US20150119433A1 - Method of treating actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) - Google Patents
Method of treating actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) Download PDFInfo
- Publication number
- US20150119433A1 US20150119433A1 US14/524,731 US201414524731A US2015119433A1 US 20150119433 A1 US20150119433 A1 US 20150119433A1 US 201414524731 A US201414524731 A US 201414524731A US 2015119433 A1 US2015119433 A1 US 2015119433A1
- Authority
- US
- United States
- Prior art keywords
- ingenol
- diethylisoxazole
- carboxylate
- actinic keratosis
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
Definitions
- the invention relates to the topical treatment of actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate).
- the active compound, ingenol 3-(3,5-diethylisoxazole-4-carboxylate), of the present invention has previously been described in PCT/DK2011/000154.
- the compound has previously been studied with respect to safety and tolerability for field therapy in 25 cm 2 on 4 separate areas on the forearm in concentrations of 0.025%, 0.05% and 0.075% in a gel formulation.
- Picato® which is launched in many countries around the world for treatment of actinic keratosis on the face or balding scalp has a dosage regimen of two or three days depending on the location of the actinic keratosis. According to the FDA label for Picato®, the size of the treatment area is limited to about 25 cm 2 (2 inches ⁇ 2 inches).
- the present invention provides a topical treatment regimen for actinic keratosis (AK) which is of short duration and applicable to a large skin area, a full balding scalp.
- AK actinic keratosis
- the treatment is simple by the two day regimen.
- the treatment is directed against treating nonhyperkeratotic actinic keratosis.
- the treatment is optimized towards acceptable side-effects in terms of measured local skin reactions (LSR).
- the invention provides a method of treating a subject diagnosed with actinic keratosis on the balding scalp, said method comprising applying topically an effective amount of the active compound, ingenol 3-(3,5-diethylisoxazole-4-carboxylate), to a treatment area for two days to achieve reduction in the number of the actinic keratosis in the treated area.
- the present invention simplifies prior and existing treatments by a simple two day regimen independent of the location of the actinic keratosis.
- the present invention describes treatment of actinic keratosis on the full balding scalp.
- the lesions are not of atypical clinical appearance such as for example hypertrophic, hyperkeratotic or cutaneous horns and/or recalcitrant diseases, such as non-responding to cryotherapy on two previous occasions.
- LSRs local skin reactions
- erythema flaking/scaling, crusting, swelling, vasiculation/postulation, and erosion/ulceration which are categorized into categories 0-4 depending on the severity of the reactions.
- DLT Dose Limiting Toxicity
- DLT Dose Limiting toxicity
- MTD Maximum tolerated dose
- Part 1 is a dose escalation study conducted with a once daily application of trial medication for two consecutive days and continue until the MTD has been identified. Dose escalation will only proceed if the safety and tolerability data of the subject up to day 8 is reviewed and considered satisfactory.
- the treatment consists of once daily treatment for 2 consecutive days. The starting dose is 0.025% and the doses are administered in an escalating manner following review of safety and tolerability. Up to 5 different doses may be investigated in cohorts of 1 subject. The number of subjects in each cohort will depend on the number of observed DLTs. However, the MTD will always be confirmed in a cohort of 12 subjects.
- Part 2 is a study of the efficacy of the MTD level identified in part 1 and the level below the identified level. Lower levels can however be chosen instead for Part 2.
- the outcome for Part 2 is efficacy in clearance of the AK.
- the trial medication applied is preferably a gel.
- the gel formulation comprises; isopropyl alcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water and active compound in various suitable concentrations.
- the active compound is ingenol 3-(3,5-diethylisoxazole-4-carboxylate).
- the present invention relates to the treatment of actinic keratosis lesions on full balding scalp by a once daily, two day treatment. More specifically, the invention relates to the treatment of actinic keratosis lesions in an area of approximately 250 cm 2 on the full balding scalp in a two day treatment. In case the balding scalp contains hairy areas, which reduces the treated area, the amount of compound applied should be reduced proportionately if feasible.
- the two day treatment is two consecutive days.
- the present invention provides the method according to the above, wherein the effective amount of active compound is applied in a gel or other topical formulation from a dosage strength formulation of active compound of between about 0.01% and about 0.1%
- the present invention provides the active compound formulated in an effective amount in a gel formulation comprising ispropylalcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water.
- the present invention provides application of active compound in a concentration of about 0.018%, about 0.025%, about 0.037%, about 0.050%, about 0.075% or about 0.1%.
- the present invention provides topical application of the active compound in a concentration of between about 0.037% and about 0.05%, and more preferably about 0.037% and about 0.05%.
- the present invention provides the amount of active compound applied is between about 0.162 mg active compound/per day/250 cm 2 treated area to about 0.9 mg active compound/per day/250 cm 2 treated area, and more preferably about 0.162 mg active compound/per day/250 cm2 treated area and about 0.9 mg active compound/per day/250 cm2 treated area.
- the present invention provides a method of treating a subject diagnosed with actinic keratosis, said method comprising applying topically an effective amount of active compound to a treatment area for two days to achieve a reduction in the number of actinic keratosis lesions in the treated area.
- Subjects who qualify for Part 1 of the trial must have 5 to 20 clinically typical, visible and discrete actinic keratosis on the balding scalp.
- the balding scalp must be between 125 cm 2 and 250 cm 2 .
- the subjects must have 5-20 clinically typical, visible and discrete actinic keratosis on the balding scalp.
- the balding scalp must be of a size of between 25 cm 2 and 250 cm 2 .
- Trial medication will be applied to full balding scalp once daily for two consecutive days until the maximum tolerated dose has been reached for each formulation.
- Up to nine different doses of active compound in gel or a cream may be investigated in cohorts of 3 to 12 subjects.
- Pre-defined grades of Local Skin Responses (LSRs) will constitute dose limiting toxicity (DLT).
- the maximum tolerated dose is defined as the highest dose level at which less than 4 out of 12 subjects experience a Dose limiting toxicity.
- the doses will be administered in an escalating manner following review of safety and tolerability data performed by the dose escalation committee. Evaluation of the safety and tolerability data will be performed after Visit 5/day 8. Then subjects will be followed for 8 weeks after first application of investigational product.
- Part 2 of the trial may include a total of 124 subjects: 62 subjects in each of the 2 active treatment arms (Part 1 identified dose and the dose below) and additionally 31 subjects in a vehicle arm.
- Exclusion criteria is incompletely healed wound, basal cell carcinoma or squamous cell carcinoma within a 5 cm of treatment area, or prior treatment with Picato® (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.
- other skin conditions, cosmetic procedures or other disease or medication which could interfere with the evaluation of the trial medication or the assessments of the treated area are exclusion criteria, as is other disease or medical conditions which make the subject unsuitable to participate in the trial.
- the patients are scheduled for 6 visits:
- Visit 1 within 35 days prior to day 1
- Visit 2 day 1 (application of trial medication)
- Visit 3 day 2 (application of trial medication)
- LSRs are evaluated at all visits following visit 1.
- An Evaluable Subjects analysis set will be defined as all subjects who receive at least one dose, and have LSRs recorded at all visits up to and including day 8 or have experienced a DLT at one or more visits up to and including day 8.
- Safety analyses will be based on the safety analysis set, which is defined as all subjects who receive at least one application of trial medication and have safety information available post treatment.
- Visit 1 within 21 days prior to day 1
- Visit 2 day 1 (application of trial medication)
- Visit 3 day 2 (application of trial medication)
- LSRs are evaluated at all visits following visit 1. AK lesion counts are performed on visit 6 and 7.
- Efficacy analyses will be based on the full analysis set, which will be defined as all randomized subjects.
- Per protocol analysis set will be used as an efficacy subset and will be defined as subjects in the full analysis set who complete the study without major protocol deviations.
- Safety analyses will be based on the safety analysis set, which is defined as all subjects who receive at least one application of trial medication and have safety information available post treatment.
- the ratio of number of lesions at week 8 relative to baseline will be tabulated by treatment group and analyzed using a negative binomial regression on actinic keratosis count at week 8 with the log baseline value as an offset variable and treatment group and analysis site as factor.
- the rate ratios and the corresponding 95% confident intervals will be estimated from this model comparing the active groups pairwise.
- Complete clearance of AKs at week 8 will be analyzed by log binomial regression with factors: Treatment group and analysis site. The number of baseline lesions will be included as a continuous variable. The rate ratios of pairwise treatment groups will be presented together with their 95% confidence intervals. Partial clearance, defined as 75% or greater reduction in AK count will be analyzed in the same way as complete clearance.
- LSRs The incidence and grade of LSRs will be summarized by treatment arm overall at each visit.
- Local skin response grades will be summarized by frequency counts and descriptive statistics by treatment arm for each of the six individual LSRs: erythema, flaking/scaling, crusting, swelling, vesiculation/postulation, and erosion/ulceration.
- a composite score will be obtained by summing the six individual LSR scores at each visit.
- the composite score and change from baseline will be summarized by treatment arm at each visit using descriptive statistics.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to the topical treatment of actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate).
Description
- The invention relates to the topical treatment of actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate).
- This application for U.S. patent claims priority to EP patent application No. 13190223.1, filed 25 Oct. 2013, the contents of which is incorporated herein by reference in its entirety, EP patent application No. 14161730.8, filed 26 Mar. 2014, the contents of which is incorporated herein by reference in its entirety, and EP patent application No. 14165659.5, filed 23 Apr. 2014, the contents of which is incorporated herein by reference in its entirety.
- The active compound, ingenol 3-(3,5-diethylisoxazole-4-carboxylate), of the present invention has previously been described in PCT/DK2011/000154. The compound has previously been studied with respect to safety and tolerability for field therapy in 25 cm2 on 4 separate areas on the forearm in concentrations of 0.025%, 0.05% and 0.075% in a gel formulation.
- Existing topical treatments for actinic keratosis on the balding scalp comprises different dosage regimens. All of them extend over weeks and/or months. Picato® which is launched in many countries around the world for treatment of actinic keratosis on the face or balding scalp has a dosage regimen of two or three days depending on the location of the actinic keratosis. According to the FDA label for Picato®, the size of the treatment area is limited to about 25 cm2 (2 inches×2 inches).
- The present invention provides a topical treatment regimen for actinic keratosis (AK) which is of short duration and applicable to a large skin area, a full balding scalp. The treatment is simple by the two day regimen. The treatment is directed against treating nonhyperkeratotic actinic keratosis. The treatment is optimized towards acceptable side-effects in terms of measured local skin reactions (LSR).
- The invention provides a method of treating a subject diagnosed with actinic keratosis on the balding scalp, said method comprising applying topically an effective amount of the active compound, ingenol 3-(3,5-diethylisoxazole-4-carboxylate), to a treatment area for two days to achieve reduction in the number of the actinic keratosis in the treated area.
- From Picato® and other topical agents used in the treatment of actinic keratosis, it is well known that differences in treatment efficacy exists between different anatomical regions. Regions like scalp, trunk (except chest) and extremities are more difficult to treat than the face. From the Picato® studies, it has been shown that local skin reactions after a given dose are milder on difficult to treat anatomical regions than on anatomical regions more easily treated with the compound. For these reasons the present invention has discovered a novel treatment of the balding scalp only.
- The present invention simplifies prior and existing treatments by a simple two day regimen independent of the location of the actinic keratosis.
- The present invention describes treatment of actinic keratosis on the full balding scalp.
- The lesions are not of atypical clinical appearance such as for example hypertrophic, hyperkeratotic or cutaneous horns and/or recalcitrant diseases, such as non-responding to cryotherapy on two previous occasions.
- Quite remarkably, local skin reactions (LSRs) occurs only sometimes in the treated area. Often LSRs are quantified by a scale evaluating the following types of skin reactions: erythema, flaking/scaling, crusting, swelling, vasiculation/postulation, and erosion/ulceration which are categorized into categories 0-4 depending on the severity of the reactions.
- In the trial pre-defined grades of LSRs will constitute Dose Limiting Toxicity (DLT). The level of skin reactivity constituting DLT does not reflect safety concerns but represent what dermatologists consider limits for peak levels of acceptable visible skin reactions.
- Dose Limiting toxicity (DLT) is defined as:
-
- Erosion/ulceration Grade 4 on the LSR scale
- other clinically relevant signs or symptoms observed, which the Investigator judges to be counted as a DLT
- Maximum tolerated dose (MTD) is declared as the highest dose level at which less than 4 subjects out of 12 experience a DLT.
- The study is designed in two parts:
- Part 1 is a dose escalation study conducted with a once daily application of trial medication for two consecutive days and continue until the MTD has been identified. Dose escalation will only proceed if the safety and tolerability data of the subject up to day 8 is reviewed and considered satisfactory. The treatment consists of once daily treatment for 2 consecutive days. The starting dose is 0.025% and the doses are administered in an escalating manner following review of safety and tolerability. Up to 5 different doses may be investigated in cohorts of 1 subject. The number of subjects in each cohort will depend on the number of observed DLTs. However, the MTD will always be confirmed in a cohort of 12 subjects.
- Part 2 is a study of the efficacy of the MTD level identified in part 1 and the level below the identified level. Lower levels can however be chosen instead for Part 2.
- The outcome for Part 2 is efficacy in clearance of the AK.
- The trial medication applied is preferably a gel. The gel formulation comprises; isopropyl alcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water and active compound in various suitable concentrations.
- The active compound is ingenol 3-(3,5-diethylisoxazole-4-carboxylate).
- The present invention relates to the treatment of actinic keratosis lesions on full balding scalp by a once daily, two day treatment. More specifically, the invention relates to the treatment of actinic keratosis lesions in an area of approximately 250 cm2 on the full balding scalp in a two day treatment. In case the balding scalp contains hairy areas, which reduces the treated area, the amount of compound applied should be reduced proportionately if feasible.
- In accordance with any of the above embodiments, the two day treatment is two consecutive days.
- In one embodiment, the present invention provides the method according to the above, wherein the effective amount of active compound is applied in a gel or other topical formulation from a dosage strength formulation of active compound of between about 0.01% and about 0.1%
- In another embodiment, the present invention provides the active compound formulated in an effective amount in a gel formulation comprising ispropylalcohol, hydroxyethyl cellulose, benzyl alcohol, citric acid monohydrate, sodium citrate dihydrate and water.
- In another embodiment, the present invention provides application of active compound in a concentration of about 0.018%, about 0.025%, about 0.037%, about 0.050%, about 0.075% or about 0.1%.
- In yet another embodiment, the present invention provides topical application of the active compound in a concentration of between about 0.037% and about 0.05%, and more preferably about 0.037% and about 0.05%.
- In still a further embodiment, the present invention provides the amount of active compound applied is between about 0.162 mg active compound/per day/250 cm2 treated area to about 0.9 mg active compound/per day/250 cm2 treated area, and more preferably about 0.162 mg active compound/per day/250 cm2 treated area and about 0.9 mg active compound/per day/250 cm2 treated area.
- In another embodiment, the present invention provides a method of treating a subject diagnosed with actinic keratosis, said method comprising applying topically an effective amount of active compound to a treatment area for two days to achieve a reduction in the number of actinic keratosis lesions in the treated area.
- Subjects who qualify for Part 1 of the trial must have 5 to 20 clinically typical, visible and discrete actinic keratosis on the balding scalp. The balding scalp must be between 125 cm2 and 250 cm2.
- To be included in the trial, Part 2, the subjects must have 5-20 clinically typical, visible and discrete actinic keratosis on the balding scalp. The balding scalp must be of a size of between 25 cm2 and 250 cm2.
- Part 1: Trial medication will be applied to full balding scalp once daily for two consecutive days until the maximum tolerated dose has been reached for each formulation. Up to nine different doses of active compound in gel or a cream may be investigated in cohorts of 3 to 12 subjects. Pre-defined grades of Local Skin Responses (LSRs) will constitute dose limiting toxicity (DLT). The maximum tolerated dose is defined as the highest dose level at which less than 4 out of 12 subjects experience a Dose limiting toxicity.
- The doses will be administered in an escalating manner following review of safety and tolerability data performed by the dose escalation committee. Evaluation of the safety and tolerability data will be performed after Visit 5/day 8. Then subjects will be followed for 8 weeks after first application of investigational product.
- Part 2 of the trial may include a total of 124 subjects: 62 subjects in each of the 2 active treatment arms (Part 1 identified dose and the dose below) and additionally 31 subjects in a vehicle arm.
- To be included in the trial, Part 1, the subjects must be at least 18 years of age. Exclusion criteria is incompletely healed wound, basal cell carcinoma or squamous cell carcinoma within a 5 cm of treatment area, or prior treatment with Picato® (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. Also other skin conditions, cosmetic procedures or other disease or medication which could interfere with the evaluation of the trial medication or the assessments of the treated area are exclusion criteria, as is other disease or medical conditions which make the subject unsuitable to participate in the trial.
- The patients are scheduled for 6 visits:
- Visit 1: within 35 days prior to day 1
- Visit 2: day 1 (application of trial medication)
- Visit 3: day 2 (application of trial medication)
- Visit 4: day 3
- Visit 5: day 8 (±1 day)
- Visit 6: week 2
- LSRs are evaluated at all visits following visit 1.
- An Evaluable Subjects analysis set will be defined as all subjects who receive at least one dose, and have LSRs recorded at all visits up to and including day 8 or have experienced a DLT at one or more visits up to and including day 8. Safety analyses will be based on the safety analysis set, which is defined as all subjects who receive at least one application of trial medication and have safety information available post treatment.
- In part 2 the patients are scheduled for 7 visits:
- Visit 1: within 21 days prior to day 1
- Visit 2: day 1 (application of trial medication)
- Visit 3: day 2 (application of trial medication)
- Visit 4: day 3
- Visit 5: day 8 (±1 day)
- Visit 6: week 2
- Visit 7: week 8
- LSRs are evaluated at all visits following visit 1. AK lesion counts are performed on visit 6 and 7.
- Efficacy analyses will be based on the full analysis set, which will be defined as all randomized subjects. Per protocol analysis set will be used as an efficacy subset and will be defined as subjects in the full analysis set who complete the study without major protocol deviations. Safety analyses will be based on the safety analysis set, which is defined as all subjects who receive at least one application of trial medication and have safety information available post treatment.
- At visit 7 in week 8, the ratio of number of lesions at week 8 relative to baseline will be tabulated by treatment group and analyzed using a negative binomial regression on actinic keratosis count at week 8 with the log baseline value as an offset variable and treatment group and analysis site as factor. The rate ratios and the corresponding 95% confident intervals will be estimated from this model comparing the active groups pairwise.
- Complete clearance of AKs at week 8 will be analyzed by log binomial regression with factors: Treatment group and analysis site. The number of baseline lesions will be included as a continuous variable. The rate ratios of pairwise treatment groups will be presented together with their 95% confidence intervals. Partial clearance, defined as 75% or greater reduction in AK count will be analyzed in the same way as complete clearance.
- The incidence and grade of LSRs will be summarized by treatment arm overall at each visit. Local skin response grades will be summarized by frequency counts and descriptive statistics by treatment arm for each of the six individual LSRs: erythema, flaking/scaling, crusting, swelling, vesiculation/postulation, and erosion/ulceration.
- A composite score will be obtained by summing the six individual LSR scores at each visit. The composite score and change from baseline will be summarized by treatment arm at each visit using descriptive statistics.
- The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference.
- Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.
Claims (17)
1. A method of treating a subject diagnosed with actinic keratosis on the full balding scalp, said method comprising topically applying an effective amount of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) to a treatment area on the full balding scalp for two days.
2. The method of claim 1 , wherein the method provides reduction in the number of actinic keratosis lesions in the treated area on the full balding scalp.
3. The method of claim 1 , wherein the two days treatment is two consecutive days.
4. The method of claims 1 -3, wherein the treated area is of a size up to about 250 cm2.
5. The method of any of the claim 1 , wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of between about 0.01% and about 0.1%.
6. The method of any of the claim 2 , wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of between about 0.01% and about 0.1%
7. The method of any of the claim 3 , wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of between about 0.01% and about 0.1%.
8. The method of any of the claim 4 , wherein the effective amount of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is applied from a dosage strength formulation of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) of between about 0.01% and about 0.1%.
9. The method of claim 1 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
10. The method of claim 2 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
11. The method of claim 3 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
12. The method of claim 4 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is 0.018%, 0.025%, 0.037%, 0.05%, 0.075% or 0.1%.
13. The method of claim 1 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.037% and about 0.05%.
14. The method of claim 1 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.037%.
15. The method of claim 1 , wherein the dosage strength formulation of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.05%.
16. The method of any of the claim 1 , wherein the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is formulated in a gel.
17. A method of treating a subject diagnosed with actinic keratosis on the full balding scalp, said method comprising topically applying an effective amount of ingenol 3-(3,5-diethylisoxazole-4-carboxylate) to a treatment are on the full balding scalp for two consecutive days,
wherein said method provides a reduction in the number of actinic keratosis lesions in the treated area on the full balding scalp,
wherein the treated area is of a size up to about 250 cm2, and
wherein the dosage strength of the ingenol 3-(3,5-diethylisoxazole-4-carboxylate) is between about 0.037% and about 0.05%.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13190223.1 | 2013-10-25 | ||
EP13190223 | 2013-10-25 | ||
EP14161730 | 2014-03-26 | ||
EP14161730.8 | 2014-03-26 | ||
EP14165659 | 2014-04-23 | ||
EP14165659.5 | 2014-04-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
US20150119433A1 true US20150119433A1 (en) | 2015-04-30 |
Family
ID=52544522
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/524,875 Expired - Fee Related US9713608B2 (en) | 2013-10-25 | 2014-10-27 | Method for topically treating actinic keratosis on the trunk (except chest) or extremities with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
US14/524,738 Abandoned US20150119434A1 (en) | 2013-10-25 | 2014-10-27 | Method for Topically Treating Actinic Keratosis with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
US14/524,731 Abandoned US20150119433A1 (en) | 2013-10-25 | 2014-10-27 | Method of treating actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
US14/704,854 Abandoned US20160089362A1 (en) | 2013-10-25 | 2015-05-05 | Method for Topically Treating Actinic Keratosis on the Trunk (except chest) or Extremities with Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/524,875 Expired - Fee Related US9713608B2 (en) | 2013-10-25 | 2014-10-27 | Method for topically treating actinic keratosis on the trunk (except chest) or extremities with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
US14/524,738 Abandoned US20150119434A1 (en) | 2013-10-25 | 2014-10-27 | Method for Topically Treating Actinic Keratosis with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/704,854 Abandoned US20160089362A1 (en) | 2013-10-25 | 2015-05-05 | Method for Topically Treating Actinic Keratosis on the Trunk (except chest) or Extremities with Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
Country Status (3)
Country | Link |
---|---|
US (4) | US9713608B2 (en) |
EP (3) | EP3060209A1 (en) |
WO (3) | WO2015059572A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150265567A1 (en) * | 2014-03-24 | 2015-09-24 | Leo Laboratories Limited | Method for Treating Skin Lesions with Ingenol Mebutate |
US9713608B2 (en) | 2013-10-25 | 2017-07-25 | Leo Laboratories Limited | Method for topically treating actinic keratosis on the trunk (except chest) or extremities with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017108927A1 (en) * | 2015-12-22 | 2017-06-29 | Leo Laboratories Limited | Process for preparation of ingenol 3-(3.5-diethylisoxazole-4-carboxylate) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012083953A1 (en) * | 2010-12-22 | 2012-06-28 | Leo Pharma A/S | Ingenol-3-acylates iii and ingenol-3-carbamates |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0525680D0 (en) | 2005-12-16 | 2006-01-25 | Peplin Ltd | Therapeutic compositions |
US20130251782A1 (en) | 2012-03-22 | 2013-09-26 | Leo Laboratories Limited | Topical application of ingenol mebutate with occlusion |
US9789078B2 (en) | 2012-05-16 | 2017-10-17 | Leo Laboratories Limited | Method of topically treating actinic keratosis with ingenol mebutate cycle therapy |
MY169215A (en) | 2012-06-26 | 2019-03-18 | Leo Laboratories Ltd | 3-o-heteroaryl-ingenol |
GB201222406D0 (en) | 2012-12-12 | 2013-01-23 | Leo Lab Ltd | Gel compositions |
US20140249218A1 (en) | 2013-01-22 | 2014-09-04 | Leo Laboratories Limited | Administration of ingenol mebutate |
EP3060209A1 (en) | 2013-10-25 | 2016-08-31 | Leo Laboratories Limited | A method for topically treating actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
US9526714B2 (en) | 2014-03-24 | 2016-12-27 | Leo Laboratories Limited | Method for treating skin lesions with ingenol mebutate |
-
2014
- 2014-10-27 EP EP14838791.3A patent/EP3060209A1/en not_active Withdrawn
- 2014-10-27 US US14/524,875 patent/US9713608B2/en not_active Expired - Fee Related
- 2014-10-27 US US14/524,738 patent/US20150119434A1/en not_active Abandoned
- 2014-10-27 WO PCT/IB2014/002940 patent/WO2015059572A1/en active Application Filing
- 2014-10-27 US US14/524,731 patent/US20150119433A1/en not_active Abandoned
- 2014-10-27 EP EP14841326.3A patent/EP3060210A1/en not_active Withdrawn
- 2014-10-27 WO PCT/IB2014/002970 patent/WO2015059577A1/en active Application Filing
- 2014-10-27 WO PCT/IB2014/002951 patent/WO2015059574A1/en active Application Filing
- 2014-10-27 EP EP14838790.5A patent/EP3060304A1/en not_active Withdrawn
-
2015
- 2015-05-05 US US14/704,854 patent/US20160089362A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012083953A1 (en) * | 2010-12-22 | 2012-06-28 | Leo Pharma A/S | Ingenol-3-acylates iii and ingenol-3-carbamates |
Non-Patent Citations (1)
Title |
---|
Anderson et al. ( J Am Acad Dermatol 2009;60:934-43). * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9713608B2 (en) | 2013-10-25 | 2017-07-25 | Leo Laboratories Limited | Method for topically treating actinic keratosis on the trunk (except chest) or extremities with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) |
US20150265567A1 (en) * | 2014-03-24 | 2015-09-24 | Leo Laboratories Limited | Method for Treating Skin Lesions with Ingenol Mebutate |
US9526714B2 (en) * | 2014-03-24 | 2016-12-27 | Leo Laboratories Limited | Method for treating skin lesions with ingenol mebutate |
Also Published As
Publication number | Publication date |
---|---|
WO2015059574A1 (en) | 2015-04-30 |
EP3060210A1 (en) | 2016-08-31 |
US20150119434A1 (en) | 2015-04-30 |
EP3060209A1 (en) | 2016-08-31 |
US20150258071A1 (en) | 2015-09-17 |
US20160089362A1 (en) | 2016-03-31 |
US9713608B2 (en) | 2017-07-25 |
WO2015059577A1 (en) | 2015-04-30 |
EP3060304A1 (en) | 2016-08-31 |
WO2015059572A1 (en) | 2015-04-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Heras‐Mosteiro et al. | Interventions for Old World cutaneous leishmaniasis | |
US11497750B2 (en) | Methods of treating and/or preventing actinic keratosis | |
Draelos et al. | A new proprietary onion extract gel improves the appearance of new scars: a randomized, controlled, blinded-investigator study | |
JP2024023429A (en) | Compositions for treatment of skin conditions | |
CN101843637B (en) | External spray for preventing and treating beriberi and preparation method | |
JP2022510377A (en) | Composition for treatment of the condition | |
US20150119433A1 (en) | Method of treating actinic keratosis on the full balding scalp with ingenol 3-(3,5-diethylisoxazole-4-carboxylate) | |
Leemans et al. | Salmeterol or doxycycline do not inhibit acute bronchospasm and airway inflammation in cats with experimentally-induced asthma | |
US9789078B2 (en) | Method of topically treating actinic keratosis with ingenol mebutate cycle therapy | |
US20170258769A1 (en) | A Method for Topically Treating Actinic Keratosis on the Trunk (except chest) and Extremities with Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) | |
US20170258756A1 (en) | A Method for Topically Treating Actinic Keratosis on the Scalp with Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) | |
WO2015075125A1 (en) | A method for treating skin lesions | |
TWI841523B (en) | Methods of treating and/or preventing actinic keratosis | |
US20170258770A1 (en) | Method for Topically Treating Actinic Keratosis on the Full Face or 250 cm2 on the Chest with Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) | |
Stough et al. | CUTIS Do Not Copy | |
Muratori et al. | Xioglican Cream in Italian Patients with Chronic Venous Disease: A Post-Marketing Study Investigating Effects on Clinical and Cutaneous Signs and Symptoms | |
Biradar et al. | Photodynamic therapy for conventional treatment resistant acne vulgaris | |
Nguyệt et al. | ASSOCIATED DEMOGRAPHIC CHARACTERISTICS OF ACNE RECURRENCE IN SEVERE ACNE PATIENTS TREATED WITH ORAL ISOTRETINOIN | |
Non-Ablative et al. | FDA Grants Full Approval to ONTAK®(denileukin diftitox) for Use in Patients with CTCL | |
Whitley et al. | INFECTION (FUNGAL) | |
Marinela et al. | Rosacea. etiological aspects and staging. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: LEO LABORATORIES LIMITED, IRELAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SELMER, JOHAN;KNUDSEN, KIM MARK;REEL/FRAME:037967/0503 Effective date: 20160224 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |