Imiquimod 2.5% and 3.75% for the Treatment of Actinic Keratoses: Two Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies

November 2013 | Volume 12 | Issue 11 | Original Article | 1278 | Copyright © 2013

Neil Swanson MDa, Christina Cognata Smith MDb, Mandeep Kaur MDb, and Gary Goldenberg Mc

aOregon Health and Science University, Department of Dermatology, Portland, OR
bFormerly at Medicis (a division of Valeant Pharmaceuticals), Scottsdale, AZ
cMount Sinai School of Medicine, Department of Dermatology, New York, NY

Abstract

BACKGROUND: Imiquimod 3.75% and 2.5% creams were studied for the treatment of actinic keratosis (AK) of the full face or balding scalp, to determine comparable efficacy and tolerability to imiquimod 5% cream.
METHODS: In two identical multicenter, randomized, double-blind, placebo controlled studies. Adult subjects with 5 to 20 visible lesions, or palpable AKs in an area that exceeded 25cm2 on either the face or balding scalp were randomized to imiquimod 3.75%, 2.5% or vehicle cream (1:1:1) applied once daily for two 2-week treatment cycles, with a 2-week, no-treatment interval between cycles. Efficacy was assessed 8 weeks posttreatment (End of Study Visit [EOS]). Primary efficacy was rate of complete clearance of AK lesions. Secondary efficacy endpoints were rate of partial clearance at EOS (≥ 75% reduction in number of AK lesions compared to baseline) and median percent decrease from baseline lesion count. Safety assessments included visual assessment of local skin reactions (LSRs), number and duration of study treatment rest periods required due to intolerant LSRs, adverse events (AEs) and clinical laboratory tests.
RESULTS: Overall 479 patients were randomized to imiquimod 3.75%, 2.5%, or vehicle. Complete clearance rates were 35.6%, 30.6%, and 6.3% respectively (both P<.001 versus vehicle). The difference in complete clearance rates (imiquimod minus vehicle) was 29.3% and 24.3%, respectively. Partial clearance rates were 59.4%, 48.1%, and 22.6% respectively (both P<.001 versus vehicle). Median % reductions in AK lesions were 81.8%, 71.8%, and 25.0% respectively (-<.001 versus vehicle). All primary and secondary efficacy endpoints were greater in Study 1. Photodamage in the treatment area was 'much improved' with imiquimod 3.75%. Both active creams were well tolerated with few treatment-related discontinuations.
CONCLUSIONS: In two well-controlled Phase 3 studies, both imiquimod 3.75% and 2.5% creams were more effective than vehicle and well tolerated when administered daily as a 2-week on/off/on regimen to treat AK. Reduction in AK lesions was comparable to that reported with imiquimod 5% with fewer local AEs.

J Drugs Dermatol. 2013;12(11):1278-1282.

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INTRODUCTION

Actinic keratosis (AK) is one of the most common skin conditions seen in dermatological practice.1 From 2000 to 2003, there were an estimated 5.2 million physician visits annually in the United States, and the incidence of AK and associated physician visits appear to be rising.2,3 AKs are typically found on sun-exposed skin, such as the face, balding scalp, and back of the hand, especially in fair-skinned individuals (Fitzpatrick skin types I-III) of advanced age.4 One study found that head, neck, and forearms comprised 75% of all reported AK lesions;5 multiple lesions are commonly observed,6 and they are more prevalent in men.7

Most AKs are diagnosed clinically (red, scaly papules or plaques, 2–5 mm in diameter, occurring in sun-exposed sites such as face, ears, neck, forearms, hands, and balding scalp) and rarely confirmed histologically. Although AKs can spontaneously regress untreated;8 effective treatment combined with routine surveillance is important, especially in patients with multiple AKs due to the possibility of malignant transformation into squamous cell carcinoma (SCC),9 something that increases with increased duration of presence of an AK.10

The Food and Drug Administration (FDA) approved Imiquimod 5% cream for treatment of AK in 2004. A systematic review and meta-analysis of five randomized double-blind studies in 1293 patients demonstrated its safe and effective use in the short-term treatment of AK.11 Complete clearance occurred in 50% of patients treated with imiquimod 5% cream, compared to 5% treated with vehicle, and the number needed to treat (NNT) for one patient to have their AKs completely cleared after 12–16 weeks was 2.2.11

Although treatment adherence was good in these studies, the long duration and frequent dosing with imiquimod 5% cream (applied continuously for 16 weeks or as two 4-week cycles) may

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