Key clinical-trial evidence for ingenol mebutate gel

Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2012.


Introduction

The FDA approval for the use of ingenol mebutate gel is based on data from four phase III studies in over 1000 people showing that ingenol mebutate gel applied once-daily for two or three consecutive days is significantly more effective than placebo at clearing actinic keratoses.

Actinic keratosis of the face and scalp

In two double-blind, vehicle-controlled, clinical trials, 547 adult subjects with actinic keratoses on the face or scalp were randomised to treatment with either ingenol mebutate gel, 0.015% or vehicle gel for 3 consecutive days, followed by an 8-week follow-up period.

The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete actinic keratoses within a 25 cm2 contiguous treatment area.

On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 536 subjects (98%) completed these studies. Study subjects ranged from 34 to 89 years of age (mean 64 years). Approximately 85% of subjects were male, and all ingenol mebutate-treated subjects were Caucasian.

Efficacy was assessed at day 57. Complete clearance rate was defined as the proportion of subjects with no clinically visible actinic keratoses in the treatment area.

Partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of actinic keratoses lesions at baseline in the selected treatment area.

Key results are tabulated below.

Actinic keratosis of the face and scalp
  Study 1Study 2
Ingenol mebutate gel, 0.015% (n = 135)Vehicle (n = 134)Ingenol mebutate gel, 0.015% (n = 142)Vehicle (n = 136)
Overall Complete clearance on day 57 50 (37%) 3 (2%) 67 (47%) 7 (5%)
Overall Partial clearance on day 57 81 (60%) 9 (7%) 96 (68%) 11 (8%)
Complete clearance of scalp lesions (day 57) 4/26 (15%) 0/25 (0%) 9/31 (29%) 1/25 (4%)
Complete clearance of facial lesions (day 57) 46/109 (42%) 3/109 (2%) 58/111 (52%) 6/111 (5%)
  • Subjects who achieved complete clearance at day 57 in Study 1 and Study 2 entered a 12-month follow-up period.
  • Based on 108 ingenol mebutate gel-treated subjects who achieved complete clearance in Study 1 and Study 2, the recurrence rate at 12 months was 54%.
  • Recurrence was defined as the percentage of subjects with any identified actinic keratosis in the previously treated area who achieved complete clearance at day 57.

Actinic keratosis of the trunk and extremities

In two double-blind, vehicle-controlled clinical trials, 458 adult subjects with actinic keratoses on the trunk or extremities were randomized to treatment with either ingenol mebutate gel, 0.05% or vehicle gel for 2 consecutive days, followed by an 8-week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete actinic keratoses lesions within a 25 cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 447 subjects (98%) completed these studies. Study subjects ranged from 34 to 89 years of age (mean 66 years).

Approximately 62% of subjects were male, and all ingenol mebutate-treated subjects were Caucasian.

Complete and partial clearance rates were defined as in study 1.

Key results are tabulated below.

Actinic keratosis of the trunk and extremities
  Study 3Study 4
Ingenol mebutate gel, 0.05% (n = 126)Vehicle (n = 129)Ingenol mebutate gel, 0.05% (n = 100)Vehicle (n = 103)
Overall Complete clearance on day 57 35 (28%) 6 (5%) 42 (42%) 5 (5%)
Overall Partial clearance on day 57 (≥75%) 56 (44 %) 9 (7 %) 55 (55 %) 7 (7 %)
Complete clearance (CR) arm lesions (day 57) 22/84 (26 %) 4/82 (5 %) 27/59 (46 %) 3/67 (5 %)
CR hand lesions (day 57) 4/25 (16 %) 0/29 (0%) 6/28 (21 %) 0/27 (0 %)
CR chest lesions (day 57) 8/9 (89 %) 1/8 (13 %) 3/5 (60 %) 1/3 (33 %)
CR (leg/shoulder/back) 1/8 (13 %) 1/10 (10 %) 6/8 (75 %) 1/6 (17 %)
  • Subjects who achieved complete clearance at day 57 in study 4 entered a 12-month follow-up period. Based on 38 ingenol mebutate gel-treated subjects who achieved complete clearance in study 4, the recurrence rate at 12 months was 50%.
  • Recurrence was defined as the percentage of subjects with any identified actinic keratoses lesion in the previously treated area who achieved complete clearance at day 57.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of ingenol mebutate.

The effects of ingenol mebutate on fertility have not been evaluated.

Use in the elderly

  • Of 1165 subjects treated with ingenol mebutate gel in clinical trials, 56% were 65 years and older and 21% were 75 years and older.
  • No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Further information

Return to page on Ingenol mebutate gel

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References:

  • Anderson L, Melgaard A, Xu Z. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled, phase 3 study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head locations (Study PEP005-028). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2180.
  • Berman B, Melgaard A, Larsson T. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled phase 3 study of the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (face or scalp) (Study PEP005-016). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2179.
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  • Anderson L, Schmieder GJ, Werschler WP, Tschen EH, Ling MR, Stough DB, Katsamas J. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009 Jun; 60(6):934-43.
  • Ko CJ. Actinic keratosis: facts and controversies. Clin Dermatol 2010;28(3):249-53.
  • Stockfleth E, Kerl H. Guidelines for the management of actinic keratoses. Eur J Dermatol 2006;16(6):599-606.

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The New Zealand approved datasheet is the official source of information for this prescription medicine, including approved uses and risk information. Check the New Zealand datasheet on the Medsafe website.