TOPICS

Tolerability and Pharmacokinetics of Ingenol Mebutate 0.05% Gel Applied to Treatment Areas up to 100cm2 on the Forearm(s) of Patients with Actinic Keratosis

aLAWRENCE ANDERSON, MD; bMICHAEL JARRATT, MD; cGEORGE SCHMIEDER, DO;

dSTEPHEN SHUMACK, MB, BS; eJANELLE KATSAMAS; ePETER WELBURN, PhD

aDermatology Associates of Tyler, Texas; bDermResearch Inc., Austin, Texas; cPark Avenue Dermatology, Orange Park, Florida;

dUniversity of Sydney, Sydney, Australia; eLEO Pharma Pty Ltd, Brisbane, Australia

Disclosure: See author disclosures at the end of this article. The study was funded by LEO Pharma.

Abstract

Objective: To determine safety, tolerability, and systemic absorption of ingenol mebutate 0.05% gel applied for two consecutive days to treatment areas up to 100cm2 on the forearm(s) of patients with actinic keratosis. Design and setting: Two studies are reported: a Phase 1, multicenter, open-label, dose-area escalation cohort study (http://www.clinical trials.gov/ct2/show/NCT00659893) and a Phase 2, double-blind, vehicle-controlled pharmacokinetic study (http://clinical trials.gov/ct2/show/NCT00852137). Participants: The Phase 1 study included male patients (n=65), mean age 68.1 years; the Phase 2 study included both male and female patients (n=16), mean age 63.3 years. Measurements: In the Phase 1 study, patients assigned to escalating dose-area cohorts were evaluated for local skin responses, adverse events, and any other relevant safety data. In the pharmacokinetic study, blood samples were collected pre-dose and for up to 24 hours after administration on Day 2, and analyzed for ingenol mebutate and its primary metabolites. In both studies, safety assessments were performed on Days 2, 3, 8, 15, 29, and 57 (study end). Results: In the Phase 1 study, most adverse events were mild, and all treatment-related adverse events resolved before the end of the study. The 100cm2 treatment area showed a small increase in the overall intensity of mean composite local skin response scores. There was no quantifiable systemic exposure to ingenol mebutate or its primary metabolites. Conclusion: Ingenol mebutate 0.05% gel has a good safety profile when applied to treatment areas up to 100cm2 with acceptable tolerability and local skin responses. There is no systemic absorption following application to areas of 100cm2. (J Clin Aesthet Dermatol. 2014;7(12):19–29.)

Actinic keratosis is prevalent in fair-skinned populations worldwide, with lesions occurring most frequently on sun-exposed areas, such as the head, neck, forearms, hands, and shoulders.[1–3] Actinic keratoses (AKs) have the potential to progress into squamous cell carcinoma (SCC) and it is estimated that 40 to 80 percent of all SCCs arise from AKs.[1],[4–6] The risk of progression to SCC is between 0.025 and 16 percent per year[4],[6],[7]; however, predicting which AKs will progress to SCC is not possible, therefore treatment of all AKs is recommended.[1],[8],[9]

Lesion-directed cryosurgery is effective in treating individual AK lesions,10 but this does not address field cancerization, and high recurrence rates have been observed following cryosurgery alone.[11] Ingenol mebutate gel is a field treatment for AKs with a dual mechanism of action, inducing direct lesion cell death and infiltration of immunocompetent cells.[12] Phase 3 studies have shown ingenol mebutate gel at concentrations of 0.015% for the face/scalp and 0.05% for the trunk/extremities to be effective in clearing AKs both in the short term[13] and long term, with sustained clearance over 12 months.[14] In these studies ingenol mebutate was applied once daily for three or two consecutive days, respectively, over a 25cm2 contiguous area of skin. Treatment was well tolerated and adherence was high. Local skin responses (LSRs) associated with ingenol mebutate application typically occurred within one day of treatment initiation and peaked up to one week following completion of treatment. LSRs generally returned to pre-treatment levels within two weeks of treatment initiation when treating areas on the face and scalp, and within four weeks of treatment initiation when treating areas on the trunk and extremities.

In clinical practice, some patients may require treatment for skin areas larger than 25cm2, and so the authors present here results of two safety studies (NCT00659893 and NCT00852137) designed to determine safety and tolerability (including LSR incidence) and potential for systemic absorption of ingenol mebutate 0.05% gel applied to treatment areas up to 100cm2 on the forearm(s) of patients with AKs. Some topical treatments for AKs, such as imiquimod, fluorouracil, and diclofenac are systemically absorbed,[15–22] so data from these studies are important to quantify the extent of systemic absorption and assess safety and tolerability of ingenol mebutate 0.05% gel.

Both studies were conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice23 with patients providing written consent.[24]

Methods

Dose-area escalation study (www.clinical trials.gov NCT00659893, PEP005-022).

Trial design. This was a Phase 1, multicenter, open-label study in patients with AKs on the dorsal forearm(s). The study was conducted at four study sites in Australia and eight study sites in the United States and ran from April 3, 2008, to September 4, 2008. Patients were assigned to receive increasing doses through the application of ingenol mebutate 0.05% gel with the same amount per cm2 applied to progressively larger areas of skin (described as dose-area escalation). Patients were assigned to treatment cohorts starting with Cohort 1 and escalating through to Cohort 8 ( “href=”https://jcadonline.com/wp-content/uploads/Anderson_Figure1_Dec14.jpg”>Figure 1). Patients were assigned centrally and chronologically by the study sponsor to a cohort across all study sites. The allocation scheme aimed to ensure that an individual site enrolled no more than two patients in each cohort.

LSRs, photographs, adverse events (AEs), and any other relevant safety data were evaluated for each cohort. The decision to escalate to the next treatment cohort(s) was made by an independent review team after assessments of acceptable safety and tolerability up to Day 15 for at least 80 percent of patients in a cohort.

Participants. The study included male patients who were at least 18 years of age with a 100cm2 contiguous treatment area on both the right and left dorsal forearms, each containing a minimum of five AK lesions. Patients were screened for inclusion between 42 days and one day prior to administration of ingenol mebutate gel. The date of the first dose of study medication was considered study Day 1.

Patients were excluded if they had undergone:

  • Cosmetic or therapeutic procedures (e.g., use of liquid nitrogen, surgical excision, curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing) within two weeks prior to the study screening visit and within 2cm of the selected treatment area(s);
  • Treatment with immunomodulators, or interferon/ interferon inducers or systemic medications that suppress the immune system within four weeks prior to screening;
  • Treatment with 5-fluorouracil, imiquimod, diclofenac, or photodynamic therapy within eight weeks prior to screening and within 2cm of the selected treatment area(s).

Interventions. Ingenol mebutate 0.05% gel was administered by the patient under supervision of the investigator, from individual study medication kits that contained two boxes labeled for use on either Day 1 or Day 2, respectively. Each box contained one to four individual unit dose tubes as appropriate for the cohort to which the patient was assigned. Each unit dose tube contained sufficient ingenol mebutate 0.05% gel for the treatment of one 25cm2 skin area. Four times the nominal dose for 25cm2 was used for the 100cm2 application to ensure that the same amount per cm2 was applied over the entire field when compared with the 25cm2 area.

Assessments. Follow-up visits for safety assessments were made on Days 2, 3, 8, 15, 29, and 57 (end of study). All AEs occurring during the course of the study from Day 1 (post-dose) through Day 57, whether or not they were considered related to the study, were recorded and assessed for severity and causality with study medication. Pigmentation and scarring assessments were made on Day 1 (pre-dose) and Day 57. Treatment area(s) were assessed for LSRs prior to application of ingenol mebutate 0.05% gel and at each subsequent visit. LSR assessments were made by a board-certified dermatologist using a standardized, quantitative LSR grading scale.25 Treatment areas were assessed for six types of individual LSRs: erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. Skin reactions other than those identified and listed above were recorded as AEs. Each LSR was graded from 0 (not present) to 4 (maximum possible response). A composite score representing the sum of the scores for the six individual LSR categories was calculated, giving a total score between   0 and 24 at each assessment time point.

Endpoints. The primary outcome measure was safety and tolerability of two consecutive applications of ingenol mebutate 0.05% gel applied once daily to 25, 50, 75, or 100cm2 treatment area(s) on the dorsal forearm(s).

Statistical methods. Safety reporting and analysis were performed on the safety population, which comprised patients who were assigned to receive study medication and who received at least one dose. No statistical hypothesis testing was performed. The incidence rates of AEs, serious AEs (SAEs), and AEs leading to discontinuation of study medication were examined by single contiguous treatment area and total body exposure. LSR composite scores were analyzed in a mixed model with size of treatment area as fixed effect and subject as random effect. All LSR, pigmentation, and scarring data were also summarized descriptively.

Pharmacokinetic study (www. clinicaltrials.gov NCT00852137, PEP005-017).

Trial design. This was a Phase 2, double-blind, vehicle-controlled pharmacokinetic study in patients with AK lesions on the dorsal forearm undertaken at a single study site in the United States. The study ran from March 18, 2009, to May 27, 2009.

Participants. Patients were screened for eligibility between 14 days and one day prior to administration of ingenol mebutate 0.05% gel. The study included patients aged at least 18 years with multiple AKs in a contiguous 100cm2 treatment area on the dorsal aspect of one forearm, and with four to eight clinically typical, visible, and discrete AKs in a 25cm2 unit area located within the 100cm2 treatment area. Exclusion criteria were the same as for the dose-area escalation study.

Interventions. Patients were randomized in a 4:1 ratio on study Day 1 to receive either ingenol mebutate 0.05% gel or vehicle gel. Study medication was packaged individually for each patient in a study medication kit of eight unit-dose tubes containing either ingenol mebutate 0.05% gel or vehicle gel (i.e., four tubes for each 100cm2 treatment area for 2 days). Study medication was applied on Days 1 and 2 in the clinic by site staff. Study personnel, investigators, and patients were blinded to treatment assignment.

Assessments. Pharmacokinetic blood samples were collected for all patients prior to application of study medication on Day 1, 24 hours post-dose (but prior to Day 2 application) and at 30 minutes, 1, 2, 4, 8, 12, and 24 hours following study medication application on Day 2. Analysis for ingenol mebutate and its primary metabolites PEP015 and PEP025 used liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) and a validated assay with a lower limit of quantification (LLOQ) of 0.1ng/mL using only 100?L of blood.

As for the dose-area escalation study, safety assessments were performed on Days 2, 3, 8, 15, 29, and 57 (study end). Efficacy assessment was performed on Day 57. Assessments for LSRs and pigmentation and scarring were performed prior to treatment on Day 1 and Day 2 and at each subsequent visit. Patients with unresolved (at Day 57) treatment-related AEs, LSRs, and pigmentation or scarring greater than observed at baseline (Day 1 prior to treatment) underwent post-study follow-up visits.

Endpoints. The primary outcome measures were maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration–time curve from 0 to 24 hours (AUC[0–24]) of ingenol mebutate, PEP015, and PEP025, quantified in whole blood samples.

Secondary outcome measures were:

  • Incidence of AEs, SAEs, and AEs leading to discontinuation during the study;
  • Incidence and grade of LSRs, pigmentation, and scarring, following study treatment to study end (Day 57);
  • Percentage of patients with complete (100%) clearance (no clinically visible AKs in a 25cm2 area within the selected treatment area at Day 57);
  • Percentage reduction in AKs from baseline in a 25cm2 area within the selected treatment area at Day 57.

Statistical methods. The pharmacokinetic (PK) analysis was performed using the PK population, defined as all randomized patients who had received at least one dose of study medication and who had at least one post-baseline PK blood sample. The safety analysis was based on the safety population, defined as all randomized patients who had received at least one dose of study medication and who had at least one post-baseline safety evaluation. Patients were assessed for safety in the group in which they were treated. The efficacy analysis was based on the intent-to-treat (ITT) population, defined as all patients randomized. No inferential analyses were performed. Descriptive summaries included the mean, standard deviation, median, and range for continuous variables, and counts and percentages for categorical variables.

RESULTS

Dose-area escalation study. In the dose-area escalation study, 74 patients were screened, 65 of whom were assigned to treatment. Eight patients were assigned to each cohort except for Cohort 6, which included nine patients ( “href=”https://jcadonline.com/wp-content/uploads/Anderson_Figure2A_Dec14.jpg”>Figure2A). Two patients were withdrawn from the study by the investigator (injured forearm and protocol violation). Treatment area assignment, treatment location, and disease severity (ITT population) is shown in Table 1. The safety population comprised 64 patients.

Patient demographics are shown in Table 2A. Mean age was 68.1 years in the dose-area escalation study, all patients were male, and most were Caucasian. Most patients had Fitzpatrick skin type II or III.

All patients in Cohorts 1, 2, and 8 received two consecutive daily doses of ingenol mebutate 0.05% gel, as planned. Five of 64 (7.8%) patients had the second dose withheld due to LSRs and/or AEs in the treatment area(s) (two patients in Cohort 3 and one in each of Cohorts 4, 5, and 6). A sixth patient (from Cohort 7) was withdrawn prior to the second dose because of a protocol violation. All patients with a treatment area of 100cm2 tolerated two doses.

Adverse events. Overall, 27 patients (42.2%) experienced a total of 49 treatment-related AEs Table 3. Application-site pruritus (26.6%) and application-site irritation (14.1%) were the most common AEs. Most AEs were mild and all treatment-related AEs resolved before the end of the study. In the single treatment area cohorts (Cohorts 1, 2, 5, and 8), the incidence of treatment-related AEs was highest in the 75cm2 group (62.5%), followed by 50cm2 and 100cm2 (37.5% in each case), and was the lowest for 25cm2 (12.5%).

Three SAEs were reported: SCC in one patient (classified as possibly treatment-related) and one case each of exacerbation of pre-existing hypertension and worsening pancreatitis, both of which were considered unrelated to treatment. All three SAEs resolved by Day 57 and none of the patients withdrew from the study. Systemic AEs that were evaluated as possibly treatment-related included two cases of dysgeusia, and one case each of dry mouth, frequent bowel movement, and rales. There were no deaths during the study and all patients completed follow-up to Day 57.

Local skin responses. The mean composite LSR score by treatment area size within each cohort ranged from 0.8 to 1.6 prior to treatment and 0.1 to 1.6 by the end of the study. The mean composite LSR score peaked during Days 3 and 8. The highest individual composite score out of a possible maximum of 24 reported during the study was 15 in Cohort 8 and ranged between 8 and 13 in all other cohorts.

The mean maximum composite LSR scores across standard visits (Days 3, 8, 15, 29, and 57) were 6.8, 7.4, 7.8, and 9.8 in the 25, 50, 75, and 100cm2 treatment areas, respectively. Mean composite LSR scores increased with increasing treatment area size ( “href=” https://jcadonline.com/wp-content/uploads/Anderson_Figure3_Dec14.jpg”>Figure 3). At Day 57, mean composite LSR score was at or slightly below pretreatment levels for all treatment area sizes.

The most common LSRs during the study were erythema and flaking/scaling, both of which were prevalent to a degree at baseline. Erosion/ulceration was the least common LSR and the highest grade encountered during the study was Grade 2 (epithelial desquamation with no ulceration).25 The size of the treated area appeared to be associated with the maximum incidence of some LSRs when assessed by pooled treatment area. Swelling and vesiculation/pustulation on Day 3 (the peak day for these LSRs) were higher in the 75 and 100cm2 treatment areas than in the 25 and 50cm2 areas. Peak incidence of erosion/ulceration on Day 8 was higher in the 100cm2 treatment area (62.5%) than in the 25cm2 (12.5%), 50cm2 (28.1%), and 75cm2 (25%) areas.

While pigmentary features and scarring were present at baseline, new or worsened pigmentary changes occurred in 14.1 percent of patients during or after the study, with some patients experiencing both hypo- and hyper-pigmentation within the treatment areas. Scarring occurred during or at the end of study in 4.7 percent of patients. These changes were rated not clinically significant in eight patients and mild in two patients. One patient had worsened hypopigmentation that was graded as moderate at Day 57.

Pharmacokinetic study. In the pharmacokinetic study, 16 patients were enrolled and randomized to treatment (ingenol mebutate 0.05% gel n=13; vehicle gel n=3) (Figure 2B). All 16 patients completed the study. Patient demographics are shown in “href=”https://jcadonline.com/wp-content/uploads/Anderson_Table2B_Dec14.jpg”>Table 2B. Mean age was 63.3 years in the pharmacokinetic study; 63 percent were female and all were Caucasian. Most patients had Fitzpatrick skin type II or III. No quantifiable systemic absorption was detected with two consecutive once-daily applications of ingenol mebutate 0.05% gel (LLOQ 0.1ng/mL).

Adverse events. All patients received the planned treatment regimen of either ingenol mebutate 0.05% gel or vehicle gel once daily for two consecutive days. Of seven reported AEs, only one (mild diarrhea) was considered related to treatment; however, upon unblinding, this patient was found to be randomized to vehicle gel. All AEs were located outside the treatment area, with the exception of an insect bite. No SAEs occurred in this study.

Local skin responses. The mean composite LSR score in patients receiving ingenol mebutate gel was 0.1 at baseline, reached a maximum of 6.6 on Day 3, and returned to pretreatment levels by the end of the study. In patients who received vehicle gel, the mean composite LSR score was 0.3 at baseline, and zero throughout the remainder of the study ( “href=” https://jcadonline.com/wp-content/uploads/Anderson_Figure4_Dec14.jpg”>Figure 4).

All patients treated with ingenol mebutate 0.05% gel (n=13) experienced erythema and flaking/scaling. Swelling and vesiculation/pustulation were reported in 69 and 54 percent of patients, respectively. One patient had Grade 1 erythema at Day 57, while all other LSRs resolved during the study. Grade 4 erythema and/or flaking/scaling occurred in 38 percent of patients.

In the pharmacokinetic study, there were no changes compared with baseline in hypopigmentation or hyperpigmentation in the ingenol mebutate group at Day 57. Transient pigmentary changes occurred during the study in two patients treated with ingenol mebutate 0.05% gel (one case each of Grade 1 hypopigmentation and Grade 1 hyperpigmentation, both of which resolved by the end of the study). No patients had scarring or abnormal proliferation.

In the 25cm2 area assessed for efficacy, complete clearance of all AK lesions was experienced by 77 percent of patients treated with ingenol mebutate 0.05% gel; all patients had partial clearance of their lesions. None of the three patients treated with vehicle gel had complete or partial clearance. The median percentage reduction in AK lesion count was 100 percent in patients treated with ingenol mebutate 0.05% gel and zero in those patients treated with vehicle gel.

 

DISCUSSION

The forearm is a very common area for sun damage and AK lesions and is relevant to the study of AK treatment.[1–3] A treatment area of 100cm2 represents an anatomical unit for application of topical therapy that covers the entire dorsal forearm. Field treatment of AKs with ingenol mebutate gel in a treatment area of 25cm2 has been shown to be efficacious and well tolerated in Phase 3 trials, with an average sustained reduction of baseline lesions of 87 percent at 12 months in patients who were initially cleared.[13],[14] The results of the two studies presented here support an acceptable safety profile of topical ingenol mebutate 0.05% gel applied to an area of up to 100cm2.

The safety and tolerability results from the dose-area escalation study demonstrated that a treatment field of 100cm2 could be used as an acceptable treatment area for evaluation in a pharmacokinetics study. There was no systemic absorption following application of ingenol mebutate 0.05% gel to a treatment area of up to 100cm2. Blood levels of ingenol mebutate and its two metabolites were below the LLOQ (0.1ng/mL) in all the blood samples of the patients evaluated.

Topical treatments for AKs, such as imiquimod, fluorouracil, and diclofenac, are systemically absorbed and the relevant Summaries of Product Characteristics or Prescribing Information contain warnings about side effects related to systemic drug exposure.[15–19],[21],[22] Pharmacokinetic studies with imiquimod have confirmed very low serum concentrations following topical use, reflecting minimal dermal absorption.[26] However, systemic side effects, although infrequent, have been reported, including headache, flu-like symptoms, fatigue, nausea, and myalgia.[27–29] Some of these reactions have been severe in intensity with the hypothesis that severity of the symptoms could be related to the surface area of skin reactions to imiquimod.[30–32]

LSRs observed in this pharmacokinetic study were comparable to those seen in the Phase 3 studies on the trunk and extremities; however, LSR scores seen in the 100cm2 treatment area of the dose-area escalation study were higher than those seen in the Phase 3 trunk and extremities studies (9.8 vs. 6.8).[13] The size of the treated area appeared to be associated with the maximum incidence of some LSRs when assessed by pooled treatment area. The mean composite LSR score peaked during Days 3 and 8. The most common LSRs during the study were erythema and flaking/scaling, both of which were prevalent to a degree at baseline. Erosion/ulceration was the least common LSR and the highest grade encountered during the study was Grade 2 (epithelial desquamation with no ulceration).25

The patient with AK is susceptible to SCC development in areas of high actinic exposure, such as the forearms.[1],[6],[7],[33] It is thus possible that the SCC, which developed on the forearm of one study patient who was rated as having severe actinic damage at baseline, may have been present at study screening and mistakenly diagnosed as an AK. It is also possible that an irritation effect of ingenol mebutate 0.05% gel may have precipitated the transformation of an AK into an SCC as has occasionally been observed clinically with other field therapies and following local trauma to the skin.

Transient pigmentary changes (generally mild or not clinically significant) occurred during both studies but resolved before, or were deemed not clinically significant at the study end in all patients, except one in the dose-area escalation study who had hypopigmentation graded as moderate at Day 57. Scarring was reported in 4.7 percent of patients; however, this was assessed as not clinically significant at the completion of study in all cases. It is possible that upon clearing of actinic damage, some minor scarring from previous injury became more apparent.

AEs, particularly LSRs, may affect treatment adherence for topical agents with long treatment duration.[34] Phase 3 trials demonstrated excellent treatment adherence of ingenol mebutate gel.13 With its two- or three-day consecutive treatment duration and approximately 98-percent treatment adherence in clinical studies,13 good tolerability profile, and absence of systemic absorption, ingenol mebutate gel is likely to provide very high adherence to treatment and thus support efficacy in real-world clinical practice. In addition, results from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirritation, or photoallergic potential.[35]

The efficacy results seen in the pharmacokinetic study are higher than those seen in Phase 3 studies of ingenol mebutate gel on trunk and extremities.[13] This may be due to small sample size or the small number of AK lesions per patient.

Limitations of the studies presented here include the open-label design of the dose-area escalation study and small patient numbers in the pharmacokinetic study. In addition, as with all topical treatments for AKs, some unblinding of treatment regimen may occur due to LSRs; however, LSRs vary between patients and have also been seen in patients treated with vehicle gel,[36] which although at lower intensity, may limit the ability of the investigator to identify treatment assignment. Treatment in both studies was only applied to the forearm and results cannot therefore be generalized to other anatomical locations. Although no pharmacokinetic data are available following application of ingenol mebutate gel to the face or scalp, concentration used in these areas is lower (0.015%) than that used in the studies presented here (0.05%) and no systemic exposure is anticipated.

In conclusion, ingenol mebutate 0.05% gel has a good safety profile when applied once daily for two consecutive days to a contiguous treatment area on the dorsal forearm of up to 100cm2 in patients with AK lesions giving acceptable tolerability and LSRs. There is no quantifiable systemic exposure to ingenol mebutate following topical application to treatment areas of 100cm2.

AUTHOR CONTRIBUTIONS AND DISCLOSURES

Lawrence Anderson has been involved with clinical trials since 2002. He has been a consultant, investigator, and/or speaker for Allergan, Amgen, Abbott, Balilea, Biogen Astellas, Galderma, Genentech, Glenmark Generics, Healthpoint, LEO Pharma, Novartis, Novum, Paragon Biomedical, Peplin, Pfizer, Quintiles, Symbio, and TolerRX. He has been an investigator and principal investigator on multiple trials involving ingenol mebutate receiving honoraria, consultant, speaker, travel, and research grants. He has served on advisory boards for LEO Pharma and Peplin. He has been the Chairman of several Dose Escalation and Safety Committees, most recently serving as Chairman, Dose Management Committee of an ongoing clinical trial for LEO Pharma. Dr. Anderson has participated in the writing, discussion, and review of multiple manuscripts involving ingenol mebutate.

Michael Jarratt has been a consultant for Allergan, Galderma, Stiefel Laboratories, and Valeant; has received honoraria from Allergan, Galderma, Stiefel Laboratories, Tolmar, and Valeant; and has been a principal investigator for Abbott, Activis Elizabeth, Allergan, Amgen, Anacor, Bayer/Intendis, Cutanea Life Sciences, Galderma, Glenmark Generics, Kythera Biopharmaceuticals, LEO Pharma and Peplin, Lilly Research Laboratories, Lithera, McNeil (Johnson & Johnson), Maruho North America, Merck, Merz, Novartis, Pfizer, Photocure, Promius Pharma, Stiefel Laboratories, Taro, Tolmar, Topica, Valeant, Warner Chilcott, and Xoma. He has participated in manuscript discussion and review for LEO Pharma.

George Schmieder has been participating in clinical research since 2005. He has been an investigator for Abbott, Anacor Pharmaceuticals, AstraZeneca, Basilea, Ciphor, Otsuka, Pfizer, Promius, and Tolmar. He has worked with Biotechnology Corp. Genentech and Biopharmaceutical Inhibitex. He was an investigator for the dose-area escalation studies for actinic keratosis by LEO Pharma and Peplin, and participated in their manuscript discussion and review. He has been a speaker for and has received a travel grant from LEO Pharma.

Stephen Shumack has been an investigator in the dose-area escalation study and has participated in manuscript discussion and review for, has participated in an advisory board for, has been a speaker for, and has received a travel grant from LEO Pharma.

Janelle Katsamas and Peter Welburn are employees of LEO Pharma.

Acknowledgment

The study was funded by LEO Pharma. Study statisticians were Nancy L. Fitzgerald of Cu-Tech, LLC, and Andrew Barnes of Omnicare Clinical Research and pharmacokinetic methodology was developed by Karen Cawkill and Leslie Henderson of Covance Laboratories Limited. Marie Louise Østerdal of LEO Pharma generated additional statistical outputs including composite LSR score figures.

Medical writing services were provided by Mark O’Connor of iMed Comms and were funded by LEO Pharma. The authors thank the patients and investigators who participated in these studies.

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