Treatment of Actinic Keratosis With Picato (ingenol mebutate) Gel

This supplement is supported by
LEO Pharma Inc.
Treatment of Actinic Keratosis With
Picato® (ingenol mebutate) Gel
Stephen K. Tyring, MD, PhD
Clinical Professor
Departments of Dermatology, Microbiology and Immunology,
and Internal Medicine
University of Texas Health Science Center
Houston, Texas
Actinic keratoses (AK) are precancerous
keratinocytic lesions caused by overexposure to ultraviolet radiation.1 Actinic
keratoses are confined to the epidermis,
and have variable presentation. Actinic
keratoses may present as rough, dry, or
scaly patches of skin, horny growths, and
may be pigmented or skin-toned. Lesions
vary in size and may have clearly defined
and/or diffuse margins. Itching, burning,
and tenderness may be present around
the lesion.2 Multiple lesion types may be
present in a single patient, and nonvisible
lesions—known as subclinical lesions—
are common, especially in sun-damaged
skin.3 Subclinical lesions, like visible lesions, have focal areas of abnormal keratinocyte proliferation and differentiation. All AK lesions have the potential
to evolve into squamous cell carcinoma
(SCC) and warrant treatment.1,3-5
In the United States, AK is the second
most common reason for visits to dermatologists.2 It is most prevalent among
light-skinned peoples, with Caucasian
men having the greatest risk, along with
immunocompromised individuals, and
those with mutations to the p53 tumor
suppressor gene. Cumulative sun exposure, however, is the primary cause of
AK.2,6 The age-adjusted prevalence in
the United States is estimated at 6.5%,
but it is much higher among specific age
groups. For example, among those aged
60 to 69 years, 83% of men and 64% of
women have at least 1 lesion.2 In total,
58 million individuals are estimated to
have at least 1 lesion during a calendar
year, and 26 million (≈45%) of these individuals are aged ≥65 years.2
In 2004, AK was associated with annual
direct costs of approximately $1.2 billion,
the vast majority of which ($1 billion or
92%) was accounted for by in-office treatments and prescription drugs ($60 million
or 5%).2 Indirect costs from lost productivity were estimated at $295 million.2
Although AK does not pose immediate health risks, these lesions, over time,
are associated with progression to SCC,
but it is impossible to accurately predict which AK lesions are mostly like to
convert to cancer.1-3,7 Therefore, treatment of all AK lesions is recommended,
and a variety of topical and nontopical
treatment options are available, making patient-tailored treatment strategies
possible.6 This supplement will focus
on topical treatment options, specifically Picato® (ingenol mebutate) gel, the
most recent US Food and Drug Administration (FDA)-approved treatment.
When selecting treatment for AK, a variety of factors require consideration, such
as the size, location, and duration of lesions; patient’s age and medical history;
Dr. Tyring discloses that
he has conducted clinical
research and given
presentations sponsored
by LEO Pharma Inc., the
manufacturer of Picato®.
costs of treatment; physician’s familiarity
and comfort with specific treatments;
and the patient’s personal preference.
Lesion-directed treatment options, such
as cryosurgery (the most widely used
treatment option in the United States),
produce high cure rates for individual lesions.3,6 However, when treating patients
with multiple lesions over large swaths
of skin or when subclinical lesions are
suspected, field-directed therapy with
topical agents may be more appropriate.3
Nevertheless, although the number of
subclinical lesions may be 10 times higher than visible lesions in a single patient, a
2004-2005 survey of 293 dermatologists
found that 74% of patients receive only
lesion-directed therapy (usually cryosurgery), 16% field-directed therapy alone,
and only 10% received both (sometimes
known as sequential therapy).3
Multiple topical treatments are available
for AK. These include various formulations of 5-fluorouracil (5-FU), imiquimod cream 5%, 3.75%, and 2.5%, and
diclofenac sodium gel 3%. These topical
treatments are generally associated with
complete clearance rates of about 50%
and partial response rates of about 70%.3
However, these agents are limited by prolonged application periods and the potential for severe local skin reactions, especially with 5-FU, which may limit adherence
and, therefore, outcome (Table 1).8-13 For
example, cure rates with 5-FU may reach
Application Frequency and Duration of Treatment With Topical Actinic Keratosis Therapies
Application Frequency
Duration of Treatment
5-FU 0.5%8
Once daily
Up to 4 weeks
5-FU 5%9
Twice daily
2-4 weeks
Imiquimod 2.5%, 3.75%10
Once daily
6 weeks (2 weeks on, 2 weeks off, 2 weeks on)
Imiquimod 5%11
Twice weekly
16 weeks
Diclofenac sodium 3%12
Twice daily
60-90 days
Ingenol mebutate gel 0.015%
Once daily
3 days
Ingenol mebutate gel 0.05%
Once daily
2 days
93% when used completely and correctly,
but unfortunately, many patients discontinue treatment early because of adverse
events, leading to failure rates of up to
Picato® (ingenol mebutate) gel, an inducer of cell death indicated for the topical treatment of AK, is the newest topical
treatment for AK, approved by the FDA in
2012.13 The application periods of ingenol
mebutate’s formulations are substantially
shorter than other available treatments:
for the face and scalp, the 0.015% formulation is applied once daily for 3 consecutive days; for the trunk and extremities, the
0.05% formulation is applied once daily
for 2 consecutive days.13 The shorter treatment periods with Picato® may improve
patient adherence and outcome.3
proximately 1 gram of Picato® gel 0.05%
was applied to an area 100 cm2 of the
dorsal forearm once daily for 2 consecutive days. Blood levels of Picato® and its
2 metabolites were below the lower limit
of quantification in all patients.13
The safety and efficacy of Picato®
were evaluated in 4 randomized, vehiclecontrolled studies in 2008 and 2009. All
patients enrolled were at least 18 years of
age and had 4 to 8 visible AK lesions within a 25-cm2 contiguous field on the face or
scalp or trunk or extremities.7 Two stud-
Picato® Gel: Cell Death Within Hours
Picato® is derived from the Euphorbia
peplus plant and has long been used in
the treatment of cutaneous lesions, including skin cancers.7 Ingenol mebutate’s mechanism of action in the resolution of AK lesions is unknown, but it is
believed to induce direct cell death via
mitochondrial swelling of precancerous
cells and also a secondary immune response via activation of protein kinase
C delta (Figure 1 and Figure 2).3,7,13 Systemic absorption of Picato® is nondetectable and was assessed in 2 studies with a
total of 16 patients. In both studies, ap2
ies (N = 547) randomized patients with
face or scalp lesions to Picato® 0.015%
(n = 277) or vehicle (n = 270). The 2 other trials (N = 458) randomized patients
with lesions on the trunk or extremities
to Picato® 0.05% (n = 226) or vehicle
(n = 232). In all studies, safety endpoints
included local skin reactions (LSR), pigmentation, and scarring evaluated at days
3 (trunk or extremity lesions) or 4 (face
and scalp lesions), and days 8, 15, 29, and
57. The primary efficacy endpoint for all
studies was the complete clearance rate in
Picato® Gel: Immune Response Within Days
the treatment area at day 57. The secondary efficacy endpoint was partial clearance, defined as a 75% or more reduction
in the number of visible lesions, at day 57.
In the face and scalp studies combined,
the partial clearance rates with Picato®
and vehicle were 63.9% and 7.4%, respectively (P < .001). The complete clearance
rates were 42.2% versus 3.7%, respectively (P < .001). Overall, in the Picato® arm,
there was a median 83% reduction from
baseline in the number of AK lesions
versus no reduction in those treated with
vehicle.7 In the trunk and extremity combined studies, partial clearance rates with
Picato® and vehicle were 49.1% vs 6.9%,
respectively (P < .001). Complete clearance was achieved by 34.1% of ingenol
mebutate-treated patients versus 4.7% in
vehicle-treated patients (P < .001). The
mean number of AK lesions was reduced
by 75% with Picato® vs 0% with vehicle.7
Safety was evaluated quantitatively using a 4-point LSR grading scale. Patients
were scored for 6 responses: erythema,
flaking or scaling, crusting, swelling, vesiculation or pustulation, and erosion or
ulceration. Scores were summed for a
composite LSR at each follow-up visit.
In the face and scalp studies, the mean
maximum composite LSR in ingenol mebutate-treated patients was 9.1 versus 1.8
among vehicle-treated patients. The composite score peaked at day 4 for most patients and then rapidly declined, returning to baseline at 2 weeks. Application
site reactions were the most common adverse event, occurring in 19% and 2.6% of
ingenol mebutate- and vehicle-treated patients, respectively. Other adverse events
are shown in Table 2. Only 1 patient
(0.4%) in each arm discontinued treated
because of an adverse event.7
In the trunk and extremity studies, the
mean maximum composite LSR were 6.8
and 1.6 for Picato® and vehicle, respec-
Adverse Events Occurring in >2% of the Study Population
Face & Scalp Studies
Picato® 0.015%
Trunk & Extremities Studies
Picato® 0.05%
Number of patients (percent)
Any adverse event
102 (37.2)
60 (22.1)
8 (3.6)
12 (5.2)
52 (19)
7 (2.6)
27 (12)
6 (2.6)
22 (8)
3 (1.1)
19 (8.4)
38 (13.9)
1 (0.4)
5 (2.2)
Application site irritation
5 (1.8)
8 (3.6)
1 (0.4)
Application site infection
7 (2.6)
1 (0.4)
6 (2.2)
3 (1.1)
1 (0.4)
Any application site event
Application site pruritus
Application site pain
Periorbital edema
tively. Composite LSR were highest at
days 3 or 8 for most patients (55.1% and
32.4%, respectively), with some patients
peaking at day 15 (8.4%), returning to
baseline values at 4 weeks. Application
site reactions were the most common adverse events (12% with Picato® vs 2.6%
with vehicle), and no serious adverse
events leading to treatment discontinuation were reported (Table 2).7
A phase III, multicenter, randomized,
double-blind study examined the efficacy
and safety of Picato® after cryosurgery as
part of sequential treatment for AK.14 All
patients (N=329) received cryosurgery
with liquid nitrogen and were randomized to receive treatment with Picato®
0.015% gel (n=167) or vehicle (n=162)
3 weeks thereafter. The study results
demonstrated that complete clearance
rates were greater with Picato® compared
with vehicle at 11 weeks after cryosurgery (60.5% vs 49.4%, respectively) and
at 12 months (30.5% vs 18.5%, respec-
tively).15 Picato® also demonstrated a
greater reduction in the number of AK lesions compared with baseline at 11 weeks
(82.7% vs 75.6%, respectively) and at
12 months (68.2 vs 54.1, respectively).15
Treatment with Picato® after cryosurgery
was well tolerated.
Prevention is the best treatment of AK
and skin cancer. Patients should be advised to avoid sun exposure, and to
wear sunscreens and protective hats and
clothing. When prescribing Picato®, it is
important that patients understand the
need for treatment and, more specifically, the need for field-directed therapy.
Physicians should explain to patients
that AK are precursors to SCC, but that
it is not possible to predict which specific lesions—those that are visible and
not-yet-visible—will convert to malignancy. To prevent cancer, the safest
course is to treat all AK lesions, both visible and subclinical.
To ensure that patients complete treatment, thereby creating the greatest po-
1. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratosis: Natural history
and risk of malignant transformation in the Veterans Affairs Topical Tretinoin
Chemoprevention Trial. Cancer. 2009;115(11):2523-2530.
2. Lewin Group. The burden of skin diseases: 2005.
media/Lewin/Site_Sections/Publications/april2005skindisease.pdf. Accessed
May 12, 2014.
3. Berman B, Cohen DE, Amini S. What is the role of field-directed therapy in the
treatment of actinic keratosis? Part 1: overview and investigational topical
agents. Cutis. 2012;89(5):241-250.
4. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers RP. Frequency of preexisting actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol.
5. Czarnecki D, Meehan CJ, Bruce F, Culjak G. The majority of cutaneous
squamous cell carcinomas arise in actinic keratoses. J Cutan Med Surg.
6. Dinehart SM. The treatment of actinic keratoses. J Am Acad Dermatol.
2000;42(1 pt 2):S25-S28.
A supplement to
Actinic keratoses are common skin lesions caused by overexposure to sunlight
with the potential to convert to malignancy. As it is impossible to predict which
lesions will convert to cancer, treatment
of all AK lesions is recommended. Topical treatments offer the best strategy for
treating large areas of clinically visible
and subclinical lesions. Of the available
topical treatments, Picato®, available in
2 formulations, and proven to safely and
effectively clear AK, has the shortest application period, which may help improve
patient adhere and overall outcomes.
7. Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol
mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010-1019.
8. Carac [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North
America LLC; 2012.
9. Fluorouracil Cream 5% [package insert]. Randolph, NJ: Spear Pharmaceuticals;
10. Zyclara [package insert]. Scottsdale, AZ: Medicis Pharmaceutical; 2012.
11. Aldara [package insert]. Bristol, TN: Gateway Pharmaceuticals, LLC; 2010.
12. Solaraze [package insert]. Melville, NY: PharmaDerm; 2012.
13. Picato [package insert]. Parsippany, NJ: LEO Pharma Inc.; 2012.
14. Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol
mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week
results. J Drugs Dermatol. 2014;13(2):154-160.
15. Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol
mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results.
J Drugs Dermatol. 2014;13(6):741-747.
Editorial assistance was provided to the
authors by Skin & Allergy News and
LEO Pharma Inc.
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tential for a good outcome, prepare them
for possible adverse events, the duration
of adverse events, and emphasize that adverse events are transient and quick to resolve. Photographs showing patients before, during, and after treatment can help
reinforce the transience of adverse events
and outcome potential. Patients should
also be advised to keep Picato® refrigerated, ensure it dries completely after application, and to avoid showers immediately
after application.
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