AU2014100280A4 - A method of treating skin lesions - Google Patents

Abstract

The invention relates to a method of treating skin lesions using ingenol-3-mebutate.

Description

1 AUSTRALIA Patents Act 1990 INNOVATION PATENT SPECIFICATION FOR THE INVENTION ENTITLED: A method of treating skin lesions Applicant: Leo Pharma A/S The invention is described in the following statement: 2 A method of treating skin lesions Field of the invention The invention relates to a method of treating skin lesions using ingenol-3-mebutate. Background of the invention 5 Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art. Existing topical treatments for various dermatological conditions comprise different dosage 0 regimens. Many of these dosage regimens extend for weeks or months and require treatment of discrete areas of affected skin. The compound ingenol-3-angelate (also known as ingenol mebutate, PEP005, or (1 aR,2S,5R,5aS,6S,8aS,9R,1 OaR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-1 1 -oxo 1 a,2,5,5a,6,9,1 0,1 Oa-octahydro-1 H-2,8a-methanocyclopenta[a]cyclpropa[e][1 O]annulen-6-yl (2Z)-2 5 methylbut-2-enoate; Sayed, M.D. et.al.; Experienta, (1980), 36, 1206-1207) can be isolated from various Euphorbia species. Specifically, ingenol mebutate can be isolated from Euphorbia peplus (Hohmann, J. et al., Planta Med., (2000), 66, 291-2940) and Euphorbia drummondii by extraction followed by chromatography as described in US 7,449,492. Pharmaceutical formulation of the compound ingenol mebutate has been described in .0 W02007/068963, which discloses various gel formulations of the compound. PICATO @ is an aqueous gel formulation comprising ingenol-3-angelate at a strength of 0.015% or 0.05%. PICATO @ was granted regulatory approval in 2012 by the FDA for the topical treatment of actinic keratosis with a treatment regimen of two or three consecutive days, depending on the location of the actinic keratosis lesions. For lesions located on the head (for example, the face or 25 scalp), the approved dose is 0.015% ingenol mebutate applied for 3 consecutive days. For lesions located on a 'non-head' region (for example, the forearm or back), the approved dose is 0.05% ingenol mebutate applied for 2 consecutive days (see also Lebwohl et al,. 2012, New England Journal of Medicine, 366: 1010-9). The application of PICATO @ for the treatment of dermatological lesions such as actinic 30 keratosis and other lesions resulting from photo-damaged skin, has previously been limited to discrete regions of the skin containing a few lesions. For example, the region of skin indicated for treatment is generally no larger than 25 cm2 and contains typically no more than 8 lesions. However, dermal conditions such as actinic keratosis and other lesions resulting from photodamaged skin, are often present in larger areas of skin. Accordingly, there is a need to provide a treatment for larger regions of 35 skin containing multiple lesions.

3 Summary of the invention In one aspect, the present invention provides a method for treating or reducing the progression of cancerous or pre-cancerous lesions on a region of skin requiring treatment, the method including: 5 - administration of an effective amount of ingenol mebutate to the region requiring treatment - wherein the region requiring treatment is a contiguous area of more than 25 cm2 - wherein the effective amount of ingenol mebutate is provided as a gel formulation; and - wherein the concentration of ingenol mebutate in the gel is greater than about 0.015% and less than about 0.05%. 0 In a further aspect, the invention provides a composition of ingenol mebutate wherein the composition is in the form of a gel and wherein the concentration of ingenol mebutate is between about 0.015% and 0.05% by weight. Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of 5 example and with reference to the accompanying drawings. Brief description of the drawings Figure 1. Design of study Part IA. Part 1A of the study involved the treatment of actinic keratosis lesions on the face only for 3 days for the purposes of determining the Maximum tolerated dose (MDT). Patients were treated with 0.005%, 0.008%, 0.012%, 0.018%, 0.027% or 0.04% ingenol .0 mebutate gel as follows: 3 patients (0.005% gel), 12 patients (0.008% gel), 10 patients (0.012% gel), 12 patients (0.018% gel), 12 patients (0.027% gel) and 10 patients (0.04% gel). Figure 2. Design of study Part I B. Part 1 B of the study involved the treatment of actinic keratosis lesions on the face only for 2 days. 11 and 12 subjects received 0.04% and 0.06% ingenol mebutate gel, respectively, on the face only for 2 consecutive days of treatment. 25 Detailed description of the embodiments As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps. Ingenol mebutate is currently approved from the treatment of actinic keratoses wherein the 30 size of the lesions are 25 cm2 or smaller. The dosage forms approved are 0.015% for treatment of lesions on the face and scalp and 0.05% for the treatment of lesions on the extremities and trunk. The present inventors have found however, that the optimal dose for treatment of lesion is between 0.015% and 0.05%. Further, the inventors have found that concentrations of ingenol mebutate within 4 this range are suitable for treating a larger number of pre-cancerous and cancerous lesions, wherein the lesions are present on an area of skin that is larger than 25 cm2 Accordingly, the present invention provides a method for treating or reducing the progression of cancerous or pre-cancerous lesions in a region of skin requiring treatment, the method including: 5 - administration of an effective amount of ingenol mebutate to the region requiring treatment - wherein the region requiring treatment is a contiguous area of more than 25 cm2 - wherein the effective amount of ingenol mebutate is provided as a gel formulation, - wherein the concentration of ingenol mebutate in the gel is greater than about 0.015% and less than about 0.05%. 0 The invention also provides the use of ingenol mebutate in the manufacture of a medicament for the treatment or reduction of cancerous or pre-cancerous lesions in a region of skin requiring treatment, wherein the medicament is applied to a contiguous region of more than 25 cm2, wherein the effective amount of ingenol mebutate is provided as a gel formulation, wherein the concentration of ingenol mebutate in the gel is greater than about 0.015% and less than about 0.05%. 5 In further embodiments the area to be treated is larger than 25 cm2, for example, a contiguous area of at least 30, 40, 60, 80, 100, 150, 200, or 250 cm2. It will also be understood that the size of the treatment area can range from at least 25cm2, to at least 500cm2 including any size which is incorporated by the above range. It is common for pre-cancerous and cancerous skin lesions caused by sun-exposure to be .0 found on areas of the body which are greater than 25 cm2 . The successful treatment of areas greater than 25 cm2 have hitherto been unreported. Accordingly, in a further embodiment, the present invention provides a method for treating or reducing the progression of cancerous or pre-cancerous lesions in a region of skin requiring treatment, the method including: - administration of an effective amount of ingenol mebutate to the region requiring treatment 25 - wherein the region requiring treatment is a contiguous area of more than 100 cm2, and - wherein the effective amount of ingenol mebutate is provided as a gel formulation, wherein the concentration of ingenol mebutate is greater than about 0.015% and less than about 0.05%. In further embodiments the area to be treated is larger than 100 cm2, for example, a contiguous area of at least 150, 200, or 250 cm2. It will also be understood that the size of the 30 treatment area can range from at least 25cm2, to at least 500cm2 including any size which is incorporated by the above range. In a further embodiment, the region to be treated contains at least 5 clinically typical, visible and discrete lesions in an area larger than 25 cm 2. The region to be treated can have between at least 5 and 20 or more lesions, or any number of lesions within this range. For example, an individual may 35 have 10, 11, 13 or 18 lesions in a contiguous area larger than 25 cm2 5 The region to be treated can be any part of the body where exposure to the sun or UV radiation can lead to the development of cancerous or pre-cancerous lesions. In some examples, the region to be treated can be the face or scalp. Alternatively, the lesions can be on a non-head location of the body, for example, on the back or extremities (legs and feet or arms and hands). 5 It will also be understood that an individual may have more than one area of skin requiring treatment. For example, an individual may have two, three, four, ten or more discrete regions, which require treatment, wherein each region can be of a size ranging from 25 cm2 to more than 250 cm2 The different regions requiring treatment can be on different parts of the body. For example one or more regions requiring treatment can be on the face, scalp, chest, back or extremities. 0 The ingenol mebutate applied to the region to be treated is typically provided in a gel wherein the concentration of ingenol mebutate in the gel is between about 0.015% and 0.05%. It will be understood that the dosage of ingenol mebutate required for treatment will vary depending on the area of the body to be treated. For example, typically, lesions on the face will be treated with a lower dose than required for treatment of the extremities. For example, the concentration of ingenol 5 mebutate can be between about 0.016% and 0.02%, between about 0.018% and 0.022%, between about 0.02% and 0.024%, between about 0.022% and 0.026%, between about 0.024% and 0.028%, between about 0.026% and 0.030%, between about 0.028 and 0.032%, between about 0.030% and 0.034%, between about 0.032% and 0.036%, between about 0.034% and 0.038%, between about 0.036% and 0.040%, between about 0.038% and 0.042%, between about 0.040% and 0.044%, .0 between about 0.042% and 0.046%, between about 0.044% and 0.048% or between about 0.046% and 0.050%, or any concentration within the above listed ranged. In some embodiments, the concentration of ingenol mebutate if about 0.018%, 0.027%, 0.04% or about 0.05%. In a particularly preferred embodiment, the concentration of ingenol mebutate used is about 0.018%. In another embodiment, the concentration of ingenol mebutate used is about 0.027%. 25 Typically, the ingenol mebutate is applied to the area requiring treatment over a period of 2, 3, 4 or 5 consecutive days. In particularly preferred embodiments, the treatment period does not exceed 3 days. In some examples, the ingenol mebutate is applied to the area requiring treatment once or twice a day. In a preferred embodiment, the ingenol mebutate is applied once a day. In a further embodiment, the area requiring treatment may not have previously received 30 treatment, for example, cryotherapy, for treating or reducing the progression of pre-cancerous or cancerous lesions. Accordingly, in one embodiment, the treatment with ingenol mebutate represents the first-line treatment of the area requiring treatment. The present invention also includes embodiments wherein the area requiring treatment is treated with cryotherapy after the step of administration of the effective amount of ingenol mebutate. 35 Previous dosage regimens for treating actinic keratoses on the chest have assumed that the same dosage regimen should be applied to both chest and forearm (with both regions falling within the definition of "trunk and extremities"). However, the findings of the present invention indicate that a 6 significantly lower dosage of ingenol mebutate can successfully be employed for the treatment of such lesions on the chest. Accordingly, in a further aspect, the present invention provides a method for treating or reducing the progression of cancerous or pre-cancerous lesions on a region of skin requiring 5 treatment, the method including: - administration of an effective amount of ingenol mebutate to the region requiring treatment - wherein the effective amount of ingenol mebutate is provided as a gel formulation wherein the concentration of ingenol mebutate is greater than about 0.015% and less than about 0.05%; and 0 - wherein the region requiring treatment is a contiguous area of about 250 cm2 on the face, balding scalp or chest. It further examples, the individual may have more than one area of skin requiring treatment on the face, balding scalp or chest. For example, an individual may have two, three, four, ten or more discrete regions, which require treatment, wherein each region can be about 250 cm2 . The different 5 regions requiring treatment can be on different parts of the body. For example one or more regions requiring treatment can be on the face, and further regions can be on the chest or balding scalp. In further embodiments, the region of the face, scalp and chest to be treated is a contiguous area of at least 50, 100, 150, 200, or 250 cm2. In yet further embodiments, the region to be treated is full balding scalp or full face. It will be understood that the size of the treatment area can range from .0 at least 25 cm2 to at least 150 cm2, or 50 cm2 to 200 cm2 or 100 cm2 to 250 cm2 or 100 cm2 to 500cm2 including any size which is incorporated by the above range. In a further embodiment, the region on the face, balding scalp or chest may contain 5 or more discrete lesions in an area of about 250cm2 or greater. The region to be treated can have between at least 5 and 20 or more lesions, or any number of lesions within this range. For example, 25 an individual may have 10, 11, 13 or 18 lesions in a contiguous area of about 250 cm 2 or larger. The outcomes of the above discussed methods of treatment are assessed by measurement of the degree of clearance of the pre-cancerous or cancerous lesions. In some embodiments, the treatment results in the complete clearance of lesions. In examples where the lesions are actinic keratoses, the outcome may be measured by observing complete clearance of actinic keratosis 30 lesions at week 8 after commencement of treatment. Alternatively, the assessment of the treatment may be conducted by measuring a reduction in the number of lesions from baseline at week 8 after commencement of treatment. In certain embodiments, the reduction in the number of lesions in the area requiring treatment is at least a 50% reduction. In some embodiments, the reduction is one of at least 60%, 35 70%, 80%, 90%, 95% or 100% reduction in the number of lesions in the area requiring treatment.

7 In a further aspect, the invention provides a composition of ingenol mebutate wherein the composition is in the form of a gel and wherein the concentration of ingenol mebutate is 180 pg/1 g (0.018%) or 270 pg/1 g (0.027%). Conditions to be treated 5 The methods and uses of the present invention may be useful for the topical treatment of dermal diseases or conditions including actinic keratosis, seborrheic keratosis, skin cancer, warts, keloids, scars, photoaged or photodamaged skin, and acne. In particular, the use of ingenol mebutate according to the present invention, is particularly useful for the topical treatment of actinic keratosis. In a further embodiment, the methods may, for instance, be useful for the topical treatment of 0 hyperkeratotic actinic keratosis. The uses and methods may be used for the topical treatment of skin cancers such as non melanoma skin cancer, malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma or basal cell carcinoma (including superficial basal cell carcinoma and nodular basal cell carcinoma). The uses and methods may be used for the topical treatment of warts, e.g. human papilloma 5 virus (HPV) infections on the skin, genitals and mouth. The uses and methods may be used for the topical treatment of photodamaged skin such as fine lines, wrinkles and UV-ageing. UV-ageing is often manifested by an increase in the epidermal thickness or epidermal atrophy, most notably by solar elastosis, the accumulation of elastin containing material just below the dermal-epidermal junction. Collagen and elastic fibres become fragmented and .0 disorganised. At a cosmetic level this can be observed as a reddening and/or thickening of the skin resulting in a leathery appearance, skin fragility and irregular pigmentation, loss of tone and elasticity, as well as wrinkling, dryness, sunspots and deep furrow formation. The uses and methods may be useful for reducing or minimizing scar tissue or improving cosmesis or functional outcome in a wound. For instance, the uses and methods may be useful for 25 improving functional outcome in a wound which is cutaneous, chronic or diabetes associated, e.g. when the wound includes cuts and lacerations, surgical incisions, punctures, graces, scratches, compression wounds, abrasions, friction wounds, chronic wounds, ulcers, thermal effect wounds, chemical wounds, wounds resulting from pathogenic infections, skin graft/transplant, immune response conditions, oral wounds, stomach or intestinal wounds, damaged cartilage or bone, 30 amputation sides and corneal lesions. Therefore, in some embodiments, the uses and methods are cosmetic. Dosage forms The dosage forms of ingenol mebutate used in accordance with the methods and uses of the present invention are typically provided as a gel composition. The gel compositions may contain 35 ingenol mebutate at a final concentration of between about 0.015% and about 0.05%. A gel formulation has been described previously in W02007/68963 and comprises ingenol mebutate, 8 isopropyl alcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water. In one example, the invention provides a composition of ingenol mebutate as follows: Table 1: 0.018% ingenol mebutate gel formulation (1 g) Component Amount Description Ingenol mebutate 180 pg Active ingredient Isopropyl alcohol 300 pg Solvent Hydroxyethylcellulose 15 mg Gelling agent Benzyl alcohol 9 mg Solvent Citric acid 5.6 mg pH controlling agent monohydrate Sodium citrate 1.4 mg pH controlling agent Water, purified up to 1 g Base 5 In a further example, the invention provides the following gel formulation of ingenol mebutate. Table 2: 0.027% ingenol mebutate gel formulation (1 g) Component Amount Description Ingenol mebutate 270 pg Active ingredient Isopropyl alcohol 300 pg Solvent Hydroxyethylcellulose 15 mg Gelling agent 9 Benzyl alcohol 9 mg Solvent Citric acid 5.6 mg pH controlling agent monohydrate Sodium citrate 1.4 mg pH controlling agent Water, purified up to 1 g Base The gel compositions are typically packaged in hermetically sealed containers, e.g. a unit dose tube. In some embodiments, the unit dose tube would typically contain about 0.67 g of gel having 0.018% or 0.027% ingenol mebutate. Preferably, one unit dose tube (tube with screw cap or individual 5 packets) may be used for one treatment area. Due to a residual amount of medication in the tubes the actual amount applied for the patient is estimated to be 0.45 g medication per tube and two tubes are provided for each day of treatment. Thus the invention provides 0.9 g medication at 0.018% or 0.027% ingenol mebutate/250 cm2 skin per day of treatment. This amounts to an effective dose of 162 pg or 243 pg of ingenol mebutate per day 0 to an area of about 250 cm2 It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Examples 15 Example I Part 1 of the study involved the treatment of actinic keratosis (AK) lesions on the face only. In Part 1A, the Maximum tolerated dose (MTD) was determined for once daily application of ingenol mebutate for 3 consecutive days. Subjects were then recruited to Part 1 B of the study (once daily application for 2 consecutive days with dose escalation). 20 Maximum tolerated dose (MTD) was defined as the highest dose at which less than 4 subjects out of 12 experience dose limiting toxicity (DLT). Dose limiting toxicity was pre-defined grades of LSRs. Local skin reactions (LSRs) sometimes occur in the treated area. Often LSRs are quantified by a scale evaluating the following types of skin reactions: erythema, flaking/scaling, crusting, swelling, 10 vasiculation/postulation, and erosion/ulceration which are categorized into categories 0-4 depending on the severity of the reactions. DLT was defined as one or more of the following three LSRs: Crusting Grade 54, erosion/ulceration Grade 4, vesiculation/postulation Grade 4 or two or 5 more of the following five LSRs: Erythema Grade 4, crusting Grade 3, Swelling Grade 4, Erosion/Ulceration Grade 3, Vesiculation/postulation Grade 3. In Part 2 of the study, the efficacy of two dose levels below the MTD was tested in four treatment groups with 62 subjects in each (0.018% or 0.027% ingenol mebutate gel; 2 or 3 consecutive days of application on face, chest or scalp). Two vehicle arms (2 day or 3 day treatment) 0 were included 31 patients in each vehicle arm. Part 2 of the trial was evaluated with regard to efficacy in the different doses after once daily treatment for 2 or 3 consecutive days compared to vehicle gel. Also the safety of ingenol mebutate gel in different doses after once daily treatment for 2 or 3 consecutive days compared to vehicle gel was evaluated. 5 The outcome of the treated is measured as either: (a) complete clearance of AKs at week 8; or (b) reduction in AK count from baseline at week 8. Also the treatment provides the following safety measures: (a) adverse events and serious adverse events; and .0 (b) LSRs Subjects who qualified for the trial had 5 to 20 clinically typical, visible and discrete actinic keratosis on the face (Part 1A and Part1 B), or face, balding scalp or within a contiguous area of approximately 250 cm2 on the chest (Part 2). In Part 1A the objective was to find the MTD for ingenol mebutate gel after once daily 25 treatment for 3 consecutive days. Whereas the trial was designed for the possibility of up to seven different doses of ingenol mebutate gel could be invested in cohorts of 3 to 12 subjects, the actual trial only investigated 6 doses. The number of subjects in each cohort depended on the number of observed DLTs. However, the MTD was always confirmed in a cohort of 12 subjects. The doses were administered in an escalating manner following review of safety and tolerability data performed by the 30 dose escalation committee (see Figure 1). The doses applied ranged from 0.005% to 0.06%. A total of 59 patients participated in Part 1A of the study. For Part 1A, evaluation of the safety and tolerability data was performed after visit 6/day 8. The outcomes of Part 1A indicate that the preferred concentration of ingenol mebutate to be administered to patients is about 0.018% and about 0.027%.

11 In Part 1 B the objective was to find the MTD for ingenol mebutate gel after once daily treatment for 2 consecutive days. The starting dose for Part 1 B was the dose level above the MTD found in Part 1A. In this particular trial it was 0.04% and 0.06%. The doses were administered in an escalating manner following review of safety and tolerability data performed by the dose escalation 5 committee. This was evaluated after visit 5, day 8. Part 2 was a multicenter, randomised, double-blind, parallel group and vehicle-controlled trial. In Part 2, the objective was to evaluate efficacy of ingenol mebutate gel in two different doses, after once daily treatment for 2 or 3 consecutive days, respectively, compared to vehicle gel. The dose levels investigated correspond to the dose levelsjust below the identified MTD levels in Parts 1A and 0 1B. In the present trial, the doses were 0.027% and 0.018%. In Part 2 the treatment area was full face, full balding scalp or a contiguous area of approximately 250cm2 on the chest. Subjects were allocated to ingenol mebutate gel or vehicle gel in a randomised manner (4 active treatment arms with 62 subjects each and 2 vehicle arms with 31 subjects each). Randomisation was stratified by located (face/chest or scalp) of the treatment area. The 5 enrolment was controlled so that approximately 20% of the subjects were treated on the scalp and approximately 80% of the subjects were treated on the face or chest. The subjects were followed for 8 weeks after first application. Complete clearance was assessed at week 8. Exclusion criteria were: incompletely healed wound, basal cell carcinoma or squamous cell .0 carcinoma within 5 cm of treatment area, or prior treatment with ingenol mebutate gel on the treatment area, or atypical clinical appearance on the lesions such as hypertrophic, hyperkeratotic or cutaneous hors, and/or recalcitrant disease such as non-responding to cryotherapy on two previous occasions. The patients were scheduled for 7 visits: Visit 1: within 35 days prior to day 1 25 Visit 2: day 1 application of trial medication Visit 3: application of trial medication/LSR assessment Visit 4: application of trial medication (only part 1 a)/LSR assessment Visit 5: day 4 in part 1 a and day 8 ± 1 day in part 1 b. LSR assessment. LSRs were evaluated at all visits following the first application of trial medication. All trial 30 medication are applied during a patient visit in Part 1. Efficacy analyses were based on the full analysis set, which were defined as all randomised subjects. Per protocol analysis set are were used as an efficacy subset and were defined as subjects in the full analysis set who completed the study without major protocol deviations. Analysis based on the full analysis set was considered the primary analysis, whereas the per protocol analysis serve a 12 supportive purpose. Safety analyses were based on the safety analysis set, which is defined as all subjects who received at least one application of trial medication and have safety information available post treatment. Randomisation was stratified by anatomical location (face/chest or scalp) in order to obtain at 5 least subjects per site per treatment arm, trial sites yielding fewer than 20 subjects will be combined together into "analysis sites" in order of geographical proximity. The exact composition of these analysis sites was determined and documented prior to breaking the trial blind. Complete clearance of AKs at week 8 was analysed by log binomial regression with factors: treatment group, anatomical location (fact/chest or scalp) and analysis site. The number of baseline 0 lesions is included as a continuous variable. The rate ratios of each active group and the corresponding vehicle group is presented together with their 95% confidence intervals. To account for multiple testing, the four tests were performed using a closed test procedure. The pre-defined hierarchical order of testing was determined as follows: the highest dose within the 2 day treatment regimen was tested first and provided a significant result is observed, the lowest dose 5 within the 2 day treatment regimen was tested, then the highest dose within the 3 day treatment regimen was tested and finally the lowest dose within the 3 day treatment regimen was tested thus ensuring that the overall significance level did not exceed 5%. As a supportive analysis, a Cochran-Mantel-Haenszel test adjusting for analysis site was performed. A last observation carried forward approach was used to account for missing values. A .0 sensitivity analysis was conducted, where subjects with no week 8 AK count were considered as not having complete clearance, if they had received active treatment and were considered as having complete clearance, if they had received vehicle. To account for multiple testing among the secondary endpoints, a hierarchical order of testing is determined as follows: first the four comparisons in terms of reduction in AK count from baseline to week 8 were tested using the same order as described for 25 the primary endpoint. Provided the tests were significant, the procedure was repeated for the second endpoint, partial clearance. Reduction in AK count from baseline to week 8 was tabulated (mean, 95% confidence interval, median, min, max) by treatment group and analysed by negative binomial regression on the number of lesions at week 8 including the log baseline AK count as offset and with factors: treatment group, 30 anatomical location (face/chest, scalp) and analysis site. The rate ratios of each active group and the corresponding vehicle group were presented together with their 95% confidence intervals. Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in number of AKs was analysed in the same way as the primary endpoint. Subgroup analyses by anatomical location.

13 The number of subjects with complete clearance and partial clearance as well as a summary of the reduction in AK count from baseline to week 8 is tabulated by anatomical location (face/chest/scalp). No formal hypotheses are tested in these subgroup analyses.

Claims (5)

1. A method for treating or reducing the progression of cancerous or pre-cancerous lesions on a region of skin requiring treatment, the method including: 5 - administration of an effective amount of a topical formulation of ingenol mebutate to the region requiring treatment - wherein the region requiring treatment is a contiguous area of more than 25 cm2, and - wherein the effective amount of ingenol mebutate is provided as a gel formulation having a concentration of ingenol mebutate which is greater than about 0.015% and less 0 than about 0.05%.

2. The method according to claim 1 wherein the lesion is selected from the group consisting of: actinic keratosis, nevoid basal cell carcinoma and superficial basal cell carcinoma, seborrheic keratosis, skin cancer, warts, keloids, scars, photoaged or photodamaged skin, and acne. 5

3. The method according to claim 1 or claim 2 wherein the region requiring treatment is a contiguous area on the face, balding scalp or chest of about 250 cm2 or greater.

4. The method according to any one of the previous claims wherein the region of skin requiring treatment has not previously been treated with cryotherapy.

5. A composition of ingenol mebutate wherein the composition is in the form of a gel and .0 wherein the concentration of ingenol mebutate is between about 0.015% and about 0.05% by weight.