melanoma is an aggressive skin cancer with a generally poor prognosis at Stage III-IV disease. Traditionally, metastatic melanoma was treated by surgical resection, when possible, and with systemic chemotherapy. New developments in molecular biology have led to the identification of immune checkpoints which are exploited by malignant cells, allowing them to go undetected by the immune system. Nivolumab (Opdivo®) is a human monoclonal antibody which prevents immune inhibition by interacting with PD-1 on tumor cells; thus, increasing tumor-specific T cell proliferation. Nivolumab has demonstrated efficacy superior to that of standard chemotherapy and relative safety in clinical trials. Indeed, the outcomes for patients with advanced melanoma are being improved by novel biologic agents such as nivolumab.

Key Words:
antineoplastic agent, melanoma, Opdivo®, PD-1 inhibitor, programmed cell death 1 receptor, signal transduction, skin neoplasms

Introduction

A melanoma is an aggressive tumor often occurring on the skin that is caused by the transformation of melanocytes into malignant cells.1 Many cases are classified as melanoma in situ, with tumors localized only to the epidermis (Stage 0); however, some melanomas are invasive and infiltrated the dermis (Stage I-II), and still others spread to nearby lymph node(s) (Stage III), or to distant lymph nodes and/or organ systems (Stage IV).2 Stage III- IV disease is termed ‘metastatic melanoma’ and occurs in roughly 30% of patients after excision of the primary tumor.2,3 The 5-year survival rate is 23% when metastatic melanoma presents in the skin.4 In order to evade immune recognition, certain tumors may exploit immune-regulatory checkpoints which suppress excessive T lymphocyte function in normal physiologic conditions; thereby permitting unregulated proliferation of malignant cells.5

Preclinical cancer studies suggest that interrupting co-receptor interactions responsible for inhibitory signaling on tumor- specific T cells would activate the anti-tumor immune response.5 One such co-receptor is programmed death receptor-1 (PD-1). PD-1 inhibits T cell activation, leading to reduced proliferation, cytokine production, and cytolysis via interactions with its ligands PD-L1 and PD-L2.6 On December 22, 2014, nivolumab (Opdivo®), a human monoclonal antibody against PD-1 receptor, was approved by the US FDA for the treatment of unresectable or metastatic melanoma that is unresponsive to other drugs.7 Nivolumab binds PD-1 with high affinity and impedes both PD-L1 and PD-L2 interaction; thus, increasing tumor-specific T cell proliferation.

Phase I and II

Two phase I dose-escalation trials were performed to assess the preliminary efficacy, safety and pharmacokinetics of nivolumab.6,8 Both trials enrolled participants with advanced metastatic non- small cell lung cancer (NSCLC), melanoma, castrate-resistant prostate cancer, renal cell carcinoma, and colorectal cancer. Doses ranging from 0.1-10 mg/kg of nivolumab were administered by intravenous (IV) infusion every 2 weeks. Pharmacokinetic data from these studies showed that the median time to peak serum concentration of nivolumab is 1 to 4 hours after dosing.8 Nivolumab yields an approximate serum half-life (t1/2) of 12 days for 0.3, 1, and 3 mg/kg doses and up to 20 days for the 10 mg/kg dose.6 Maximum concentration (Cmax) and area under the curve (AUC) are directly related to dose.6,8 PD-1-receptor occupancy on the surface of circulating CD3+ cells was also assessed.6,8 After one infusion at a dose of 0.1 to 10 mg/kg, surface occupancy was dose-independent with a mean peak occupancy of 85% (70% to 97%) observed at 4 to 24 hours and a mean plateau occupancy of 72% observed at ≥57 days;6 however, another study of cell surface occupancy in participants with melanoma showed that the median occupancy was 64% to 70% and varied according to dose.8 Tumor biopsies from phase I suggested a potentially significant association between PD-L1 cell surface expression and clinical response to nivolumab (P=0.048)6 which was further investigated in subsequent studies.

One-hundred and seven advanced melanoma participants from the phase I trial were followed for up to 4 years after treatment initiation to monitor survival, tumor remission and the long-term safety of nivolumab.8 Sixty-two percent of these participants had received at least two prior systemic treatments.9 The objective response rate (ORR), defined as the proportion of participants who had a complete or partial response was 25%, 18/26 participants were treated for a year or more.8 The ORR increased to 33% at 4 years’ follow-up, with a median response duration of 2 years.8,9 Stable disease lasting ≥24 weeks was originally observed in 6% of participants and increased by another 1% at 4 years’ follow-up.8,9 Median overall survival was 16.8 months (95% confidence interval [CI] = 12.5-31.6), and 1 and 2 year survival rates were 62% (95% CI = 53%-72%) and 44% (95% CI = 32%-53%), respectively.9

The most common treatment emergent adverse events (TEAEs) in participants treated with nivolumab were fatigue (32%), rash (23%), and diarrhea (18%).9 TEAEs of immunologic significance included skin disorders (35%), gastrointestinal disorders (18%), and endocrinopathies (13%). Five participants experienced Grade 3 or 4 TEAEs.9 The majority of AEs occurred within the first 6 months of treatment and the frequency of AEs did not increase with prolonged use.9

Yamazaki and colleagues reported preliminary results from their phase II study of 35 participants with advanced melanoma.10 Nivolumab was administered at a dose of 2 mg/kg every 3 weeks until unacceptable toxicity, disease progression, or complete response. The ORR was 23% (8/35) with median progression- free survival of 6.14 months. TEAEs occurred in 45.7% of participants and consisted mainly of elevated gamma-glutamyl transpeptidase, anemia, decreased hematocrit, hemoglobin and red blood cell counts, and loss of appetite. No drug-related deaths were reported.

Phase III

A randomized, double-blind, phase III trial assessed the efficacy and safety of nivolumab versus standard chemotherapy (dacarbazine) in melanoma without BRAF mutation.11 Four- hundred and eighteen participants were randomized to nivolumab 3 mg/kg every 2 weeks (N=210) or dacarbazine 1000 mg/m2 every 3 weeks (N=208). ORRs and median progression-free survival are presented in Table 1. The ORR was significantly higher in the nivolumab group compared to the dacarbazine group and the proportion of participants with a complete response was higher with nivolumab than with dacarbazine (7.6% vs. 1.0%). The duration of progression-free survival was also longer in participants treated with nivolumab compared to those treated with dacarbazine.

The trial was stopped early due to nivolumab’s clear benefit over standard chemotherapy in improving overall survival.12 The median overall survival was not reached in the nivolumab group and was 10.8 months (95% CI = 9.3%-12.1%) in the dacarbazine group.11 Overall survival rates at 1 year were 72.9% (95% CI = 65.5%-78.9%) and 42.1% (95% CI = 33%-50.9%) in the nivolumab and dacarbazine groups, respectively. Nivolumab significantly increased overall survival compared to dacarbazine (hazard ratio for death = 0.42; 99.79% CI = 0.25-0.73; P<0.001).

The incidence of AEs was similar between treatments (74.3% vs. 75.6% in the nivolumab and dacarbazine groups, respectively); yet the frequency of AEs of grade 3 or 4 was lower for participants treated with nivolumab than with dacarbazine (11.7% vs. 17.6%).11 The most common TEAEs with nivolumab were fatigue (19.9%), pruritus (17.0%), and nausea (16.5%). The proportion of participants who discontinued the study due to TEAEs was 6.8% and 11.7% in the nivolumab and dacarbazine groups, respectively. No drug-related deaths occurred in either group.

Nivolumab’s efficacy in treating ipilimumab- or ipilimumab/ BRAF inhibitor-refractory melanoma was investigated in 405 participants.13 Participants were randomized to receive an IV infusion of nivolumab at a dose of 3 mg/kg, or investigator’s choice of chemotherapy (ICC), either dacarbazine 1000 mg/m2 every 3 weeks or carboplatin AUC 6 plus paclitaxel 175 mg/m2 every 3 weeks by IV infusion, until disease progression or unacceptable toxicity. Tumors were assessed at baseline, 9 weeks, and every 6 weeks for the first year, then every 12 weeks until disease progression, death or study withdrawal. Safety was assessed in all participants who received at least one dose of study drug. The primary endpoint was the proportion of participants who had an OR. Secondary endpoints included progression-free survival rates, and PD-L1 tumor expression.

ORRs and median progression-free survival are displayed in Table 1. ORRs were higher with nivolumab than with ICC, although no statistical comparison was made. Median time to response was 2.1 months and 3.5 months in the nivolumab and ICC groups, respectively. Median progression-free survival was not significantly different between nivolumab and ICC. The ORR with nivolumab was higher for PD-L1 positive tumors (43.6%) than PD-L1 negative tumors (20.3%), while ORRs were similar with ICC in both types of tumors (9.0% vs. 13.0%).

Rates of TEAEs were 68% in the nivolumab group and 79% in the ICC group. Fatigue, pruritus and diarrhea were the most common AEs with nivolumab, while nausea, alopecia and fatigue were the most common AEs with ICC. Grade 3 to 4 AEs occurred in 9% of participants treated with nivolumab and in 31% of participants treated with ICC. Drug toxicity led to the discontinuation of treatment in 3% and 7% of the participants in the nivolumab and ICC groups, respectively.

Clinical trials have also assessed the safety and efficacy of nivolumab in combination with ipilimumab for the treatment of advanced melanoma.14,15 Eighty-six participants in a phase I trial were treated either concurrently with escalating doses of nivolumab (cohort 1: 0.3 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 3: 3 mg/kg nivolumab + 1 mg/kg ipilimumab, cohort 4: 3 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 5: 10 mg/kg nivolumab + 3 mg/kg ipilimumab, 10 mg/kg nivolumab + 10 mg/kg ipilimumab), or sequentially with nivolumab 1 mg/kg and 3 mg/kg every 2 weeks for up to 48 doses.14 Participants were followed for 2.5 years after the start of treatment. Clinical activity was assessed at weeks 12, 18, 24, 30 and 36, and every 12 weeks thereafter in the concurrent therapy cohorts, while the sequentially treated cohorts were assessed at week 8 and every 8 weeks thereafter. PD-L1 tumor-cell expression was also characterized.

The ORR in the concurrent regimen cohorts was 40% (95% CI = 27-55) across all doses.14 Sixteen participants experienced a ≥80% reduction in tumor size. Five complete responses were included among those with a ≥80% reduction. Nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg were the maximum doses associated with an acceptable safety profile in the sequential treatment cohort. The ORR in participants who received the sequential regimen was 53% (95% CI = 28%-77%), including three complete responses; all participants who attained OR had a ≥80% tumor reduction at the rst scheduled assessment. Twenty percent of participants (95% CI = 8%-39%) in the sequenced regimen cohorts had an OR, including one complete response. Four participants in the sequenced regimen cohorts had a tumor reduction of ≥80%. ORs were noted in 6/13 and 9/22 participants with PD-L1 positive and PD-L1 negative tumors, respectively. Ninety-three percent of participants experienced TEAEs, the most common being rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Eleven participants (11%) in the concurrent regimen group and three (9%) in the sequenced regimen discontinued treatment due to TEAEs.

Study Arms Objective Response (%) 95% CI (%) P-value Median Progression- free Survival (months) 95% CI P-value
Robert et al. 2015 Nivolumab 3 mg/kg a

Dacarbazine 1000 mg/m2

40.0
13.9
33.3-47.0
9.5-19.4
<0.001 5.1
2.2
3.5-10.8
2.1-2.4
<0.001
Weber et al. 2015 Nivolumab 3 mg/kg
Investigator’s choice of chemotherapy
31.1
4.7
23.1-40.2
4.3-6.5
8.3
4.2
2.8-18.4
2.1-6.3
ns
Larkin et al. 2015 Nivolumab 3 mg/kg

Ipilimumab 3 mg/kg

Nivolumab 1 mg/kg +

ipilimumab 3 mg/kg +

nivolumab 3 mg/kg

43.7
19.0
57.6
38.1-49.3
14.9-23.8
52.0-63.2
6.9
2.9
11.5
4.3-9.5
2.8-3.4
8.9-16.7
<0.001*
Table 1: Objective response and median-progression-free survival11,13,15

a Objective response was 52.7% (95% CI = 40.8%-64.3%) in PD-L1 positive tumors and 33.1% (95% CI = 25.2%-41.7%) in PD-L1 negative tumors.

* Comparing nivolumab + ipilimumab to ipilimumab alone and comparing nivolumab alone to ipilimumab alone. ns = not significant

In a double-blind, phase III study, 945 participants were randomized to receive either: 1) nivolumab 3 mg/kg every 2 weeks (plus ipilimumab matched placebo) for 4 doses; 2) nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks for cycle 3 and thereafter; or 3) ipilimumab 3 mg/kg every 3 weeks (plus nivolumab-matched placebo) for 4 doses by IV infusion.15 Treatment continued until disease progression, unacceptable toxicity or study withdrawal.

Median progression-free survival was significantly longer with nivolumab plus ipilimumab than with ipilimumab alone and with nivolumab than with ipilimumab (Table 1).15 No significant difference in the hazard of death or disease progression between the combination treatment and nivolumab only groups was found. The ORRs were highest among participants treated with nivolumab plus ipilimumab, followed by those treated with nivolumab only, and ipilimumab only (Table 1). Median time to OR was similar in the three groups (2.76, 2.78, and 2.79 months in the nivolumab plus ipilimumab, nivolumab, and ipilimumab groups, respectively). Complete response rates were also highest with nivolumab plus ipilimumab (11.5%), than with nivolumab (8.9%) or ipilimumab (2.2%) alone. The highest ORRs were observed in participants with PD-L1-positive tumors treated with nivolumab plus ipilimumab (72.1%; 95% CI = 59.9%-82.3%) or nivolumab only (57.5%; 95% CI = 45.9%-68.5%).

TEAEs occurred in 95.5% of the nivolumab plus ipilimumab group, in 86.2% of the ipilimumab group, and in 82.1% of the nivolumab group.15 The most common TEAEs in all groups were diarrhea, fatigue, pruritus and rash. The incidence of grade 3 or 4 AEs was highest in the combination group (55.0%), compared to the ipilimumab (27.3%) and nivolumab-only (16.3%) groups. TEAEs led to study discontinuation in 36.4%, 14.8% and 7.7% of the nivolumab plus ipilimumab, ipilimumab only and nivolumab only groups, respectively. One participant in the nivolumab group died of neutropenia and one participant in the ipilimumab group died of cardiac arrest. No deaths were reported with the combination treatment.

Discussion

Nivolumab has demonstrated greater efficacy when compared to standard chemotherapy in clinical trials.11,13 Nivolumab produced higher objective response rates, longer median progression-free survival, and increased overall survival compared to standard chemotherapy.11,13 Participants with ipilimumab- or ipilimumab/ BRAF inhibitor-refractory melanoma treated with nivolumab also had higher response rates and a faster time to response than those treated with investigator’s choice of chemotherapy.13 Participants treated with nivolumab had significantly longer progression-free survival and higher OR and complete response rates compared to participants treated with ipilimumab monotherapy.14 Furthermore, patients who did not respond to previous ipilimumab therapy did have a response to treatment with nivolumab.14 Nivolumab/ipilimumab combination therapy is also encouraging.15 Nivolumab treatment is associated with a risk of immune-mediated pneumonitis, colitis, hepatitis, renal dysfunction and endocrinopathy.16 The most common TEAEs with nivolumab were fatigue, pruritus, rash, diarrhea and nausea; however, AE rates were similar or lower with nivolumab than with dacarbazine or carboplatin plus paclitaxel.11,13 Furthermore, the incidence of grade 3 or 4 AEs was lower with nivolumab compared to standard chemotherapy or with ipilimumab monotherapy.11,13,15

Until recently, surgical resection, when possible, coupled with standard chemotherapy was the rst-line treatment for Stage III melanoma and for palliation of Stage IV disease. However, the rates of recurrence and metastasis remained high, as the disease is often refractory to surgery and/or systemic treatment. Advances in genetics and tumor biomarker recognition have led to the synthesis of novel biological agents for the treatment of metastatic melanoma. Nivolumab is one such agent and with an improved safety and efficacy profile over traditional therapy, it proves a promising development in the treatment of advanced melanoma.

References

  1. Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. 2011 Nov;65(5):1032-47.
  2. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206.
  3. Essner R, Lee JH, Wanek LA, et al. Contemporary surgical treatment of advanced- stage melanoma. Arch Surg. 2004 Sep;139(9):961-6; discussion 6-7.
  4. Sandru A, Voinea S, Panaitescu E, et al. Survival rates of patients with metastatic malignant melanoma. J Med Life. 2014 Oct-Dec;7(4):572-6.
  5. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015 Apr 13;27(4):450-61.
  6. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti- programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75.
  7. Gohil K. Pharmaceutical approval update. P T. 2015 Mar;40(3):172-3.
  8. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54.
  9. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30.
  10. Yamazaki N, Tahara H, Uhara H, et al. Phase 2 study of nivolumab (Anti-PD-1; ONO-4538/BMS-936558) in patietns with advanced melanoma. Eur J Cancer. 2013;49(s2):s868.
  11. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30.
  12. Improved survival ends nivolumab trial early. Cancer Discov. 2014 Sep;4(9): 979-80.
  13. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84.
  14. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33.
  15. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34.
  16. Opdivo® (nivolumab) injection, for intravenous use [Full prescribing information]; revised January 2016. Bristol-Myers Squibb Company Princeton, NJ. Available at: http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed February 1, 2016.
]]>
Ivermectin 1% Cream for Rosacea https://www.skintherapyletter.com/rosacea/ivermectin-cream/ Sat, 01 Aug 2015 19:02:23 +0000 https://www.skintherapyletter.com/?p=392 Gita Gupta, MD1,2; Deanne Daigle, MSc;2; Aditya K. Gupta, MD, PhD, FRCPC2,3; Linda Stein Gold, MD4

1Wayne State University, Detroit, MI, USA
2Mediprobe Research Inc., London, ON, Canada
3Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
4Henry Ford Medical Center, Department of Dermatology, Detroit, MI, USA

ABSTRACT
The etiology of papulopustular rosacea (PPR) is not well understood yet appears to involve both the innate and adaptive immune response in addition to possible infestation with Demodex mites. Current treatments for PPR consist mainly of antibiotics. Ivermectin cream 1%, a new topical treatment for PPR, possesses both anti-inflammatory and anti-parasitic properties. After 12 weeks of treatment, subjects treated with ivermectin cream 1% had significantly greater reductions in PPR symptoms and enhanced diseaserelated quality of life improvements compared to subjects who received vehicle. Furthermore, PPR symptoms continued to improve with prolonged treatment (40 weeks). Ivermectin cream 1% offers a multi-pronged approach to combat the complex pathophysiology of rosacea.

Key Words:
anti-parasitic, avermectin, Demodex, erythema, inflammation, insecticide, papulopustular rosacea, Rosiver®, Soolantra®,
topical ivermectin

Introduction

Rosacea is a chronic inflammatory condition affecting the central facial skin of the cheeks, nose, chin and forehead. Rosacea typically affects females approximately 30 years of age and increases in severity throughout the lifespan.1 The exact cause of rosacea is unknown and its pathogenesis is not well understood.2,3 Innate and adaptive immune responses, vascular abnormalities, dermal microorganism imbalances, and environmental factors may interact to produce chronic inflammation and the development of fibrosis.2 Four subtypes of rosacea have been identified: 1) erythematotelangiectatic rosacea, 2) papulopustular rosacea (PPR), 3) phymatous rosacea, and 4) ocular rosacea2; yet, whether these represent a distinct variation or a continuum of disease severity remains a matter of debate.2 PPR, previously known as acne rosacea, is characterized by erythema, telangiectasia, papules, pustules, edema, and sometimes pain, stinging or burning.4 Patients report that symptoms are a cause of low self-esteem, as they are a source of shame, embarrassment, and physical discomfort.5 Treatment is strongly encouraged to moderate the detrimental effect on patient quality of life (QoL) and to prevent the condition from worsening. Few therapeutic alternatives exist for the treatment of PPR. There is some evidence supporting the efficacy of azelaic acid, topical metronidazole and sub-antimicrobial dose doxycycline in the treatment of moderate to severe rosacea, although it remains unclear which agent is most effective.6

Ivermectin is derived from avermectin, a class of broadspectrum anti-parasitic agents isolated from the fermentation of Streptomyces avermitilis.7 Ivermectin possesses both antiparasitic and anti-inflammatory properties and has been shown to reduce the number of Demodex mites in demodicidosis and blepharitis and to inhibit the production of lipopolysaccharide inflammatory cytokines, such as tumor necrosis factor-alpha and interlukin (IL)-1b, while upregulating the production of the anti-inflammatory cytokine IL-10.8 Because PPR is recognized as an inflammatory condition whose pathogenesis may involve parasitic infestation with Demodex mites, vehicle-controlled and active comparator trials were undertaken to evaluate the efficacy and safety of topical ivermectin 1% cream in the treatment of PPR.

Pivotal Phase 3 Studies

Two pivotal phase 3 trials assessed the efficacy and safety of ivermectin cream 1% for moderate to severe PPR.9 These trials were part of a larger study comprised of a second long-term active comparator trial10 and a 4 week follow-up safety study. The pivotal phase 3 studies were identically designed multicenter, randomized, double-blind, vehicle-controlled trials that enrolled participants aged 18 years or older with moderate to severe PPR and 15-70 inflammatory facial lesions.9 Subjects were randomized in a 2:1 ratio to receive either ivermectin 1% cream or vehicle cream for 12 weeks. Participants were instructed to apply their respective cream to the face once daily at bedtime while avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers, such as specific foods and environments, whenever possible. Evaluations occurred at baseline and at weeks 2, 4, 8 and 12. Co-primary efficacy outcomes for this study included the percentage of participants who achieved an Investigator Global Assessment (IGA) of “clear” or “almost clear” and mean change in inflammatory lesion counts between groups at week 12. Other efficacy outcomes were percent change in inflammatory lesion counts from baseline, subjective assessment of rosacea improvement, and QoL scores on the Dermatology Life Questionnaire Index (DLQI) and the Rosacea Quality of Life Index (RosaQoL™). Adverse events (AEs) and laboratory parameters (hematology and blood chemistry) were also monitored.

Study 1 Study 2
Ivermectin 1% cream (n=451) Vehicle (n=232) Ivermectin 1% cream (n=459) Vehicle (n=229)
IGA ‘clear’ or ‘almost clear’ 38.4%† 11.6% 40.1%† 18.8%
Reduction in inflammatory lesion count from baseline 76.0%† 50.0% 75.0%† 50.0%
Subjective rosacea improvement ‘excellent’ or ‘good’ 69.0%† 38.6% 66.2%† 34.4%
Table 1. Efficacy endpoints for the pivotal phase 3 trials of ivermectin 1% cream vs. vehicle IGA = Investigator global assessment; †P

Study 1 enrolled 683 participants and Study 2 enrolled 688 participants, the majority of whom were female (Study 1: 68.2% and Study 2: 66.7%) and approximately 50 years of age on average. Participants in Study 1 had an average of 30.9 lesions, while subjects in Study 2 had an average 32.9 inflammatory lesions at baseline. The proportion of participants with an IGA of ‘severe’ was 18% and 24.1% in Studies 1 and 2, respectively. There were no differences in DLQI scores between treatment groups at baseline.

Efficacy results are presented in Table 1. In both studies, a significantly higher percentage of participants who received ivermectin 1% had an IGA of ‘clear’ or ‘almost clear’ at week 12 compared to vehicle (P<0.001) and the significant difference between active and control arms was noted at week 4 (10.9% and 11.8% vs. 5.6% and 5.7%, respectively; P The mean difference in inflammatory lesion counts between ivermectin 1% and vehicle from baseline to week 12 was -8.13 and -8.22 for Studies 1 and 2, respectively (ivermectin 1% vs. vehicle, both P<0.001). There was also a significant difference in the median reduction in lesion count from baseline between the ivermectin 1% and vehicle groups (both studies P<0.001) observed as early as week 2. In both studies, a significantly higher proportion of participants who received ivermectin 1% cream reported improvement of their rosacea symptoms as ‘excellent’ or ‘good’ compared to participants who received vehicle (P<0.001). QoL scores also improved in the ivermectin 1% groups compared to vehicle at the end of 12 weeks. In both studies, a significantly greater proportion of participants in the ivermectin 1% group (approximately 53%) than the vehicle group (approximately 35%) considered their rosacea had no effect on their QoL (P<0.001). Improvement in RosaQoL scores was also significantly higher for ivermectin 1% compared to vehicle (-0.64 ± 0.7 and -0.60 ± 0.6 vs. -0.35 ± 0.5 in both vehicle groups; P=0.001 for Studies 1 and 2).

For Studies 1 and 2, no serious treatment-related AEs were reported in either the ivermectin 1% cream or vehicle groups. Burning (1.8% for ivermectin 1% cream and 2.6% for vehicle) was the most commonly reported treatment-related AE in Study 1, while pruritus and dry skin were the most commonly reported treatment-related AEs in Study 2 (pruritus: 0.7% vs. 0% and dry skin: 0.7% vs. 0.9% for ivermectin 1% cream vs. vehicle). Furthermore, treatment-related AEs with active drug were less than with vehicle alone. Laboratory tests showed no clinically significant abnormalities.

Ivermectin 1% Cream vs. Azelaic Acid 15% Gel

Ivermectin 1% cream was then evaluated against azelaic acid 15% gel in a 40 week extension study.10 In this continuation of the pivotal phase 3 trials, participants with PPR originally assigned to ivermectin 1% cream once daily in the 12-week study continued to be treated as such and participants initially randomized to vehicle were switched to azelaic acid 15% gel twice daily for 40 weeks. Efficacy was assessed at 4 week intervals using the IGA. Safety assessments were comprised of documentation of AEs, tolerability signs and symptoms, and laboratory tests.

Six hundred and twenty-two and 683 participants enrolled in the 40-week extension studies (see previous section for participant demographics). The efficacy of ivermectin 1% cream increased over time as IGA scores of ‘clear’ and ‘almost clear’ increased from 38.4% to 71.1% by the end of Study 1 and from 40.1% to 76% by the end of Study 2; 59.4% and 57.9% of participants who received azelaic acid had an IGA of ‘clear’ or ‘almost clear’ by the end of Studies 1 and 2, respectively. No statistical comparisons were made because of the differing treatments lengths between the ivermectin 1% and azelaic acid 15% groups. Furthermore, because the ivermectin group had already been treated with ivermectin for 3 months, while the azaleic acid group had previously received vehicle, baseline factors may not have been comparable between groups.

The incidence of treatment-related AEs in the ivermectin 1% cream and azelaic acid 15% gel groups was 1.9% vs. 6.7% and 2.1% vs. 5.8% in Studies 1 and 2, respectively. No severe or serious AEs were deemed related to ivermectin 1% cream in Studies 1 or 2 and no serious AEs were considered related to azelaic acid 15% gel in either study; however, 1 severe case of skin irritation was considered related to azelaic acid in Study 2. In Study 1, 4 participants in the azelaic acid group and 5 in the ivermectin group discontinued the study as a result of AEs. In Study 2, 5 participants in the azelaic acid group and 3 in the ivermectin group discontinued the study due to AEs. None of the AEs in either study were considered related to ivermectin 1% cream; however, in the azaleic acid group, 3 AEs in Study 1 and 4 AEs in Study 2 were considered related to azaleic acid (Study 1: skin irritation, eye and skin irritation, and skin pain and burning; Study 2: skin irritation, skin burning, skin discomfort, and skin burning and pruritus).

Ivermectin 1% cream (n=478) Metronidazole 0.75% cream (n=484)
IGA ‘clear’ or ‘almost clear’ 84.9%† 75.4%
Reduction in inflammatory lesion count from baseline 83.0%† 73.7%
Table 2. Efficacy endpoints for the phase 3 trial of ivermectin 1% cream vs. metronidazole 0.75% cream IGA = Investigator global assessment; †P

Ivermectin 1% Cream vs. Metronidazole 0.75% Cream

Another phase 3, investigator-blinded, randomized trial conducted in Europe explored the efficacy and safety of ivermectin 1% cream compared to metronidazole 0.75% cream for the treatment of moderate to severe PPR (Table 2).1 Nine-hundred and sixty-two participants age 18 years or older with moderate or severe PPR and presenting with 15-70 facial lesions were randomized 1:1 to receive either ivermectin 1% cream (n=478) once daily or metronidazole 0.75% gel (n=484) twice daily for 16 weeks. Treatments were applied to the entire face, avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers. Study visits were at baseline and at weeks 3, 6, 9, 12 and 16. Efficacy endpoints included inflammatory lesion counts, the IGA, participants’ subjective evaluation of rosacea improvement, and the DLQI. The safety evaluation consisted of AE assessments over the course of the study, as well as local tolerance and laboratory parameters.

At baseline, the majority of participants had moderate rosacea (16.7% severe) with an average 32.5 inflammatory lesions. Participants had a mean age of 52 years and were primarily female (65.2%). In terms of efficacy at week 16, ivermectin was significantly more effective than metronidazole 0.75% cream in reducing the percentage of inflammatory lesions (83% vs. 73.7%; P<0.001) with a significant difference between the two treatments observed at week 3. The IGA of disease severity was also significantly better for ivermectin 1% cream compared to metronidazole 0.75%, with 84.9% of the ivermectin 1% cream and 75.4% of the metronidazole 0.75% cream groups rated as ‘clear’ or ‘almost clear’ at week 16 (P<0.001), with the greatest difference in IGA noted at week 12. Approximately 86% of the ivermectin group rated their global improvement as ‘excellent’ or ‘good’ compared to 74.8% in the metronidazole 0.75% group. Although the DLQI scores were similar between treatment groups at baseline (6.93 and 6.05 for ivermectin and metronidazole, respectively), participants treated with ivermectin 1% cream showed a greater improvement in QoL as indicated by a reduction in their DLQI scores (-5.18 vs. -3.92; P<0.01).

A similarly low proportion of participants experienced a treatment-related AE (1.9% in the ivermectin 1% cream group and 2.5% in the metronidazole 0.75% group). The most common treatment-related AE was skin irritation experienced by 3 and 4 participants in the ivermectin 1% cream and metronidazole 0.75% cream groups, respectively. Three participants in the ivermectin 1% cream group discontinued the study because of skin irritation and hypersensitivity, while 10 participants in the metronidazole 0.75% cream group discontinued the study due to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritus and feeling hot. Worsening of local tolerance parameters from baseline was more pronounced in
the metronidazole 0.75% group than the ivermectin 1% cream group for stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs. 10%), and itching (11.4% vs. 8.8%). No clinically significant abnormalities in laboratory parameters were found.

Discussion

Ivermectin 1% cream is markedly more effective than vehicle in reducing inflammatory lesions of rosacea as it results in a significant reduction in lesion counts after only 2 weeks of treatment and produces substantially greater improvements in IGA ratings of ‘clear’ or ‘almost clear’ as early as week 4.9 The efficacy of ivermectin 1% cream increases with prolonged treatment as evidenced in the 40 week trials.10 Also, when compared to the standard treatment for PPR, metronidazole 0.75% cream, topical ivermectin was markedly superior to metronidazole in terms of reducing inflammatory lesions and IGA ratings.1 Ivermectin 1% cream had a significantly greater positive impact on patient QoL compared to vehicle or metronidazole 0.75%.1,9 Ivermectin 1% cream was well-tolerated and demonstrated a favorable safety profile across phase 3 studies, with skin irritation being the most common treatmentrelated AE.

In phase 3 trials, ivermectin 1% cream produced greater objective and subjective outcomes and improvements in disease-specific QoL over vehicle and an active comparator. Topical ivermectin represents a novel approach to the treatment of PPR that appears to confer superior efficacy and tolerability as compared to current treatment options, while offering the added convenience of once daily dosing. Since ivermectin possesses both anti-parasitic and anti-inflammatory properties, its effectiveness in treating PPR may be attributed to its ability to combat several pathogenic factors linked to the condition. Further studies are needed to elucidate the contribution of the anti-parasitic versus the antiinflammatory modes of action of ivermectin.

References

  1. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015 Apr;172(4):1103-10.
  2. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41.
  3. Diamantis S, Waldorf HA. Rosacea: clinical presentation and pathophysiology. J Drugs Dermatol. 2006 Jan;5(1):8-12.
  4. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1): S15-26.
  5. van der Linden MM, van Rappard DC, Daams JG, et al. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015 Apr 15;95(4):395-400.
  6. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81.
  7. Merck & Co. Inc. Stromectal (ivermectin) tablets [Internet]. 2010 [cited 2015 Feb 20].
  8. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogenactivated protein kinase activation pathway. Fundam Clin Pharmacol. 2009 Aug;23(4):449-55.
  9. Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014 Mar;13(3):316-23.
  10. Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled,investigator-blinded trials. J Drugs Dermatol. 2014 Nov;13(11):1380-6.
]]>
Sinecatechins 10% Ointment: A Green Tea Extract for the Treatment of External Genital Warts https://www.skintherapyletter.com/human-papilloma-virus/sinecatechins-external-genital-warts/ Sun, 01 Feb 2015 19:04:10 +0000 https://www.skintherapyletter.com/?p=412 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 provider assisted, 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.
  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% . 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.
]]>