Emily C. Murphy, BS1,2 and Adam J. Friedman, MD1
1The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
2Georgetown University School of Medicine, Washington, DC, USA
Conflict of interest:
AJF is a consultant for Aclaris Therapeutics. ECM has no conflicts to declare for this work.
HP40 (Eskata™) is a stabilized, topical solution of 40% hydrogen peroxide (H2O2) packaged in an applicator pen that is US FDA-approved to treat seborrheic keratoses (SKs). By harnessing the oxidative capabilities of H2O2 , 1-2 treatments with HP40 produced a higher rate of clearance of four SKs per patient compared to vehicle in two phase 3 trials. The clearance rate was higher for the face than the trunk and extremities. Similarly, the risks of pigmentary changes and scarring from HP40 were lower for the face than other locations. Further, based on an ex vivo study, HP40 may be less cytotoxic to melanocytes than cryotherapy, but clinical trials comparing these therapies are needed. Limitations of HP40 are its low efficacy and requirement of multiple treatments, which can result in elevated costs. The application can also be time-consuming, though extenders or even staff members can apply it. Therefore, HP40 may be better reserved for the treatment of facial SKs.
efficacy, Eskata, hydrogen peroxide, safety, seborrheic keratoses, topical therapy
Seborrheic keratoses (SKs) are benign epithelial tumors estimated to affect more than 83 million Americans.1 Existing as at least nine variants, SKs present as round to oval macules or papules with variable surface textures that appear “stuck on” and can occur anywhere on the body, except the palms and soles.2-4 The incidence and frequency of SKs per person increase with age.4 In one study of Korean males, the authors found that 79% of patients had SKs at age 40 (with 5.5 SKs per patient) compared to 94% of patients at age 50 (with 9.9 SKs per patient).5
In addition to increasing age, potential risk factors for SKs include ultraviolet light, as they occur with a higher prevalence on sun-exposed skin,5,6 friction given they commonly occur in intertriginous areas,7 and genetic predisposition.7,8 However, the true etiologic risk factors and pathogenesis of SKs are not fully known. Inhibition of apoptosis may occur in SKs, contributing to their formation.4Additionally, mutations in the fibroblast growth factor receptor8 and oncogenic phosphoinositide 3-kinase pathway9 may impact their development; however, these changes are not present in all SKs so additional genes are likely involved.8
While SKs do not require treatment, patients often request removal to relieve symptoms of irritated SKs or for cosmetic reasons.10 The most common treatment is cryotherapy with liquid nitrogen; surgical therapies are also used including electrodessication, curettage, shave excision, or laser therapy.7,11
Among other side effects, these invasive methods can cause pain, bleeding, pigmentary changes, and scarring.7,12-15 The risk of pigmentary changes is especially high in patients with skin of color.7 These side effects motivated the pursuit for efficacious topical therapies that minimize long-term adverse effects. Existing keratolytics (ammonium lactate, imiquimod, and tazarotene) and vitamin D analogs were examined to treat SKs, but these agents demonstrated limited efficacy in small clinical trials.16-19
The first topical therapy to be US FDA-approved for the treatment of raised SKs is HP40 (Eskata™), a stabilized topical solution of 40% hydrogen peroxide (H2O2).20 This therapy was approved in December 2017 based on the results of two phase 3 trials.20 An earlier phase 2 dose-ranging trial additionally confirmed that HP40 was more efficacious than 32% H2O2 while still having a satisfactory side effect profile.21, In this review, we will discuss the evidence for and limitations of HP40 based on these clinical trials as well as an ex vivo model of Fitzpatrick Skin Type (FST) V skin that examined HP40’s cytotoxicity.20,22,23
Application and Mechanism
HP40 is applied by a healthcare professional with a single use pen that includes 0.7 mL of 40% H2O2 and can treat about seven SKs.24 According to the manufacturer’s instructions, the tip of the pen is pressed to an SK and the solution is applied in a circular motion for about 20 seconds. This process is repeated up to three additional times per SK with 1 minute between each application. After 3 weeks, the SK can be re-treated if satisfactory clearance was not achieved.
The mechanism by which HP40 destroys keratinocytes is not fully elucidated, but is thought to involve H2O2‘s oxidizing power21 as both a direct oxidant and indirect oxidant through the formation of hydroxyl radicals.25 When this oxidative stress overwhelms the antioxidant properties of the skin, H2O2 can lead to cellular destruction by damaging proteins, lipids, and nucleic acids.25 Applied at a supra-physiologic concentration, a portion of the HP40 dose likely diffuses through the stratum corneum (SC) and into the epidermis.20,21 Free radicals generated by H2O2 can then induce apoptosis or necrosis of seborrheic keratinocytes among other cell types (Figure 1). Given this mechanism, HP40 should not be applied to open or infected SKs; without an intact SC to act as a barrier, high concentration H2O2 can cause rapid death of adjacent cells (Figure 1).26 Additionally, HP40 should not be applied within the orbital rim where contact with H2O2 can cause corneal injury.24
Efficacy of HP40
In two phase 3 trials with a total of 937 patients, four raised SKs per patient were treated with either HP40 or vehicle using the previously described method (Application and Mechanism).20 Three weeks later, residual SKs were re-treated. Pedunculated SKs or SKs in intertriginous areas, hair-bearing areas, or within 5 mm of the orbital rim were excluded. The therapeutic efficacy was assessed with a 4-point scale, Physician’s Lesion Assessment (PLA), developed by the manufacturer where 0 is clear, 1 is nearly clear, 2 is a thin SK with a depth of 1 mm or less, and 3 is a thick SK with a depth greater than 1 mm. The primary endpoint was complete clearance (0 on PLA) of all four SKs.20
The treatment and control groups had similar demographic characteristics, with an average age of 68.7 years, and the completion rate was nearly 100% for each trial (99%, 98% per trial). At the end of the study (day 106), HP40 resulted in a significantly higher rate of complete clearance of all four SKs than vehicle; however, the rate of clearance of all four SKs with HP40 was low overall (4%, 8% per study for HP40 versus 0% for both studies for vehicle). Post hoc, the authors also calculated the mean per-patient percentage of clear/nearly clear SKs, which was higher for HP40 than vehicle (47%, 54% versus 10%, 5%, respectively).20
To examine the efficacy of HP40 by location, the percentage of clear/nearly clear SKs at day 106 for each anatomic site was calculated in another study.22 A total of 1,868 SKs were treated in the HP40 group and 1,880 SKs were treated in the vehicle group; 59% of SKs were on the trunk, 30% on the face, and 11% on the extremities. The highest rate of clearance/near-clearance with HP40 treatment was observed for the face (65%), followed by the trunk (46%), and then the extremities (38%). The authors theorized that these efficacy differences may be due to variations in skin topography, such as varying water or lipid content or SC thickness. For instance, the thin SC of the face may allow enhanced penetration of HP40 compared to other anatomical sites. Another explanation proposed by the authors was that the high exposure of the face to ultraviolet radiation may impair its ability to respond to H2O2-induced oxidative stress.22
Adverse Effects of HP40
In the phase 3 trials, 21% of the HP40 group and 19% of the vehicle group reported adverse effects; most were mild to moderate and all were limited to local skin reactions.20 Three events related to HP40 were considered severe: application site pain, a burn from treatment, and a burning sensation. Ten minutes after HP40 application, erythema was observed in 91% of SKs and edema in 75% of SKs. By day 106, the percentage of HP40-treated SKs with erythema decreased to 10.1% and no SKs exhibited edema. Other symptoms at day 106 included scaling (8.0%), hyperpigmentation (7.8%), crusting (5.4%), hypopigmentation (3.0%), scarring (<1%), and erosion (<1%).20 Examining skin reactions by anatomic location, Smith et al. found that SKs on the face showed the lowest rates of hyperpigmentation (2.3% versus 10.8% trunk, 6.9% extremities), hypopigmentation (1.9% versus 3.5% trunk, 3% extremities), and scarring (0% versus 0.6% trunk, 1% extremities).22
While the risks of pigmentary changes and scarring at day 106 were low, especially for facial SKs, 98.8% of the study sample were FST I-IV, with only 7.3% having FST IV, so the effects on patients with FST IV or higher could not be adequately assessed.20 A study by Kao et al. used an ex vivo model of human FST V skin to explore the toxicity of HP40 (1 and 2 μL) compared to cryotherapy (5- and 10-second cycles).23 A colorimetric MTT assay was used to measure overall cytotoxicity and S100 stained-melanocytes were quantified to assess melanocyte toxicity. The authors found that HP40 was less cytotoxic overall and to melanocytes compared with cryotherapy, meaning that HP40 may cause less pigmentary changes in patients with dark skin.23 However, clinical trials comparing the adverse effects of HP40 and cryotherapy are needed before conclusions can be drawn. Given hyperpigmentation was seen in 8% of HP40-treated SKs20 and patients with darker skin are more prone to pigmentary changes,7 HP40 should be used cautiously in FST IV-VI patients until further research is done.
Limitations and Future Directions
HP40 was found to be superior to vehicle for the treatment of raised SKs, but its efficacy is limited overall, producing complete clearance of all four SKs in only 4% and 8% of patients per study.20 As Bauman et al. discussed, patient satisfaction was not evaluated in the trials, and considering patients determine therapeutic success based on their appearances in the mirror rather than on physician-completed scales, superior results may have been observed with self-assessments.20 Regardless, patients still often require repeat treatments to produce adequate SK clearance (97% of the trial participants required second treatments), which can be cost prohibitive and time intensive for patients.20 HP40 is not covered by insurance and costs about $131 (US dollars) per treatment (as reported by The Medical Letter on Drugs and Therapeutics24).
HP40 is also time consuming to apply for the dermatology clinic. In the clinical trials, treatment of four SKs took about 5 minutes and 20 seconds,20 and this time would be almost doubled for the average of seven SKs that can be treated with each HP40 pen.24 With four 20-second treatment cycles recommended per SK, this therapy is more time intensive than cryotherapy, which requires only 5 to 10 seconds of freezing for thin lesions.12 Thicker SKs may require an additional freeze-thaw cycle with cryotherapy,12 but this is still a shorter process than HP40 application. However, trained non-physician staff can also administer HP40, so practices can develop protocols to maximize application efficiency.
When choosing a strategy for SK removal, it is important to consider the SK’s location as well as the patient’s skin type and treatment expectations. Based on the finding that HP40 is most efficacious for SKs on the face compared to the trunk and extremities, HP40 may be a good therapy to discuss with patients seeking treatment for SKs in cosmetically-sensitive areas like the face. While additional clinical studies are needed to explore this assertion, HP40 may destroy fewer melanocytes than cryotherapy, meaning that HP40 may be a potentially beneficial therapy for patients with dark skin who are susceptible to pigmentary changes with cryotherapy.7 On the contrary, because of the high cost of HP40 and need for repeat treatments, it is likely less useful for symptomatic SKs in non-cosmetically sensitive locations where patients desire rapid relief without as much concern about the cosmetic outcomes.
In terms of pregnancy and lactation risk, topical H2O2 is not systemically absorbed. Therefore, application of HP40 during pregnancy or while lactating should not result in exposure of the fetus or breastfeeding infant.24
Given our current options for the treatment of SKs include only more invasive, non-topical therapies, HP40 fills a void in our therapeutic repertoire as the first FDA-approved topical therapy for SKs. However, this therapy has limited efficacy with 1-2 treatments, producing only about 50% clearance per patient.20 Further, HP40 is expensive and can be time-intensive to apply. Nevertheless, considering HP40 produces higher clearance of SKs on the face than other anatomic locations22 and that it may be less cytotoxic to melanocytes than cryotherapy,23 HP40 may be useful for the treatment of facial SKs. Given 92% of the phase 3 trial participants were FST I-III, further research is needed to explore the risk of pigmentary changes with HP40 in patients of FST IV or higher.
- Bickers DR, Lim HW, Margolis D, et al. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006 Sep;55(3):490-500.
- Kao S, Kiss A, Efimova T, et al. Managing seborrheic keratosis: evolving strategies and optimal therapeutic outcomes. J Drugs Dermatol. 2018 Sep 1;17(9):933-40.
- Coyne JD. Classification of the seborrheic keratosis. Int J Surg Pathol. 2016 Feb;24(1):51-2.
- Noiles K, Vender R. Are all seborrheic keratoses benign? Review of the typical lesion and its variants. J Cutan Med Surg. 2008 Sep-Oct;12(5):203-10.
- Kwon OS, Hwang EJ, Bae JH, et al. Seborrheic keratosis in the Korean males: causative role of sunlight. Photodermatol Photoimmunol Photomed. 2003 Apr;19(2):73-80.
- Yeatman JM, Kilkenny M, Marks R. The prevalence of seborrhoeic keratoses in an Australian population: does exposure to sunlight play a part in their frequency? Br J Dermatol. 1997 Sep;137(3):411-4.
- Jackson JM, Alexis A, Berman B, et al. Current understanding of seborrheic keratosis: prevalence, etiology, clinical presentation, diagnosis, and management. J Drugs Dermatol. 2015 Oct;14(10):1119-25.
- Hafner C, Vogt T. Seborrheic keratosis. J Dtsch Dermatol Ges. 2008 Aug;6(8): 664-77.
- Hafner C, Lopez-Knowles E, Luis NM, et al. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13450-4.
- Del Rosso JQ. A closer look at seborrheic keratoses: patient perspectives, clinical relevance, medical necessity, and implications for management. J Clin Aesthet Dermatol. 2017 Mar;10(3):16-25.
- Peredo M, Murphy E, Karibayeva D. Clinical experience with 40% hydrogen peroxide topical solution for the treatment of seborrheic keratosis. J Drugs Dermatol. 2019 Jul 1;18(7):s173-7.
- Andrews MD. Cryosurgery for common skin conditions. Am Fam Physician. 2004 May 15;69(10):2365-72.
- Kundu RV, Joshi SS, Suh KY, et al. Comparison of electrodesiccation and potassiumtitanyl- phosphate laser for treatment of dermatosis papulosa nigra. Dermatol Surg. 2009 Jul;35(7):1079-83.
- Wood LD, Stucki JK, Hollenbeak CS, et al. Effectiveness of cryosurgery vs curettage in the treatment of seborrheic keratoses. JAMA Dermatol. 2013 Jan;149(1):108-9.
- Ferrandiz L, Moreno-Ramirez D, Camacho FM. Shave excision of common acquired melanocytic nevi: cosmetic outcome, recurrences, and complications. Dermatol Surg. 2005 Sep;31(9 Pt 1):1112-5.
- Stockfleth E, Rowert J, Arndt R, et al. Detection of human papillomavirus and response to topical 5% imiquimod in a case of stucco keratosis. Br J Dermatol. 2000 Oct;143(4):846-50.
- Klaus MV, Wehr RF, Rogers RS 3rd, et al. Evaluation of ammonium lactate in the treatment of seborrheic keratoses. J Am Acad Dermatol. 1990 Feb;22(2 Pt 1):199- 203.
- Mitsuhashi Y, Kawaguchi M, Hozumi Y, et al. Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis. J Dermatol. 2005 Jun;32(6):420-3.
- Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: a study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol. 2004 Apr;43(4):300-2.
- Baumann LS, Blauvelt A, Draelos ZD, et al. Safety and efficacy of hydrogen peroxide topical solution, 40% (w/w), in patients with seborrheic keratoses: Results from 2 identical, randomized, double-blind, placebo-controlled, phase 3 studies (A-101- SEBK-301/302). J Am Acad Dermatol. 2018 Nov;79(5):869-77.
- DuBois JC, Jarratt M, Beger BB, et al. A-101, a proprietary topical formulation of high-concentration hydrogen peroxide solution: a randomized, double-blind, vehicle-controlled, parallel group study of the dose-response profile in subjects with seborrheic keratosis of the face. Dermatol Surg. 2018 Mar;44(3):330-40.
- Smith SR, Xu S, Estes E, et al. Anatomic site-specific treatment response with 40% hydrogen peroxide (w/w) topical formulation for raised seborrheic keratoses: pooled analysis of data from two phase 3 studies. J Drugs Dermatol. 2018 Oct 1;17(10):1092-8.
- Kao S, Kiss A, Efimova T, et al. Ex vivo evaluation of cytotoxicity and melanocyte viability after A-101 hydrogen peroxide topical solution 40% or cryosurgery treatment in seborrheic keratosis lesions. J Am Acad Dermatol. 2018 Oct;79(4):767-8.
- Hydrogen peroxide 40% (Eskata) for seborrheic keratoses. Med Lett Drugs Ther. 2018 Sep 24;60(1556):157-8. Republished in JAMA. 2019 Jan 1;321(1):99-100.
- Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol. 2001 Mar;54(3):176-86.
- Bito T, Izu K, Tokura Y. Evaluation of toxicity and Stat3 activation induced by hydrogen peroxide exposure to the skin in healthy individuals. J Dermatol Sci. 2010 May;58(2):157-9.
- Izu K, Yamamoto O, Asahi M. Occupational skin injury by hydrogen peroxide. Dermatology. 2000 201(1):61-4.