Methods of treating and / or preventing actinic keratosis

Abstract

To provide a treatment for actinic keratosis.SOLUTION: The method of treating and / or preventing actinic keratosis includes a step of administering, to subjects in need thereof, a therapeutically effective amount of KX-01.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority to and benefit of U.S. Provisional Application No. 62 / 469,889, filed March 10, 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Actinic or solar keratoses are scaly, crusted growths (lesions) resulting from damage by the sun's ultraviolet rays. They are typically found on sun-exposed areas such as the face, bald scalp, lips, and backs of the hands, and are raised, rough to the touch, and often resemble warts. Most are red, but some are tan, pink, and / or flesh-colored. If left untreated, up to 10 percent of actinic keratoses will develop into squamous cell carcinoma (SCC), the second most common form of skin cancer. In rarer cases, actinic keratoses can transform into basal cell carcinoma, the most common form of skin cancer. It is estimated that over 58 million Americans have actinic keratoses. Treatments for actinic keratoses include cryotherapy, surgical removal, chemical peels, photodynamic therapy, laser skin resurfacing, and / or drug-containing gels and creams. Due to the prevalence of actinic keratosis and its ability to transform into skin cancer if not properly treated, there is a need for the development of additional treatments. Summary of the Invention

[0003] overview In one aspect, the present application provides a method for the treatment of a disease comprising administering to a subject in need thereof: [ka] The present invention relates, at least in part, to a method for treating and / or preventing actinic keratosis comprising administering a therapeutically effective amount of

[0004] In one aspect, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 10 mg.

[0005] In one aspect, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 5 mg.

[0006] In one aspect, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.5 mg to about 2.5 mg.

[0007] In one aspect, KX-01 is administered to the subject at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, or about 5 mg to the affected area.

[0008] In one aspect, KX-01 is administered to the subject at a dose of about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg to the affected area.

[0009] In one aspect, KX-01 has a concentration of about 0.0003 mg / cm 2 ~about 10mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0010] In one aspect, KX-01 has a concentration of about 0.001 mg / cm 2 ~about 0.4mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0011] In one aspect, KX-01 has a concentration of about 0.005 mg / cm 2 ~about 0.1mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0012] In one aspect, KX-01 has a concentration of about 0.005 mg / cm 2 ~ approx. 0.02 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0013] In one aspect, KX-01 has a concentration of about 0.025 mg / cm 2 ~about 0.1mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0014] In one aspect, KX-01 has a concentration of about 0.001 mg / cm 2 , about 0.002mg / cm 2 , about 0.003mg / cm 2 , about 0.004mg / cm 2 , about 0.005mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.02 mg / cm 2 , about 0.03mg / cm 2 , about 0.04 mg / cm 2 , about 0.05mg / cm 2 , about 0.06mg / cm 2 , about 0.07mg / cm 2 , about 0.08 mg / cm 2 , about 0.09mg / cm 2 , about 0.1mg / cm 2 , about 0.15mg / cm 2 , about 0.2mg / cm 2 , about 0.25mg / cm 2 , about 0.3mg / cm 2 , about 0.35mg / cm 2 , or about 0.4 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0015] In one aspect, KX-01 has a concentration of about 0.005 mg / cm 2 , about 0.006mg / cm 2, about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.015mg / cm 2 , about 0.02 mg / cm 2 , about 0.025mg / cm 2 , about 0.03mg / cm 2 , about 0.035mg / cm 2 , about 0.04 mg / cm 2 , about 0.045mg / cm 2 , about 0.05mg / cm 2 , about 0.055mg / cm 2 , about 0.06mg / cm 2 , about 0.065mg / cm 2 , about 0.07mg / cm 2 , about 0.075mg / cm 2 , about 0.08 mg / cm 2 , about 0.085mg / cm 2 , about 0.09mg / cm 2 , about 0.095mg / cm 2 , or about 0.1 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0016] In one aspect, the affected area of ​​the subject is approximately 0.01 cm 2 ~about 300cm 2 It is.

[0017] In one aspect, the affected area of ​​the subject is approximately 1 cm 2 ~about 200cm 2 , about 1cm 2 ~Approx. 100cm 2 , about 1cm 2 ~Approx. 75cm 2 , about 1cm 2 ~about 50cm 2 , or about 1 cm 2 ~about 25cm 2 It is.

[0018] In one aspect, the affected area of ​​the subject is approximately 10 cm 2 ~about 200cm 2 , about 10cm2 ~Approx. 100cm 2 , about 10cm 2 ~Approx. 75cm 2 , about 10cm 2 ~about 50cm 2 , or about 10 cm 2 ~about 25cm 2 It is.

[0019] In one aspect, the affected area of ​​the subject is approximately 25 cm 2 ~about 200cm 2 , about 25cm 2 ~Approx. 100cm 2 , about 25cm 2 ~Approx. 75cm 2 , or about 25 cm 2 ~about 50cm 2 It is.

[0020] In one aspect, the affected area of ​​the subject is approximately 25 cm 2 ~Approx. 100cm 2 , about 25cm 2 ~about 90cm 2 , about 25cm 2 ~about 80cm 2 , or about 25 cm 2 ~about 70cm 2 , about 25cm 2 ~about 60cm 2 , about 25cm 2 ~about 50cm 2 , about 25cm 2 ~about 40cm 2 , or about 25 cm 2 ~about 30cm 2 It is.

[0021] In one aspect, the affected area of ​​the subject is approximately 25 cm 2 , about 30cm 2 , about 35cm 2 , about 40cm 2 , about 45cm 2 , about 50cm 2 , approx. 55cm 2 , about 60cm 2 , approx. 65cm 2 , about 70cm 2 , about 75cm 2 , about 80cm2 , approx. 85cm 2 , about 90cm 2 , about 95cm 2 , or about 100 cm 2 It is.

[0022] In one aspect, the affected area of ​​the subject is the skin.

[0023] In one aspect, the affected areas of the subject are located at one or more locations independently selected from the scalp, forehead, forearms, face, nose, ears, eyelids, lips, neck, arms, hands, trunk, legs, and feet.

[0024] In one aspect, the subject has more than one affected area.

[0025] In one aspect, KX-01 is administered once a week, once every 3 days, once every 2 days, once a day, twice a day, three times a day, or four times a day.

[0026] In one aspect, KX-01 is administered once daily or twice daily.

[0027] In one aspect, KX-01 is administered once daily.

[0028] In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days.

[0029] In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0030] In one aspect, KX-01 is administered for 1, 2, 3, 4, 5, 6, or 7 days.

[0031] In one aspect, KX-01 is administered for 1, 2, 3, 4, or 5 days.

[0032] In one aspect, KX-01 is administered 1, 2, 3, 4, 5, or 6 days per week.

[0033] In one aspect, KX-01 is administered 2, 3, 4, 5, or 6 days per week.

[0034] In one aspect, KX-01 is administered once or twice daily for two or more consecutive days per week, followed by discontinuation for the remainder of the week.

[0035] In one aspect, KX-01 is administered once or twice daily on every other day.

[0036] In one aspect, KX-01 is administered once or twice daily every 3, 4, 5, 6, or 7 days.

[0037] In one aspect, KX-01 is administered once or twice daily for 2 consecutive days every 3, 4, 5, 6, or 7 days.

[0038] In one aspect, KX-01 is administered once or twice daily for three consecutive days every 4, 5, 6, or 7 days.

[0039] In one aspect, KX-01 is administered once or twice daily for four consecutive days every 5, 6, or 7 days.

[0040] In one aspect, KX-01 is administered until the actinic keratosis is completely treated.

[0041] In one aspect, KX-01 is administered locally.

[0042] In one aspect, administration of KX-01 reduces the number and / or severity of local skin reactions or other adverse side effects in a subject as compared to other treatments for actinic keratosis.

[0043] In one aspect, administration of KX-01 reduces the number of subjects with local skin reactions or other adverse side effects compared to other treatments for actinic keratosis.

[0044] In one aspect, the local skin reaction is selected from the group consisting of vesiculation, pustulation, erosion, ulceration, redness, swelling, peeling, scaling, hard lump, dryness, pus, and blistering.

[0045] In one aspect, the other side effects are selected from the group consisting of application site pain, application site pruritus, application site irritation, application site swelling, application site burning, application site infection, periorbital swelling, nasopharyngitis, chills, sore throat, droopy eyes, puffy eyes, hypopigmentation, hyperpigmentation, and headache.

[0046] In one aspect, this application relates, at least in part, to KX-01 for use (e.g., topical use) in the treatment and / or prevention of actinic keratosis. In certain aspects, KX-01 is for use in a subject in need thereof at the doses, dosing schedules, and / or in one or more affected areas described herein.

[0047] In one aspect, this application relates, at least in part, to the use (e.g., topical use) of KX-01 in the treatment and / or prevention of actinic keratosis. In certain aspects, KX-01 is used in a subject in need thereof at the doses, dosing schedules, and / or in one or more affected areas described herein.

[0048] In one aspect, this application relates, at least in part, to the use of KX-01 in the manufacture of a medicament for the treatment and / or prevention of actinic keratosis. In certain aspects, KX-01 is used in a dose, dosing schedule, and / or in one or more affected areas as described herein in a subject in need thereof. [The present invention 1001] For those who need it, KX-01: [ka] 23. A method for treating and / or preventing actinic keratosis comprising administering a therapeutically effective amount of [The present invention 1002] The method of claim 1001, wherein KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 10 mg. [The present invention 1003] The method of any of claims 1001 to 1002, wherein KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 5 mg. [The present invention 1004] Any of the methods of the present invention, wherein KX-01 is administered to the affected area of ​​the subject at a dose of about 0.5 mg to about 2.5 mg. [The present invention 1005] Any of the methods of the present inventions 1001 to 1003, wherein KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, or about 5 mg. [The present invention 1006] Any of the methods of the present invention, wherein KX-01 is administered to the affected area of ​​the subject at a dose of about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg. [The present invention 1007] KX-01 is approximately 0.0003 mg / cm 2 ~about 10mg / cm 2 any of the methods of the above-mentioned invention, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1008] KX-01 is approximately 0.001 mg / cm 2 ~about 0.4mg / cm 2 any of the methods of the above-mentioned invention, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1009] KX-01 is approximately 0.005 mg / cm 2 ~about 0.1mg / cm 2 The method according to any one of claims 1001 to 1008, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1010] KX-01 is approximately 0.005 mg / cm 2 ~ approx. 0.02 mg / cm 2 The method according to any one of claims 1001 to 1008, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1011] KX-01 is approximately 0.025 mg / cm 2 ~about 0.1mg / cm 2 The method according to any one of claims 1001 to 1008, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1012] KX-01 is approximately 0.001 mg / cm 2 , about 0.002mg / cm 2 , about 0.003mg / cm 2 , about 0.004mg / cm 2 , about 0.005mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.02 mg / cm 2 , about 0.03mg / cm 2 , about 0.04 mg / cm 2 , about 0.05mg / cm 2 , about 0.06mg / cm 2 , about 0.07mg / cm 2 , about 0.08 mg / cm 2 , about 0.09mg / cm 2 , about 0.1mg / cm 2 , about 0.15mg / cm 2 , about 0.2mg / cm 2 , about 0.25mg / cm 2 , about 0.3mg / cm 2 , about 0.35mg / cm 2, or about 0.4 mg / cm 2 The method according to any one of claims 1001 to 1008, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1013] KX-01 is approximately 0.005 mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.015mg / cm 2 , about 0.02 mg / cm 2 , about 0.025mg / cm 2 , about 0.03mg / cm 2 , about 0.035mg / cm 2 , about 0.04 mg / cm 2 , about 0.045mg / cm 2 , about 0.05mg / cm 2 , about 0.055mg / cm 2 , about 0.06mg / cm 2 , about 0.065mg / cm 2 , about 0.07mg / cm 2 , about 0.075mg / cm 2 , about 0.08 mg / cm 2 , about 0.085mg / cm 2 , about 0.09mg / cm 2 , about 0.095mg / cm 2 , or about 0.1 mg / cm 2 The method according to any one of claims 1001 to 1008, wherein the compound is administered to the affected area of ​​the subject at a dose of [The present invention 1014] The affected area is approximately 0.01 cm 2 ~about 300cm 2 The method according to any one of claims 1002 to 1013, [The present invention 1015] The affected area is about 1 cm 2 ~about 200cm 2 , about 1cm 2 ~Approx. 100cm 2 , about 1cm 2 ~Approx. 75cm 2 , about 1cm 2~about 50cm 2 , or about 1 cm 2 ~about 25cm 2 The method according to any one of claims 1002 to 1013, [The present invention 1016] The affected area is about 10 cm 2 ~about 200cm 2 , about 10cm 2 ~about 100cm 2 , about 10cm 2 ~Approx. 75cm 2 , about 10cm 2 ~about 50cm 2 , or about 10 cm 2 ~about 25cm 2 The method according to any one of claims 1002 to 1013, [The present invention 1017] The affected area is approximately 25 cm 2 ~about 200cm 2 , about 25cm 2 ~about 100cm 2 , about 25cm 2 ~Approx. 75cm 2 , or about 25 cm 2 ~about 50cm 2 The method according to any one of claims 1002 to 1013, [The present invention 1018] The affected area is approximately 25 cm 2 ~about 100cm 2 , about 25cm 2 ~about 90cm 2 , about 25cm 2 ~about 80cm 2 , or about 25 cm 2 ~about 70cm 2 , about 25cm 2 ~about 60cm 2 , about 25cm 2 ~about 50cm 2 , about 25cm 2 ~about 40cm 2 , or about 25 cm 2 ~about 30cm 2 The method according to any one of claims 1002 to 1013, [The present invention 1019] The affected area is approximately 25 cm 2 , about 30cm2 , about 35cm 2 , about 40cm 2 , about 45cm 2 , about 50cm 2 , approx. 55cm 2 , about 60cm 2 , approx. 65cm 2 , about 70cm 2 , about 75cm 2 , about 80cm 2 , approx. 85cm 2 , about 90cm 2 , about 95cm 2 , or about 100 cm 2 The method according to any one of claims 1002 to 1013, [The present invention 1020] The method according to any one of claims 1002 to 1019, wherein the affected area is the skin. [The present invention 1021] Any of the methods of inventions 1002-1020, wherein the affected area is located at one or more locations independently selected from the scalp, forehead, forearms, face, nose, ears, eyelids, lips, neck, arms, hands, trunk, legs, and feet. [The present invention 1022] The method of any one of claims 1001 to 1021, wherein the subject has more than one affected area. [The present invention 1023] The method of any of claims 1001 to 1021, wherein KX-01 is administered once a week, once every 3 days, once every 2 days, once a day, twice a day, three times a day, or four times a day. [The present invention 1024] The method of any of claims 1001 to 1021, wherein KX-01 is administered once a day or twice a day. [The present invention 1025] The method of any of claims 1001 to 1021, wherein KX-01 is administered once a day. [The present invention 1026] The method of any of claims 1001 to 1021, wherein KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. [The present invention 1027] The method of any of claims 1001 to 1021, wherein KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. [The present invention 1028] The method of any of claims 1001 to 1021, wherein KX-01 is administered for 1, 2, 3, 4, 5, 6, or 7 days. [The present invention 1029] The method of any of claims 1001 to 1021, wherein KX-01 is administered for 1, 2, 3, 4, or 5 days. [The present invention 1030] The method of any of claims 1001 to 1021, wherein KX-01 is administered for 1, 2, 3, 4, 5, or 6 days per week. [The present invention 1031] The method of any of claims 1001 to 1021, wherein KX-01 is administered for 2, 3, 4, 5, or 6 days per week. [The present invention 1032] The method of any of claims 1001 to 1021, wherein KX-01 is administered once or twice daily for two or more consecutive days per week, followed by discontinuation of administration for the remainder of the week. [The present invention 1033] The method of any of claims 1001 to 1021, wherein KX-01 is administered once or twice daily on alternate days. [The present invention 1034] The method of any of claims 1001 to 1021, wherein KX-01 is administered once or twice daily every 3, 4, 5, 6, or 7 days. [The present invention 1035] The method of any of claims 1001 to 1021, wherein KX-01 is administered once or twice daily for 2 consecutive days every 3, 4, 5, 6, or 7 days. [The present invention 1036] The method of any of claims 1001 to 1021, wherein KX-01 is administered once or twice daily for 3 consecutive days every 4, 5, 6, or 7 days. [The present invention 1037] The method of any of claims 1001 to 1021, wherein KX-01 is administered once or twice daily for 4 consecutive days every 5, 6, or 7 days. [The present invention 1038] Any of the aforementioned methods of the present invention, wherein KX-01 is administered until the actinic keratosis is completely treated. [The present invention 1039] Any of the methods of the preceding invention, wherein KX-01 is administered locally. [The present invention 1040] Any of the methods of claims 1001-1039, wherein administration of KX-01 reduces the number and / or severity of local skin reactions or other adverse side effects in the subject compared to other treatments for actinic keratosis. [The present invention 1041] The method of any of claims 1001-1039, wherein administration of KX-01 reduces the number of subjects having local skin reactions or other adverse side effects compared to other treatments for actinic keratosis. [The present invention 1042] The method of any one of claims 1040 to 1041, wherein the local skin reaction is selected from the group selected from vesiculation, pustulation, erosion, ulceration, redness, swelling, peeling, scaling, hard lump, dryness, pus, and blistering. [The present invention 1043] The method of claim 1042, wherein the other side effects are selected from the group consisting of application site pain, application site pruritus, application site irritation, application site swelling, application site burning, application site infection, periorbital swelling, nasopharyngitis, chills, sore throat, droopy eyes, puffy eyes, hypopigmentation, hyperpigmentation, and headache. [The present invention 1044] KX-01 for treating and / or preventing actinic keratosis in a subject in need thereof: [ka] Use of. [The present invention 1045] The use of the present invention 1044, wherein KX-01 is for application to an affected area of ​​a subject at a dose of about 0.1 mg to about 10 mg. [The present invention 1046] The use of any of claims 1044 to 1045, wherein KX-01 is for application to an affected area of ​​a subject at a dose of about 0.2 mg to about 5 mg. [The present invention 1047] The use of any of claims 1044 to 1046, wherein KX-01 is for application to the affected area of ​​the subject at a dose of about 0.5 mg to about 2.5 mg. [The present invention 1048] Use of any of inventions 1044 to 1046, wherein KX-01 is for application to an affected area of ​​a subject at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, or about 5 mg. [The present invention 1049] Use of any of inventions 1044 to 1048, wherein KX-01 is for application to an affected area of ​​a subject at a dose of about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg. [The present invention 1050] KX-01 is approximately 0.0003 mg / cm 2 ~about 10mg / cm 2 The use of any of claims 1044 to 1049, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1051] KX-01 is approximately 0.001 mg / cm 2 ~about 0.4mg / cm 2 The use of any of claims 1044 to 1050, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1052] KX-01 is approximately 0.005 mg / cm 2 ~about 0.1mg / cm 2The use of any of claims 1044 to 1051, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1053] KX-01 is approximately 0.005 mg / cm 2 ~ approx. 0.02 mg / cm 2 The use of any of claims 1044 to 1051, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1054] KX-01 is approximately 0.025 mg / cm 2 ~about 0.1mg / cm 2 The use of any of claims 1044 to 1051, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1055] KX-01 is approximately 0.001 mg / cm 2 , about 0.002mg / cm 2 , about 0.003mg / cm 2 , about 0.004mg / cm 2 , about 0.005mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.02 mg / cm 2 , about 0.03mg / cm 2 , about 0.04 mg / cm 2 , about 0.05mg / cm 2 , about 0.06mg / cm 2 , about 0.07mg / cm 2 , about 0.08 mg / cm 2 , about 0.09mg / cm 2 , about 0.1mg / cm 2 , about 0.15mg / cm 2 , about 0.2mg / cm 2 , about 0.25mg / cm 2 , about 0.3mg / cm 2 , about 0.35mg / cm 2 , or about 0.4 mg / cm 2The use of any of claims 1044 to 1051, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1056] KX-01 is approximately 0.005 mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.015mg / cm 2 , about 0.02 mg / cm 2 , about 0.025mg / cm 2 , about 0.03mg / cm 2 , about 0.035mg / cm 2 , about 0.04 mg / cm 2 , about 0.045mg / cm 2 , about 0.05mg / cm 2 , about 0.055mg / cm 2 , about 0.06mg / cm 2 , about 0.065mg / cm 2 , about 0.07mg / cm 2 , about 0.075mg / cm 2 , about 0.08 mg / cm 2 , about 0.085mg / cm 2 , about 0.09mg / cm 2 , about 0.095mg / cm 2 , or about 0.1 mg / cm 2 The use of any of claims 1044 to 1051, wherein the use is for application to an affected area of ​​a subject at a dose of [The present invention 1057] The affected area is approximately 0.01 cm 2 ~about 300cm 2 Use of any one of claims 1045 to 1056 of the present invention. [The present invention 1058] The affected area is about 1 cm 2 ~about 200cm 2 , about 1cm 2 ~about 100cm 2 , about 1cm 2 ~Approx. 75cm 2 , about 1cm 2 ~about 50cm2 , or about 1 cm 2 ~about 25cm 2 Use of any one of claims 1045 to 1056 of the present invention. [The present invention 1059] The affected area is about 10 cm 2 ~about 200cm 2 , about 10cm 2 ~about 100cm 2 , about 10cm 2 ~Approx. 75cm 2 , about 10cm 2 ~about 50cm 2 , or about 10 cm 2 ~about 25cm 2 Use of any one of claims 1045 to 1056 of the present invention. [The present invention 1060] The affected area is approximately 25 cm 2 ~about 200cm 2 , about 25cm 2 ~about 100cm 2 , about 25cm 2 ~Approx. 75cm 2 , or about 25 cm 2 ~about 50cm 2 Use of any one of claims 1045 to 1056 of the present invention. [The present invention 1061] The affected area is approximately 25 cm 2 ~about 100cm 2 , about 25cm 2 ~about 90cm 2 , about 25cm 2 ~about 80cm 2 , or about 25 cm 2 ~about 70cm 2 , about 25cm 2 ~about 60cm 2 , about 25cm 2 ~about 50cm 2 , about 25cm 2 ~about 40cm 2 , or about 25 cm 2 ~about 30cm 2 Use of any one of claims 1045 to 1056 of the present invention. [The present invention 1062] The affected area is approximately 25 cm 2 , about 30cm 2, about 35cm 2 , about 40cm 2 , about 45cm 2 , about 50cm 2 , approx. 55cm 2 , about 60cm 2 , approx. 65cm 2 , about 70cm 2 , about 75cm 2 , about 80cm 2 , approx. 85cm 2 , about 90cm 2 , about 95cm 2 , or about 100 cm 2 Use of any one of claims 1045 to 1056 of the present invention. [The present invention 1063] The use of any one of claims 1045 to 1062, wherein the affected area is the skin. [The present invention 1064] The use of any of claims 1045 to 1063, wherein the affected area is located in one or more locations independently selected from the scalp, forehead, forearms, face, nose, ears, eyelids, lips, neck, arms, hands, trunk, legs, and feet. [The present invention 1065] The use of any of claims 1044 to 1064, wherein the subject has more than one affected area. [The present invention 1066] The use of any of claims 1044 to 1064, wherein KX-01 is for application to an affected area of ​​a subject once a week, once every 3 days, once every 2 days, once a day, twice a day, three times a day, or four times a day. [The present invention 1067] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject once daily or twice daily. [The present invention 1068] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject once a day. [The present invention 1069] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. [The present invention 1070] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. [The present invention 1071] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject for 1, 2, 3, 4, 5, 6, or 7 days. [The present invention 1072] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject for 1, 2, 3, 4, or 5 days. [The present invention 1073] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject for 1, 2, 3, 4, 5, or 6 days per week. [The present invention 1074] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject for 2, 3, 4, 5, or 6 days per week. [The present invention 1075] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject once or twice daily for two or more consecutive days per week, followed by discontinuation of administration for the remainder of the week. [The present invention 1076] The use of any of claims 1044 to 1064, wherein KX-01 is for application to the affected area of ​​the subject once or twice daily on alternate days. [The present invention 1077] The use of any of claims 1044 to 1064, wherein KX-01 is for application to an affected area of ​​a subject once or twice daily every 3, 4, 5, 6, or 7 days. [The present invention 1078] The use of any of claims 1044 to 1064, wherein KX-01 is for application to an affected area of ​​a subject once or twice daily for 2 consecutive days every 3, 4, 5, 6, or 7 days. [The present invention 1079] The use of any of claims 1044 to 1064, wherein KX-01 is for application to an affected area of ​​a subject once or twice daily for 3 consecutive days every 4, 5, 6, or 7 days. [The present invention 1080] The use of any of claims 1044 to 1064, wherein KX-01 is for application to an affected area of ​​a subject once or twice daily for 4 consecutive days every 5, 6, or 7 days. [The present invention 1081] The use of any of claims 1043 to 1080, wherein KX-01 is for application to the affected area of ​​the subject until the actinic keratosis is completely treated. [The present invention 1082] The use of any of claims 1043 to 1080, wherein KX-01 is for local application to an affected area of ​​a subject. [The present invention 1083] The use of any of claims 1043 to 1082, wherein KX-01 reduces the number and / or severity of local skin reactions or other adverse side effects in a subject compared to other treatments for actinic keratosis. [The present invention 1084] The use of any of claims 1043 to 1082, wherein KX-01 reduces the number of subjects having local skin reactions or other adverse side effects compared to other treatments for actinic keratosis. [The present invention 1085] The use of 1083 or 1084 according to the present invention, wherein the local skin reaction is selected from the group selected from vesiculation, pustulation, erosion, ulceration, redness, swelling, peeling, scaling, hard lump, dryness, pus, and blistering. [The present invention 1086] The use of 1085 of the present invention, wherein other side effects are selected from the group consisting of application site pain, application site pruritus, application site irritation, application site swelling, application site burning sensation, application site infection, periorbital swelling, nasopharyngitis, chills, sore throat, droopy eyes, puffy eyes, hypopigmentation, hyperpigmentation, and headache. [Brief description of the drawings]

[0049] [Figure 1]Mean LSR composite score vs. time - Phase 1 study of KX-01 administered topically to the dorsal forearm. Cohort 1 (N=4): 0.5 mg KX-01 administered topically daily for 3 consecutive days to a 25 cm2 area with 4-8 typical AK lesions. Cohort 2 (N=10): 2.0 mg KX-01 administered topically daily for 3 consecutive days to a 100 cm2 area with 8-16 typical AK lesions. Cohort 3 (N=8): 0.5 mg KX-01 administered topically daily for 5 consecutive days to a 25 cm2 area with 4-8 typical AK lesions. Cohort 4 (N=8): 2.0 mg KX-01 administered topically daily for 5 consecutive days to a 100 cm2 area with 8-16 typical AK lesions. [Diagram 2] Mean LSR composite score versus time - Phase 2a study of locally administered KX-01. 0.5 mg KX-01 administered locally for 3 or 5 consecutive days to contiguous treatment areas of 25 cm2 containing 4-8 typical AK lesions. [Diagram 3] Comparison of forearm skin reactions in patients treated with Picato (ingenol mebutate)® (Figure 3A) and KX-01 (Figure 3B). [Figure 4] Comparison of forehead skin reactions in patients treated with Picato (ingenol mebutate)® (FIG. 4A) and KX-01 (FIG. 4B). [Diagram 5] Bar graph showing median number of AK lesions over time (the left bar of each pair of bars shows the results after 5 days of treatment, the right bar shows the results after 3 days of treatment). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] Detailed Description This application is directed to the KX-01: [ka] The present invention relates, at least in part, to a method for treating and / or preventing actinic keratosis comprising administering a therapeutically effective amount of

[0051] This application is directed to the KX-01: [ka] The present invention relates at least in part to a method of treating actinic keratosis comprising administering a therapeutically effective amount of

[0052] This application is directed to the KX-01: [ka] The present invention relates at least in part to a method for preventing actinic keratosis comprising administering a therapeutically effective amount of

[0053] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the subject at a dose of about 0.1 mg to about 10 mg to the affected area.

[0054] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the subject at a dose of about 0.2 mg to about 5 mg to the affected area.

[0055] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the subject at a dose of about 0.5 mg to about 2.5 mg to the affected area.

[0056] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 9 mg, about 0.1 mg to about 8 mg, about 0.1 mg to about 7 mg, about 0.1 mg to about 6 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.1 mg to about 0.9 mg, about 0.1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.6 mg, about 0.1 mg to about 0.5 mg, about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.3 mg, or about 0.1 mg to about 0.2 mg.

[0057] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 10 mg, about 0.2 mg to about 9 mg, about 0.2 mg to about 8 mg, about 0.2 mg to about 7 mg, about 0.2 mg to about 6 mg, about 0.2 mg to about 5 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 3 mg, about 0.2 mg to about 2 mg, about 0.2 mg to about 1 mg, about 0.2 mg to about 0.9 mg, about 0.2 mg to about 0.8 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.6 mg, about 0.2 mg to about 0.5 mg, about 0.2 mg to about 0.4 mg, or about 0.2 mg to about 0.3 mg.

[0058] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.3 mg to about 10 mg, about 0.3 mg to about 9 mg, about 0.3 mg to about 8 mg, about 0.3 mg to about 7 mg, about 0.3 mg to about 6 mg, about 0.3 mg to about 5 mg, about 0.3 mg to about 4 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 2 mg, about 0.3 mg to about 1 mg, about 0.3 mg to about 0.9 mg, about 0.3 mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.6 mg, about 0.3 mg to about 0.5 mg, or about 0.3 mg to about 0.4 mg.

[0059] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.4 mg to about 10 mg, about 0.4 mg to about 9 mg, about 0.4 mg to about 8 mg, about 0.4 mg to about 7 mg, about 0.4 mg to about 6 mg, about 0.4 mg to about 5 mg, about 0.4 mg to about 4 mg, about 0.4 mg to about 3 mg, about 0.4 mg to about 2 mg, about 0.4 mg to about 1 mg, about 0.4 mg to about 0.9 mg, about 0.4 mg to about 0.8 mg, about 0.4 mg to about 0.7 mg, about 0.4 mg to about 0.6 mg, or about 0.4 mg to about 0.5 mg.

[0060] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.5 mg to about 10 mg, about 0.5 mg to about 9 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 1 mg, about 0.5 mg to about 0.9 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, or about 0.5 mg to about 0.6 mg.

[0061] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.6 mg to about 10 mg, about 0.6 mg to about 9 mg, about 0.6 mg to about 8 mg, about 0.6 mg to about 7 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 5 mg, about 0.6 mg to about 4 mg, about 0.6 mg to about 3 mg, about 0.6 mg to about 2 mg, about 0.6 mg to about 1 mg, about 0.6 mg to about 0.9 mg, about 0.6 mg to about 0.8 mg, or about 0.6 mg to about 0.7 mg.

[0062] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.7 mg to about 10 mg, about 0.7 mg to about 9 mg, about 0.7 mg to about 8 mg, about 0.7 mg to about 7 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 5 mg, about 0.7 mg to about 4 mg, about 0.7 mg to about 3 mg, about 0.7 mg to about 2 mg, about 0.7 mg to about 1 mg, about 0.7 mg to about 0.9 mg, or about 0.7 mg to about 0.8 mg.

[0063] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.8 mg to about 10 mg, about 0.8 mg to about 9 mg, about 0.8 mg to about 8 mg, about 0.8 mg to about 7 mg, about 0.8 mg to about 6 mg, about 0.8 mg to about 5 mg, about 0.8 mg to about 4 mg, about 0.8 mg to about 3 mg, about 0.8 mg to about 2 mg, about 0.8 mg to about 1 mg, or about 0.8 mg to about 0.9 mg.

[0064] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.9 mg to about 10 mg, about 0.9 mg to about 9 mg, about 0.9 mg to about 8 mg, about 0.9 mg to about 7 mg, about 0.9 mg to about 6 mg, about 0.9 mg to about 5 mg, about 0.9 mg to about 4 mg, about 0.9 mg to about 3 mg, about 0.9 mg to about 2 mg, or about 0.9 mg to about 1 mg.

[0065] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, or about 1 mg to about 2 mg.

[0066] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, or about 2 mg to about 3 mg.

[0067] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 10 mg, about 0.3 mg to about 10 mg, about 0.4 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.6 mg to about 10 mg, about 0.7 mg to about 10 mg, about 0.8 mg to about 10 mg, about 0.9 mg to about 10 mg, about 1 mg to about 10 mg, about 2 mg to about 10 mg, about 3 mg to about 10 mg, about 4 mg to about 10 mg, about 5 mg to about 10 mg, about 6 mg to about 10 mg, about 7 mg to about 10 mg, about 8 mg to about 10 mg, or about 9 mg to about 10 mg.

[0068] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 9 mg, about 0.2 mg to about 9 mg, about 0.3 mg to about 9 mg, about 0.4 mg to about 9 mg, about 0.5 mg to about 9 mg, about 0.6 mg to about 9 mg, about 0.7 mg to about 9 mg, about 0.8 mg to about 9 mg, about 0.9 mg to about 9 mg, about 1 mg to about 9 mg, about 2 mg to about 9 mg, about 3 mg to about 9 mg, about 4 mg to about 9 mg, about 5 mg to about 9 mg, about 6 mg to about 9 mg, about 7 mg to about 9 mg, or about 8 mg to about 9 mg.

[0069] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 8 mg, about 0.2 mg to about 8 mg, about 0.3 mg to about 8 mg, about 0.4 mg to about 8 mg, about 0.5 mg to about 8 mg, about 0.6 mg to about 8 mg, about 0.7 mg to about 8 mg, about 0.8 mg to about 8 mg, about 0.9 mg to about 8 mg, about 1 mg to about 8 mg, about 2 mg to about 8 mg, about 3 mg to about 8 mg, about 4 mg to about 8 mg, about 5 mg to about 8 mg, about 6 mg to about 8 mg, or about 7 mg to about 8 mg.

[0070] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 7 mg, about 0.2 mg to about 7 mg, about 0.3 mg to about 7 mg, about 0.4 mg to about 7 mg, about 0.5 mg to about 7 mg, about 0.6 mg to about 7 mg, about 0.7 mg to about 7 mg, about 0.8 mg to about 7 mg, about 0.9 mg to about 7 mg, about 1 mg to about 7 mg, about 2 mg to about 7 mg, about 3 mg to about 7 mg, about 4 mg to about 7 mg, about 5 mg to about 7 mg, or about 6 mg to about 7 mg.

[0071] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 6 mg, about 0.2 mg to about 6 mg, about 0.3 mg to about 6 mg, about 0.4 mg to about 6 mg, about 0.5 mg to about 6 mg, about 0.6 mg to about 6 mg, about 0.7 mg to about 6 mg, about 0.8 mg to about 6 mg, about 0.9 mg to about 6 mg, about 1 mg to about 6 mg, about 2 mg to about 6 mg, about 3 mg to about 6 mg, about 4 mg to about 6 mg, or about 5 mg to about 6 mg.

[0072] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 5 mg, about 0.2 mg to about 5 mg, about 0.3 mg to about 5 mg, about 0.4 mg to about 5 mg, about 0.5 mg to about 5 mg, about 0.6 mg to about 5 mg, about 0.7 mg to about 5 mg, about 0.8 mg to about 5 mg, about 0.9 mg to about 5 mg, about 1 mg to about 5 mg, about 2 mg to about 5 mg, about 3 mg to about 5 mg, or about 4 mg to about 5 mg.

[0073] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 4 mg, about 0.2 mg to about 4 mg, about 0.3 mg to about 4 mg, about 0.4 mg to about 4 mg, about 0.5 mg to about 4 mg, about 0.6 mg to about 4 mg, about 0.7 mg to about 4 mg, about 0.8 mg to about 4 mg, about 0.9 mg to about 4 mg, about 1 mg to about 4 mg, about 2 mg to about 4 mg, or about 3 mg to about 4 mg.

[0074] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 3 mg, about 0.2 mg to about 3 mg, about 0.3 mg to about 3 mg, about 0.4 mg to about 3 mg, about 0.5 mg to about 3 mg, about 0.6 mg to about 3 mg, about 0.7 mg to about 3 mg, about 0.8 mg to about 3 mg, about 0.9 mg to about 3 mg, about 1 mg to about 3 mg, or about 2 mg to about 3 mg.

[0075] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 2 mg, about 0.2 mg to about 2 mg, about 0.3 mg to about 2 mg, about 0.4 mg to about 2 mg, about 0.5 mg to about 2 mg, about 0.6 mg to about 2 mg, about 0.7 mg to about 2 mg, about 0.8 mg to about 2 mg, about 0.9 mg to about 2 mg, or about 1 mg to about 2 mg.

[0076] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.1 mg to about 1 mg, about 0.2 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.4 mg to about 1 mg, about 0.5 mg to about 1 mg, about 0.6 mg to about 1 mg, about 0.7 mg to about 1 mg, about 0.8 mg to about 1 mg, or about 0.9 mg to about 1 mg.

[0077] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 3 mg, about 0.2 mg to about 2.9 mg, about 0.2 mg to about 2.8 mg, about 0.2 mg to about 2.7 mg, about 0.2 mg to about 2.6 mg, about 0.2 mg to about 2.5 mg, about 0.2 mg to about 2.4 mg, about 0.2 mg to about 2.3 mg, about 0.2 mg to about 2.2 mg, about 0.2 mg to about 2.1 mg, or about 0.2 mg to about 2.0 mg.

[0078] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.3 mg to about 3 mg, about 0.3 mg to about 2.9 mg, about 0.3 mg to about 2.8 mg, about 0.3 mg to about 2.7 mg, about 0.3 mg to about 2.6 mg, about 0.3 mg to about 2.5 mg, about 0.3 mg to about 2.4 mg, about 0.3 mg to about 2.3 mg, about 0.3 mg to about 2.2 mg, about 0.3 mg to about 2.1 mg, or about 0.3 mg to about 2.0 mg.

[0079] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.4 mg to about 3 mg, about 0.4 mg to about 2.9 mg, about 0.4 mg to about 2.8 mg, about 0.4 mg to about 2.7 mg, about 0.4 mg to about 2.6 mg, about 0.4 mg to about 2.5 mg, about 0.4 mg to about 2.4 mg, about 0.4 mg to about 2.3 mg, about 0.4 mg to about 2.2 mg, about 0.4 mg to about 2.1 mg, or about 0.4 mg to about 2.0 mg.

[0080] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.5 mg to about 3 mg, about 0.5 mg to about 2.9 mg, about 0.5 mg to about 2.8 mg, about 0.5 mg to about 2.7 mg, about 0.5 mg to about 2.6 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 2.4 mg, about 0.5 mg to about 2.3 mg, about 0.5 mg to about 2.2 mg, about 0.5 mg to about 2.1 mg, or about 0.5 mg to about 2.0 mg.

[0081] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 3 mg, about 0.3 mg to about 3 mg, about 0.4 mg to about 3 mg, about 0.5 mg to about 3 mg, about 0.6 mg to about 3 mg, about 0.7 mg to about 3 mg, about 0.8 mg to about 3 mg, about 0.9 mg to about 3 mg, or about 1 mg to about 3 mg.

[0082] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.9 mg, about 0.3 mg to about 2.9 mg, about 0.4 mg to about 2.9 mg, about 0.5 mg to about 2.9 mg, about 0.6 mg to about 2.9 mg, about 0.7 mg to about 2.9 mg, about 0.8 mg to about 2.9 mg, about 0.9 mg to about 2.9 mg, or about 1 mg to about 2.9 mg.

[0083] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.8 mg, about 0.3 mg to about 2.8 mg, about 0.4 mg to about 2.8 mg, about 0.5 mg to about 2.8 mg, about 0.6 mg to about 2.8 mg, about 0.7 mg to about 2.8 mg, about 0.8 mg to about 2.8 mg, about 0.9 mg to about 2.8 mg, or about 1 mg to about 2.8 mg.

[0084] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.7 mg, about 0.3 mg to about 2.7 mg, about 0.4 mg to about 2.7 mg, about 0.5 mg to about 2.7 mg, about 0.6 mg to about 2.7 mg, about 0.7 mg to about 2.7 mg, about 0.8 mg to about 2.7 mg, about 0.9 mg to about 2.7 mg, or about 1 mg to about 2.7 mg.

[0085] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.6 mg, about 0.3 mg to about 2.6 mg, about 0.4 mg to about 2.6 mg, about 0.5 mg to about 2.6 mg, about 0.6 mg to about 2.6 mg, about 0.7 mg to about 2.6 mg, about 0.8 mg to about 2.6 mg, about 0.9 mg to about 2.6 mg, or about 1 mg to about 2.6 mg.

[0086] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.5 mg, about 0.3 mg to about 2.5 mg, about 0.4 mg to about 2.5 mg, about 0.5 mg to about 2.5 mg, about 0.6 mg to about 2.5 mg, about 0.7 mg to about 2.5 mg, about 0.8 mg to about 2.5 mg, about 0.9 mg to about 2.5 mg, or about 1 mg to about 2.5 mg.

[0087] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.4 mg, about 0.3 mg to about 2.4 mg, about 0.4 mg to about 2.4 mg, about 0.5 mg to about 2.4 mg, about 0.6 mg to about 2.4 mg, about 0.7 mg to about 2.4 mg, about 0.8 mg to about 2.4 mg, about 0.9 mg to about 2.4 mg, or about 1 mg to about 2.4 mg.

[0088] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.3 mg, about 0.3 mg to about 2.3 mg, about 0.4 mg to about 2.3 mg, about 0.5 mg to about 2.3 mg, about 0.6 mg to about 2.3 mg, about 0.7 mg to about 2.3 mg, about 0.8 mg to about 2.3 mg, about 0.9 mg to about 2.3 mg, or about 1 mg to about 2.3 mg.

[0089] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.2 mg, about 0.3 mg to about 2.2 mg, about 0.4 mg to about 2.2 mg, about 0.5 mg to about 2.2 mg, about 0.6 mg to about 2.2 mg, about 0.7 mg to about 2.2 mg, about 0.8 mg to about 2.2 mg, about 0.9 mg to about 2.2 mg, or about 1 mg to about 2.2 mg.

[0090] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2.1 mg, about 0.3 mg to about 2.1 mg, about 0.4 mg to about 2.1 mg, about 0.5 mg to about 2.1 mg, about 0.6 mg to about 2.1 mg, about 0.7 mg to about 2.1 mg, about 0.8 mg to about 2.1 mg, about 0.9 mg to about 2.1 mg, or about 1 mg to about 2.1 mg.

[0091] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of ​​the subject at a dose of about 0.2 mg to about 2 mg, about 0.3 mg to about 2 mg, about 0.4 mg to about 2 mg, about 0.5 mg to about 2 mg, about 0.6 mg to about 2 mg, about 0.7 mg to about 2 mg, about 0.8 mg to about 2 mg, about 0.9 mg to about 2 mg, or about 1 mg to about 2 mg.

[0092] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the subject at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, or about 5 mg to the affected area.

[0093] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the subject at a dose of about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg to the affected area.

[0094] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the subject at a dose of about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg to the affected area.

[0095] In one embodiment, for any method disclosed herein, KX-01 is about 0.0003 mg / cm 2 ~about 10mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0096] In one embodiment, for any method disclosed herein, KX-01 is about 0.001 mg / cm 2 ~about 0.4mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0097] In one embodiment, for any method disclosed herein, KX-01 is about 0.005 mg / cm 2 ~about 0.1mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0098] In one embodiment, for any method disclosed herein, KX-01 is about 0.005 mg / cm 2 ~ approx. 0.02 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0099] In one embodiment, for any method disclosed herein, KX-01 is about 0.025 mg / cm 2 ~about 0.1mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0100] In one embodiment, for any method disclosed herein, KX-01 is about 0.001 mg / cm 2 , about 0.002mg / cm 2 , about 0.003mg / cm 2 , about 0.004mg / cm 2 , about 0.005mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.02 mg / cm 2 , about 0.03mg / cm 2, about 0.04 mg / cm 2 , about 0.05mg / cm 2 , about 0.06mg / cm 2 , about 0.07mg / cm 2 , about 0.08 mg / cm 2 , about 0.09mg / cm 2 , about 0.1mg / cm 2 , about 0.15mg / cm 2 , about 0.2mg / cm 2 , about 0.25mg / cm 2 , about 0.3mg / cm 2 , about 0.35mg / cm 2 , or about 0.4 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0101] In one embodiment, for any method disclosed herein, KX-01 is about 0.005 mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009 mg / cm 2 , about 0.01mg / cm 2 , about 0.015mg / cm 2 , about 0.02 mg / cm 2 , about 0.025mg / cm 2 , about 0.03mg / cm 2 , about 0.035mg / cm 2 , about 0.04 mg / cm 2 , about 0.045mg / cm 2 , about 0.05mg / cm 2 , about 0.055mg / cm 2 , about 0.06mg / cm 2 , about 0.065mg / cm 2 , about 0.07mg / cm 2 , about 0.075mg / cm 2 , about 0.08 mg / cm 2 , about 0.085mg / cm 2 , about 0.09mg / cm 2 , about 0.095mg / cm 2 , or about 0.1 mg / cm 2is administered to the affected area of ​​the subject at a dose of

[0102] In one embodiment, for any method disclosed herein, KX-01 is about 0.025 mg / cm 2 , about 0.02 mg / cm 2 , about 0.015mg / cm 2 , about 0.01mg / cm 2 , about 0.005mg / cm 2 , about 0.002mg / cm 2 , about 0.001mg / cm 2 , about 0.0005mg / cm 2 , about 0.0002 mg / cm 2 , or about 0.0001 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0103] In one embodiment, for any method disclosed herein, KX-01 is about 0.025 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0104] In one embodiment, for any method disclosed herein, KX-01 is about 0.02 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0105] In one embodiment, for any method disclosed herein, KX-01 is about 0.015 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0106] In one embodiment, for any method disclosed herein, KX-01 is about 0.01 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0107] In one embodiment, for any method disclosed herein, KX-01 is about 0.005 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0108] In one embodiment, for any method disclosed herein, KX-01 is about 0.002 mg / cm 2is administered to the affected area of ​​the subject at a dose of

[0109] In one embodiment, for any method disclosed herein, KX-01 is about 0.001 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0110] In one embodiment, for any method disclosed herein, KX-01 is about 0.0005 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0111] In one embodiment, for any method disclosed herein, KX-01 is about 0.0002 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0112] In one embodiment, for any method disclosed herein, KX-01 is about 0.0001 mg / cm 2 is administered to the affected area of ​​the subject at a dose of

[0113] In one embodiment, for any method disclosed herein, KX-01 is about 0.01 cm 2 ~about 300cm 2 The compound is administered to the affected area of ​​a subject.

[0114] In one embodiment, for any method disclosed herein, KX-01 is about 0.01 cm 2 ~about 200cm 2 , about 0.01 cm 2 ~about 100cm 2 , about 0.01 cm 2 ~Approx. 75cm 2 , about 0.01 cm 2 ~about 50cm 2 , or about 0.01 cm 2 ~about 25cm 2 The compound is administered to the affected area of ​​a subject.

[0115] In one embodiment, for any of the methods disclosed herein, KX-01 is about 0.1 cm 2 ~about 300cm 2 , about 0.1cm 2~about 200cm 2 , about 0.1cm 2 ~about 100cm 2 , about 0.1cm 2 ~Approx. 75cm 2 , about 0.1cm 2 ~about 50cm 2 , or about 0.1 cm 2 ~about 25cm 2 The compound is administered to the affected area of ​​a subject.

[0116] In one embodiment, for any method disclosed herein, KX-01 is about 1 cm 2 ~about 300cm 2 , about 1cm 2 ~about 200cm 2 , about 1cm 2 ~about 100cm 2 , about 1cm 2 ~Approx. 75cm 2 , about 1cm 2 ~about 50cm 2 , or about 1 cm 2 ~about 25cm 2 The compound is administered to the affected area of ​​a subject.

[0117] In one embodiment, for any method disclosed herein, KX-01 is about 10 cm 2 ~about 300cm 2 , about 10cm 2 ~about 200cm 2 , about 10cm 2 ~about 100cm 2 , about 10cm 2 ~Approx. 75cm 2 , about 10cm 2 ~about 50cm 2 , or about 10 cm 2 ~about 25cm 2 The compound is administered to the affected area of ​​a subject.

[0118] In one embodiment, for any method disclosed herein, KX-01 is about 25 cm 2 ~about 300cm 2 , about 25cm 2 ~about 200cm 2 , about 25cm 2 ~about 100cm2 , about 25cm 2 ~Approx. 75cm 2 , or about 25 cm 2 ~about 50cm 2 The compound is administered to the affected area of ​​a subject.

[0119] In one embodiment, for any method disclosed herein, KX-01 is about 25 cm 2 ~about 100cm 2 , about 25cm 2 ~about 90cm 2 , about 25cm 2 ~about 80cm 2 , or about 25 cm 2 ~about 70cm 2 , about 25cm 2 ~about 60cm 2 , about 25cm 2 ~about 50cm 2 , about 25cm 2 ~about 40cm 2 , or about 25 cm 2 ~about 30cm 2 The compound is administered to the affected area of ​​a subject.

[0120] In one embodiment, for any method disclosed herein, KX-01 is about 0.01 cm 2 , 0.1cm 2 , 1cm 2 , 2cm 2 , 3cm 2 , 4cm 2 , 5cm 2 , 6cm 2 , 7cm 2 , 8cm 2 , 9cm 2 , 10cm 2 , 15cm 2 , 20cm 2 , 25cm 2 , 30cm 2 , 35cm 2 , 40cm 2 , 45cm 2 , 50cm 2 , 55cm 2 , 60cm 2 , 65cm 2 , 70cm 2 , 75cm2 , 80cm 2 , 85cm 2 , 90cm 2 , 95cm 2 , or 100cm 2 The compound is administered to the affected area of ​​a subject.

[0121] In one embodiment, for any method disclosed herein, KX-01 is about 25 cm 2 , about 30cm 2 , about 35cm 2 , about 40cm 2 , about 45cm 2 , about 50cm 2 , approx. 55cm 2 , about 60cm 2 , approx. 65cm 2 , about 70cm 2 , about 75cm 2 , about 80cm 2 , approx. 85cm 2 , about 90cm 2 , about 95cm 2 , or about 100 cm 2 The compound is administered to the affected area of ​​a subject.

[0122] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of ​​the subject, and the affected area of ​​the subject is the skin.

[0123] In one embodiment, for any of the methods disclosed herein, KX-01 is administered to a subject to an affected area of ​​the skin, the affected area being located in one or more locations independently selected from the scalp, forehead, forearm, face, nose, ears, eyelids, lips, neck, arms, hands, trunk, legs, and feet.

[0124] In one embodiment, for any of the methods disclosed herein, the subject has more than one affected area.

[0125] In one embodiment, for any of the methods disclosed herein, the subject has more than one affected area located in one or more locations independently selected from the scalp, forehead, forearms, face, nose, ears, eyelids, lips, neck, arms, hands, trunk, legs, and feet.

[0126] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once a week, once every 3 days, once every 2 days, once a day, twice a day, three times a day, or four times a day.

[0127] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once daily or twice daily.

[0128] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once daily.

[0129] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days.

[0130] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days.

[0131] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0132] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 1, 2, 3, 4, 5, 6, or 7 days.

[0133] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 1, 2, 3, 4 or 5 days.

[0134] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for one day.

[0135] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for two days.

[0136] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for three days.

[0137] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 4 days.

[0138] In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 5 days.

[0139] In one embodiment, for any of the methods disclosed herein, KX-01 is administered 1, 2, 3, 4, 5, or 6 days per week.

[0140] In one embodiment, for any of the methods disclosed herein, KX-01 is administered 2, 3, 4, 5, or 6 days per week.

[0141] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily for two or more consecutive days per week, followed by discontinuation for the remainder of the week.

[0142] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily on every other day.

[0143] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily every 3, 4, 5, 6, or 7 days.

[0144] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily for 2 consecutive days every 3, 4, 5, 6, or 7 days.

[0145] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily for three consecutive days every 4, 5, 6, or 7 days.

[0146] In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily for four consecutive days every 5, 6, or 7 days.

[0147] In one embodiment, for any of the methods disclosed herein, KX-01 is administered until the actinic keratosis is completely treated.

[0148] In one embodiment, for any of the methods disclosed herein, KX-01 is administered until the actinic keratosis is completely treated, i.e., until the actinic keratosis has disappeared from the affected area of ​​the subject.

[0149] In one embodiment, for any of the methods disclosed herein, KX-01 is administered locally.

[0150] In one embodiment, for any of the methods disclosed herein, administration of KX-01 reduces the number and / or severity of local skin reactions or other adverse side effects in the subject as compared to other treatments for actinic keratosis. In one embodiment, the other treatments for actinic keratosis include topical administration of ingenol mebutate.

[0151] In one embodiment, for any of the methods disclosed herein, administration of KX-01 reduces the number of subjects with local skin reactions or other adverse side effects compared to other treatments for actinic keratosis.

[0152] In one embodiment, for any of the methods disclosed herein, the local skin reaction is selected from the group consisting of vesiculation, pustulation, erosion, ulceration, redness, swelling, peeling, scaling, hard lump, dryness, pus, and blistering.

[0153] In one embodiment, for any of the methods disclosed herein, the other side effects are selected from the group consisting of application site pain, application site pruritus, application site irritation, application site swelling, application site burning, application site infection, periorbital swelling, nasopharyngitis, chills, sore throat, droopy eyes, puffy eyes, hypopigmentation, hyperpigmentation, and headache.

[0154] In one embodiment, the present application relates at least in part to KX-01 for use (e.g., topical use) in the treatment and / or prevention of actinic keratosis. In certain aspects, KX-01 is for use in a subject in need thereof at the doses, dosing schedules, and / or in one or more affected areas described herein.

[0155] In one aspect, this application relates at least in part to the use (e.g., topical use) of KX-01 in the treatment and / or prevention of actinic keratosis. In certain aspects, KX-01 is used in a dose, dosing schedule, and / or in one or more affected areas as described herein in a subject in need thereof.

[0156] In one embodiment, the present application relates at least in part to the use of KX-01 in the manufacture of a medicament for the treatment and / or prevention of actinic keratosis. In certain aspects, KX-01 is used in the doses, dosing schedules, and / or in one or more affected areas as described herein in a subject in need thereof.

[0157] Unless otherwise specified, the terms "KX-01" and "KX2-391" refer to the basic form, i.e., the "free base," of the compound having the following structure: [ka]

[0158] The term "KX-01 MSA" refers to the mesylate salt of KX-01, i.e., the salt compound produced by reacting KX-01 with methanesulfonic acid.

[0159] As used herein, "KX-01" may also be referred to as "KX01," "KX2-391," or "KX-2-391."

[0160] KX-01 and its salts, such as KX-01 MSA, and their preparation are disclosed in PCT Application Publication Nos. WO2008 / 082637, WO2008 / 144045, and WO2010 / 135429, which are incorporated by reference herein in their entireties.

[0161] Actinic keratosis or "AK" is a common precancerous skin condition caused by overexposure to ultraviolet light. AK appears as rough, dry, tan, pink, or red lesions (lesions) that often appear on parts of the head, including the face, throat, neck, nose, forehead, ears, or lips. AK may also appear on other parts of the body that are exposed to strong sunlight for long periods of time, such as the hands, back, and other areas of the trunk and legs.

[0162] As used herein, the term "trunk" refers to a part of a subject that is not an arm, leg, or head.

[0163] AK is most commonly seen in fair-skinned, middle-aged or elderly individuals. Subjects with AK may have a single lesion or multiple lesions. AK can lead to squamous cell carcinoma.

[0164] Clinical variants of AK include classic (common), hypertrophic (or hyperkeratotic), atrophic, AK with keratin, pigmented AK, actinic cheilitis, and Bowenoid AK. Unless otherwise specified, the methods described herein are applicable to all clinical variants, including those listed herein.

[0165] Treatments for AK include cryosurgery, surgical excision and / or abrasion of the affected area, photodynamic therapy, and topical preparations (e.g., creams, gels, patches, etc.) containing steroids, fluorouracil, diclofenac, imiquimod, and 5-aminolevulinic acid (Ameluz®).

[0166] The approved treatment for AK is Picato (ingenol mebutate)®, a gel containing ingenol mebutate (0.015% or 0.05%). The gel is applied once daily for three consecutive days to affected areas of the face or scalp (0.015%), or once daily for two consecutive days to affected areas of the trunk or limbs (0.05%).

[0167] Skin toxicity associated with the use of other AK therapeutics, such as Picato (ingenol mebutate)®, is known to result in undesirable side effects or adverse reactions, namely local skin reactions (LSRs), including vesiculation, pustulation, erosion, ulceration, redness, swelling, peeling, scaling, hard lumps, dryness, pus, and blistering. Other side effects include application site pain, application site pruritus, application site irritation, application site swelling, application site burning, application site infection, periorbital swelling, nasopharyngitis, chills, sore throat, droopy eyes, swollen eyes, hypopigmentation, hyperpigmentation, and headache.

[0168] The phrase "until actinic keratosis disappears," as used herein, refers to an instance in which a subject suffering from AK has had their lesions substantially or completely disappeared from the treatment site of the subject. In one embodiment, "substantially," in this context, refers to more than 50% of the AK lesions having disappeared from the treatment site of the subject. In another embodiment, "substantially" refers to more than 60% of the AK lesions having disappeared from the treatment site of the subject. In another embodiment, "substantially" refers to more than 70% of the AK lesions having disappeared from the treatment site of the subject. In another embodiment, "substantially" refers to more than 80% of the AK lesions having disappeared from the treatment site of the subject. In another embodiment, "substantially" refers to more than 90% of the AK lesions having disappeared from the treatment site of the subject. In another embodiment, "substantially" refers to more than 95% of the AK lesions having disappeared from the treatment site of the subject. In another embodiment, "substantially" refers to more than 99% of the AK lesions having disappeared from the treatment site of the subject.

[0169] As used throughout the disclosure, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods, and reference to "a dosage" includes reference to one or more dosages and equivalents thereof known to those skilled in the art.

[0170] The term "comprising" is intended to mean that the method includes the recited elements, but does not exclude other elements. "Consisting essentially of" when used to define a method means excluding other elements that are of some essential importance to the combination when used for its intended purpose. Thus, a method consisting essentially of the elements defined herein does not exclude substantial method steps. "Consisting of" means excluding more than substantial method steps. Embodiments defined by each of these transitional terms are within the scope of this application.

[0171] Unless otherwise specified, the terms "approximately" and "about" are synonymous. In one embodiment, "approximately" and "about" refer to ±5%, ±4.5%, ±4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01% of the stated amount, value, or duration. In another embodiment, "approximately" and "about" refer to ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% of the recited amount, value, or duration. In yet another embodiment, "approximately" and "about" refer to ±1% of the recited amount, value, or duration. In yet another embodiment, "approximately" and "about" refer to ±0.5% of the recited amount, value, or duration. In yet another embodiment, "approximately" and "about" refer to ±0.1% of the recited amount, value, or duration.

[0172] The term "subject" includes any organism having or at risk of developing actinic keratosis. In one embodiment, the term "subject" refers to a mammal having or at risk of developing actinic keratosis. In one embodiment, the term subject refers to a human having or at risk of developing actinic keratosis. The term "patient" is meant to be synonymous with "subject" unless otherwise specified.

[0173] The term "therapeutically effective amount" as used herein refers to the amount of a formulation, e.g., KX-01, to treat, ameliorate, or prevent an identified disease or condition, e.g., AK, or to exert a detectable therapeutic or suppressive effect. The effect can be detected by any analytical method known in the art. The exact effective amount for each subject will vary depending on the subject's weight, size, and health status; the nature and extent of symptoms; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for each given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician.

[0174] For any compound, the therapeutically effective amount can be estimated in an animal model, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (therapeutically effective dose in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The dosage may vary within this range depending on the dosage form employed and the sensitivity of the subject.

[0175] Dosage and administration are adjusted to provide sufficient level of active ingredient or maintain desired effect.Factors that can be considered include severity of disease, location of disease in subject, general health condition of subject, age, weight, and sex of subject, diet, time and frequency of administration, drug combination, reaction sensitivity, and resistance / response to treatment.KX-01 may be administered daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every other week, or once every 2 weeks, depending on half-life and clearance rate.

[0176] For any of the methods described herein, KX-01 may be administered topically, intradermally, interepidermally, intragingivally, intraocularly, intranasally, ophthalmically, transdermally, periodontally, subconjunctivally, sublingually, transmucosally, or auricle. In one embodiment, KX-01 may be administered topically.

[0177] All percentages and ratios used herein are by weight unless otherwise specified.

[0178] All documents cited herein, including any cross-referenced or related patents or applications, are incorporated herein by reference in their entirety unless expressly excluded or limited. The citation of any document is not an admission that it is prior art with respect to any subject matter disclosed or claimed herein, or that it alone, or in combination with any other reference, teaches, suggests or discloses such subject matter. Furthermore, if a meaning or definition of a term in this specification conflicts with a meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this specification shall control.

[0179] While particular embodiments of the present disclosure have been illustrated and described, various other changes and modifications can be made without departing from the spirit and scope of the disclosure, and the appended claims include all such changes and modifications that are within the scope of the disclosure.

[0180] Other features and advantages of the present application are apparent from the various examples, which are provided to illustrate various elements and methods useful in practicing the present application.

[0181] The examples do not limit the claimed application: based on this disclosure, one of ordinary skill in the art will be able to identify and employ other elements and methodologies useful in practicing the present application. EXAMPLES

[0182] Two clinical trials (detailed in Examples 1 and 2) were conducted to evaluate the activity and safety of topically administered KX-01 in subjects with actinic keratosis. Preliminary data from these studies suggested that KX-01 exhibits clinically relevant activity in treating actinic keratosis of the face and scalp as well as actinic keratosis of the forearm. KX-01 has a very good safety profile with limited systemic exposure when administered for 5 days. Local tolerability appears to be very good, with local skin reactions (LSR) consisting mainly of mild to moderate erythema and desquamation. KX-01 was found to be safe.

[0183] Example 1 - Phase 1 study of KX-01 administered locally to the forearm for 3 or 5 days A phase 1, single-center, safety, tolerability, and pharmacokinetic study of KX-01 was conducted in subjects with AKs in the dorsal forearm. This was an open-label, uncontrolled, non-randomized, group-sequential clinical trial conducted at a single investigational center in the United States. The primary objective of the study was to evaluate the safety, tolerability, and pharmacokinetics of KX-01 in subjects with AKs. The secondary objective was to evaluate the activity of KX-01 administered locally to the dorsal forearm in subjects with AKs.

[0184] Adult subjects aged 18 years or older with clinically typical AK lesions on the dorsal forearm who met all inclusion criteria and no exclusion criteria were enrolled in a sequential cohort. Cohort 1, N=4, 25 cm with 4–8 clinically typical AK lesions on the dorsal forearm 2 0.5 mg of KX-01 administered topically to the site daily for three consecutive days. Cohort 2, N=10, 100 cm with 8–16 clinically typical AK lesions on the dorsal forearm 2 2.0 mg of KX-01 administered topically to the site daily for three consecutive days. Cohort 3, N=8, 25 cm with 4–8 clinically typical AK lesions on the dorsal forearm 2 0.5 mg of KX-01 administered topically to the site daily for 5 consecutive days. Cohort 4, N=8, 100 cm with 8–16 clinically typical AK lesions on the dorsal forearm 2 2.0 mg of KX-01 administered topically to the site daily for 5 consecutive days.

[0185] KX-01 was administered topically on treatment days. All subjects were monitored for safety and tolerability including LSR, AEs, vital signs, clinical laboratories, ECG, and physical examination at baseline and at pre-specified treatment and follow-up visits on days 1, 2, 3, 4, 5, 8, 10, 17, 31, and 45. The number of AK lesions was recorded at baseline on days 4, 10, 17, 31, and 45. Standardized photographs of treatment sites were taken. Plasma samples for pharmacokinetics were collected at pre-specified time points on days 1-8.

[0186] LSR (erythema, peeling / scaling, crusting, swelling, vesiculation / pustule formation, erosion / ulceration) was assessed by the investigator or a trained designee on a 4-point scale according to protocol. Subject assessment of symptoms related to treatment site irritation (stinging / burning, pruritus) was assessed on a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Subjects were questioned about spontaneously reported AEs at each study visit before assessment of LSR. LSRs and AEs were reported separately. All LSRs were followed up until resolution or stabilization.

[0187] A total of 30 subjects were enrolled, and 29 subjects completed the study. The subject population consisted of 19 male and 11 female subjects. The overall mean age was 63.1 years, and the mean weight was 194.9 pounds. All but one subject was white; none were Hispanic or Latino of any race. Demographic and baseline characteristics by cohort are summarized in Table 1.

[0188] Table 1. Demographic and baseline characteristics of subjects [Table 1] M=male;F=female

[0189] Local tolerability was acceptable. All 30 subjects were assessed by the investigator as having an LSR. In general, LSRs appeared on day 2 and tended to peak around day 5 in the 3-day treatment cohorts (cohorts 1 and 2) and around day 10 in the 5-day treatment cohorts (cohorts 3 and 4) before returning to near baseline. No subjects in any category had an LSR score of 4. No subjects had vesicles or pustules. Fifteen subjects had erythema and / or peeling / scaling scores of 1 or 2 at day 45 and were followed until resolution or stabilization. Maximum LSRs are shown by category and cohort in Table 2.

[0190] Subjects were specifically asked about stinging, burning, and itching at the application site at each visit. Maximum scores for each symptom are summarized in Table 2. Generally, symptoms appeared as early as day 2, peaked in severity and incidence on days 8 and 10, and resolved by day 45. Two subjects (one in cohort 2 and one in cohort 4) with mild to moderate symptoms have been followed until resolution or stabilization. One subject in cohort 3 had severe pruritus on day 17 that reduced in severity to mild at the next visit on day 31 without the need for concomitant medication.

[0191] Table 2 Number of subjects (%) with maximum LSR score by LSR category and cohort [Table 2] LSR=local skin reaction; Max=maximum. Investigator assessment of LSR, 5-point LSR score: 0=none, 1=minimal, 2=mild, 3=moderate, 4=severe. Subjects were assessed for LSR using a 4-point LSR score: 0=none, 1=mild, 2=moderate, 3=severe.

[0192] For post-hoc analysis of the LSR, a composite score was calculated by summing the scores of the six LSR categories for each subject as determined by the investigator at each assessment visit. Possible composite scores range from 0 to 24. Figure 1 shows the mean composite scores over time by cohort.

[0193] Four of the 30 subjects reported 10 treatment-emergent adverse events (TEAEs). All TEAEs were mild to moderate and responded to treatment when administered. No TEAEs were reported in cohort 1. One subject in cohort 2 had a mild upper respiratory tract infection unrelated to study drug on days 38-44. One subject in cohort 3 had a headache on day 2, back pain on days 4-5, and a urinary tract infection on days 6-14; these AEs were considered mild in severity and possibly related to study drug. The same subject had mild joint pain on days 16-49, moderate osteoarthritis on days 16-49, and moderate pain from injection of platelet-rich plasma for treatment of osteoarthritis considered unrelated to study drug on days 43-44. In cohort 4, one subject had a moderately severe basal cell carcinoma outside the treatment site considered unrelated to study drug on days 3-25, which was surgically removed. Another subject reported moderate muscle weakness and myositis unrelated to the study drug but associated with fenofibrate, which he was taking for hyperlipidemia. Fenofibrate was discontinued. At follow-up, the weakness had resolved and the myositis had improved but persisted.

[0194] There were no serious adverse events (SAEs) or deaths in this study. No subjects discontinued treatment or follow-up due to adverse events. One subject in cohort 2 withdrew consent for personal reasons after study drug application on day 1.

[0195] Clinical activity: All four cohorts showed a decrease in mean baseline AK lesion counts over time, with some patients showing complete clearance by day 45 (Table 3).

[0196] Table 3. Summary of complete / partial clearance by cohort and median (range) number of AK lesions by visit date and cohort in KX01-AK-01-US [Table 3] a Complete clearance - 100% reduction in AK lesions at day 45 compared to baseline. b Partial clearance - ≥75% reduction in AK lesions at day 45 compared to baseline.

[0197] This study provided preliminary evidence of clinical activity of topically administered KX-01 for the treatment of AKs. The data also suggested that a 5-day regimen may provide superior activity over a 3-day regimen, as indicated by a higher rate of complete and partial clearance of AKs in subjects treated for 5 days. Local skin reactions appeared to be primarily mild in nature. Safety and activity findings from this study provided impetus to initiate a larger multicenter study.

[0198] Example 2a - Phase 2a Study of KX-01 Administered Topically to the Face or Scalp Described herein is an ongoing Phase 2a, open-label, multicenter activity and safety study of topically administered KX-01 in subjects with AKs on the face or scalp. The primary objective is to evaluate the activity of topically administered KX-01 on the face or scalp in subjects with AKs, with 100% clearance at day 57 defined as the complete remission rate. The secondary objectives are to evaluate the activity of topically administered KX-01 on days 1-57 based on the reduction in AK lesion counts from baseline, to evaluate safety and tolerability and pharmacokinetics, and to compare dosing regimens (5-day treatment vs. 3-day treatment) in terms of activity and safety in subjects with AKs on the face or scalp. This uncontrolled, nonrandomized study is being conducted at 16 study sites in the United States. Two cohorts are sequentially enrolling approximately 80 subjects each. Enrollment in cohort 1 is closed, and enrollment in cohort 2 is ongoing. The two treatment cohorts are summarized below. Cohort 1: 25 cm with 4–8 clinically typical AK lesions 2 0.5 mg of KX-01 was administered topically to the consecutive treatment sites for 5 consecutive days. Cohort 2: 25 cm with 4–8 clinically typical AK lesions 2 0.5 mg of KX-01 was administered topically to the consecutive treatment sites for three consecutive days.

[0199] On the day of treatment, 0.5 mg of KX-01 was administered by facility staff onto 25 cm 2 The drug will be administered topically to the site of AK. All subjects will be monitored for safety and tolerability including LSR, hyperpigmentation, hypopigmentation, scarring, AEs, vital signs, laboratory tests, ECG, and physical examination at baseline and at pre-specified time points during treatment and follow-up on days 1, 2, 3, 4, 5, 8, 15, 29, and 57. The number of AK lesions will be recorded at baseline, days 8, 15, 29, and 57. Subjects achieving complete clearance of AK at day 57 will be followed up for the number of AK lesions, LSR, and AEs at 3, 6, 9, and 12 months after day 57 during the relapse follow-up period. Standard photographs of the treatment sites will be taken at baseline, days 8, and 57. Plasma samples will be collected at pre-specified time points on days 1 and 5 in cohort 1 and days 1 and 3 in cohort 2.

[0200] LSR (erythema, peeling / scaling, crusting, swelling, vesiculation / pustulation, erosion / ulceration) will be assessed by the investigator or trained designee using a rating scale from 0 (absent) to 4 (worst) based on the protocol-defined LSR assessment criteria. The presence or absence of hyperpigmentation, hypopigmentation, and scarring will also be assessed. Application site reactions not classified as LSR will be reported as AEs. Subjects will be questioned about any spontaneously reported AEs at each study visit prior to assessment of LSR. LSRs and AEs will be reported separately. All LSRs, pigmentation, and scarring at treatment sites will be followed up until resolution or stabilization.

[0201] Eighty-two eligible subjects were enrolled in Cohort 1. Subject demographics and baseline characteristics are shown in Table 4. There were no discontinuations prior to day 57. Because this study is ongoing, the data presented are considered preliminary. Data from Cohort 2 (3-day dosing) are not yet available.

[0202] Table 4. Demographic and baseline characteristics of subjects in cohort 1 [Table 4]

[0203] Of the 67 subjects who visited on Day 57, seven had no LSR at the treatment site throughout the study. The majority of subjects were found to have erythema (60 / 67, 90%) and peeling / scaling (47 / 67, 70%). Most of these LSRs were scored as 1 and 2. Crusting was observed in 26 / 67 (39%) subjects, mostly with a score of 1. Swelling was reported in 14 / 67 (21%) subjects. All but two subjects had swelling with a score of 1, one with a score of 2, and one with a score of 3. Three subjects had vesiculation / pustulation, and nine subjects had erosion / ulceration. LSR was generally observable from Day 3, reaching maximum scores by Days 5 and 8, before declining to or approaching baseline by Days 29 and 57. Of the 60 subjects with LSR, all but eight subjects had returned to baseline LSR by Day 57. Eight of these subjects had erythema scored 1 or 2, scaling / scaling scored 1, and / or crusting and were followed by the investigator until resolution or stabilization.

[0204] A detailed summary of local skin reactions (LSR) from this KX01-AK-002 study is provided in Table 5 below.

[0205] Table 5. Summary of local skin reactions by evaluable visit set in Cohort 1 [Table 5-1] [Table 5-2] Note 1: Cohort 1 = 25 cm 2 Treatment area / 5 consecutive days of treatment / 0.5 mg KX-01 administered locally. 2: Data are presented as number of subjects with a particular finding / number of subjects evaluated at each visit. Calculated percentages are shown in brackets.

[0206] Table 6 shows the maximum post-dosing LSR scores and maximal LSR scores experienced in the combined Picato (ingenol mebutate)® Phase 3 registration study for the treatment of facial and scalp AK. The data suggest that 5 days of treatment with topically administered KX-01 may have a milder local safety profile compared to that reported for Picato (ingenol mebutate).

[0207] Table 6. Summary of maximum local skin reactions after baseline determination for Picato (ingenol mebutate)® [Table 6] a Source: NDA202833: Statistical Review and Evaluation Pep005 (ingenol mebutate) gel, 0.015%; Table 9. b Values ​​are the number of subjects in the evaluable set classified by maximum LSR grade after baseline establishment. Percentages are based on number of subjects.

[0208] As a post-hoc analysis of the LSR, a composite score was calculated by summing the scores of the six LSR categories for each subject at each assessment visit. Possible composite scores range from 0 to 24. Figure 2 shows the mean composite scores over time in cohort 1.

[0209] All 82 subjects enrolled in cohort 1 were included in the AE analysis. Twenty-six of the 82 subjects in cohort 1 reported a total of 54 TEAEs. All TEAEs were mild to moderate in severity, with the exception of one serious case of small bowel obstruction, which was reported as an SAE (discussed below). Seven subjects reported 12 TEAEs considered related to KX-01. There were six application site reactions, including one mild tenderness, two mild stinging, and three mild pruritus. Other treatment-related AEs included two cases of mild dizziness, one mild darkening of hair near the treatment site, and one mild headache. There was one case of "worsening alanine aminotransferase elevation" from a baseline of 58 IU / mL to 61 IU / mL on day 22. A case of mild conjunctivitis near the treatment site was reported on day 4 and continued through day 5. The subject revealed only mucus discharge from the eyes due to contact lens use. There was no associated redness, itching, pain or swelling, and KX-01 did not get into the eye.

[0210] Three SAEs occurred in two subjects, all of which were considered unrelated to the study drug. All SAEs required hospitalization. One subject was an 84-year-old male who had a small bowel obstruction on day 56, a transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) on day 67, and postoperative cardiac ischemia on day 72. He subsequently recovered. The other subject was a 67-year-old Caucasian male who was hospitalized for a TURP for BPH on day 17. He recovered uneventfully.

[0211] There was one case of cancer unrelated to the study drug, a 61-year-old man diagnosed with squamous cell carcinoma outside the treatment site that was subsequently resected on Day 3. This AE was not considered serious.

[0212] Of the enrolled subjects, 67 reached the day 57 visit. Twenty-four of the 67 subjects (36%, 95% CI: 24% to 47%) reached the primary endpoint, defined as 100% clearance of AK lesions in the treatment area at day 57. Fifteen of 35 subjects treated on the face (43%, 95% CI: 26% to 59%) reached 100% clearance, whereas nine of 32 subjects treated on the scalp (28%, 95% CI: 13% to 44%) reached 100% clearance.

[0213] Thirty-four of 67 subjects (51%, 95% CI: 39% to 63%), 21 / 35 (60%, 95% CI: 44% to 76%) treated on the face and 13 / 32 (41%, 95% CI: 24% to 58%) treated on the scalp, had at least a 75% reduction in AK lesions compared to baseline at day 57. These data are summarized in Table 7.

[0214] Table 7. Analysis of Clearance Rates at Day 57 - Evaluable Set in Cohort 1 [Table 7] Note 1: The data deadline is October 12, 2016. 2: Cohort 1 = 25cm 2 Treatment area / 5 consecutive days of treatment / 0.5 mg KX-01 administered locally. (a) Clearance is calculated relative to the assessment at the first visit.

[0215] The activity of KX-01 in terms of reduction in AK lesion counts is summarized in Table 8. The median lesion count gradually decreased from 6.0 to 2.0 over the 57 day observation period.

[0216] Table 8. Summary of AK lesion numbers by visit date in cohort 1, KX01-AK-002 [Table 8]

[0217] KX-01 administered topically once daily for 5 days appears to be safe and well tolerated. There were few treatment-related adverse events and no treatment-related severe or serious adverse events.

[0218] The 5-day dosing regimen of KX-01 was associated with mild and reversible LSRs consisting mainly of erythema and peeling / scaling. No grade 4 LSRs were observed after 5 days of treatment with KX-01 in this study.

[0219] Preliminary results (Examples 1, 2a, and 2b) show that KX-01 administered topically once daily for up to five days exerts clinically relevant activity in treating AK of the dorsal forearm and both the face and scalp. The data suggest that a five-day regimen of KX-01 has greater activity than a three-day regimen.

[0220] Cross-study aggregation with published results for Picato (ingenol mebutate)® suggests that the activity of a 5-day treatment regimen of locally administered KX-01 may be comparable to that observed in Phase 3 trials of Picato (ingenol mebutate)® (Table 9).

[0221] Table 9. Inter-study summary of complete clearance rates - KX-01 and Picato (ingenol mebutate)® [Table 9] aKX01-AK-01-US and KX01-AK-002 studies, data cut-off date is October 12, 2016. b Picato (ingenol mebutate)® Prescribing Information, September 2016

[0222] Pharmacokinetic results after up to 5 consecutive days of treatment with KX-01 demonstrated low systemic exposure (<1 ng / mL) and limited drug accumulation in most subjects. The data suggest that topical treatment with KX-01 for 5 days has optimal activity and safety.

[0223] Example 2b - Phase 2a Study of KX-01 Administered Topically to the Face or Scalp The Phase 2a study described in Example 2a was completed with 84 eligible subjects enrolled in each of two cohorts, one cohort receiving treatment for 5 consecutive days and the other cohort receiving treatment for 3 consecutive days. The results are shown below and in Figure 5.

[0224] Table 10. AK clearance in the two cohorts at 57 days after treatment [Table 10]

[0225] Table 11. Summary of maximum local skin reactions after baseline determination for Picato (ingenol mebutate)® [Table 11] a. Source: NDA202833: Statistical Review and Evaluation Pep005 (ingenol mebutate) gel, 0.015%; Table 9. b. Values ​​are the number of subjects in the evaluable set classified by maximum LSR grade after baseline establishment. Percentages are based on number of subjects.

[0226] Example 3 - Summary of PK Results from the Studies in Examples 1 and 2 KX-01 was studied in adult subjects with actinic keratosis of the dorsal forearm (Example 1) and actinic keratosis of the face or scalp (Examples 2a and 2b). In Example 1, the plasma pharmacokinetics (PK) of KX-01 after topical administration was evaluated by collecting plasma on days 1 and 3 of a 3-day regimen and days 1 and 5 of a 5-day regimen (Table 12). In Examples 2a and 2b, plasma samples were collected on days 1 and 5 of cohort 1 (Table 13). Plasma samples at similar time points were collected on days 1 and 3 of cohort 2. KX-01 was measured in human plasma using a validated LC-MS / MS assay with a lower limit of quantitation (LLOQ) of 0.1 ng / mL.

[0227] Table 12. Example 1 - Treatment regimens and PK collection times [Table 12]

[0228] Table 13: Examples 2a and 2b - Treatment regimens and PK collection times [Table 13]

[0229] Review of the PK data across these studies suggests that some of the plasma concentration data may be spurious: 75% of concentrations in both studies were below the level of quantification (BLQ).

[0230] In the KX01-AK-002 study, the administration site was 25 cm from the face or scalp. 2PK data are available for 84 subjects in Cohort 1 treated with 0.5 mg KX-01 once daily for 5 days and 84 subjects in Cohort 2 treated once daily for 3 days. Of a total of 336 plasma samples analyzed from these 84 subjects after 1 day of treatment, 15 samples (approximately 4%) were above the limit of quantification. At pre-dose on day 5, 8 of the 84 subjects (approximately 9%) had quantifiable KX-01 concentrations. On day 5 of dosing, 42 of the 84 subjects had measurable plasma concentrations detected 4 hours after dosing. With the exception of 3 abnormal samples, all measurable plasma concentrations were below 0.7 ng / mL.

[0231] Two of the three abnormal PK samples were observed with plasma concentrations of 44 and 23 ng / mL occurring at 1 and 0.5 hours post-dose in two different subjects on Day 5. These primary PK samples were analyzed again with comparable results. Analysis of the backup PK samples resulted in concentrations of 0.351 ng / mL and BLQ, respectively. These results are more consistent with KX-01 plasma concentrations from 82 additional subjects and other samples obtained from these subjects. One PK sample from a subject had an apparent plasma concentration of over 12,500 ng / mL, whereas the backup sample had a plasma concentration of 30 ng / mL. The most likely cause of these abnormal results is cross-contamination, and the results are not indicative of the actual KX-01 plasma concentration. All laboratories in the KX01-AK-002 study were retrained on the proper collection, handling, and storage of PK samples.

[0232] Collectively, the PK results from these studies demonstrated that following 5 consecutive days of topical treatment with KX-01, the observed systemic exposure was low (<1 ng / mL) with limited drug accumulation.

[0233] Example 4 - Phase 3 study of KX-01 The Phase 3, double-blind, vehicle-controlled, randomized, parallel-group, multicenter efficacy and safety study of KX2-391 in adult subjects with AKs on the face or scalp will be conducted at approximately 25 sites in the United States to test: 25cm of face or scalp 2 Efficacy of KX-01 administered topically daily for 5 consecutive days compared to vehicle control in the treatment of adults with actinic keratosis (AK) when applied to consecutive sites of Safety of KX-01 administered topically daily for 5 consecutive days in terms of local skin reactions (LSR) and other safety assessments, e.g., adverse events (AEs) and laboratory evaluations The proportion of partial responders, defined as at least 75% clearance of AK lesions in treatment sites on the face or scalp at day 57 between the KX-01-treated and vehicle-treated groups

[0234] In adults with actinic keratosis of the face or scalp, topical treatment with KX administered daily for 5 consecutive days shows more complete clearance (defined as 100% clearance of clinically typical and visible AK lesions at day 57) than vehicle administered daily for 5 consecutive days.

[0235] Enrollment will be managed so that approximately two-thirds of enrolled subjects will be treated on the face and approximately one-third of enrolled subjects will be treated on the scalp. Eligible subjects will be centrally randomized to treatment in a 1:1 (KX-01 or vehicle) ratio in each treatment site subgroup. That is, in the subgroups of subjects whose faces or scalps will be treated, half of the subjects will be randomized to receive the active treatment and the other half will be randomized to receive the vehicle control.

[0236] Treatment areas will be marked with an indelible marker at the study site on day 1. Subjects will be provided with a single daily dosage unit to be administered at home for 5 consecutive days. Subjects in both groups will be instructed to wash their hands and treatment areas before applying KX-01, then dry the treatment areas. A small amount of KX-01 will be applied to the fingertips and then 25 cm 2Gently scrub the entire treatment area with KX-01. Subjects are instructed to wash their hands after applying KX-01, avoid washing the treatment area for at least 8 hours, and avoid contact of KX-01 with their eyes. Subjects will return for follow-up at pre-specified time points through Day 57 for safety, LSR, and activity (number of AK lesions) assessments. All subjects with unresolved LSR, hypo- or hyperpigmentation, scarring, or treatment-related AEs at Day 57 will return for post-study follow-up every 7-28 days until resolution or deemed stable by the investigator. Subjects who have achieved 100% clearance of AK lesions in the treatment area at Day 57 will be invited to enroll in an extension protocol of up to 12 months to determine recurrence rates and safety.

[0237] A sufficient number of subjects will be screened to randomly select approximately 300 subjects. Each site will randomly select a minimum of 10 subjects and a maximum of 20 subjects.

[0238] Each subject will remain on study for up to 85 days, with screening up to 28 days prior to Day 1, treatment for 5 consecutive days, and follow-up until Day 57. Use of any non-investigational drug therapy on AK lesions at the treatment site is prohibited until Day 57.

[0239] Selection Criteria 1. Male and female ≥ 18 years old 2. The following face or scalp treatment areas: -Size is 25cm 2 Sequential parts of Contains 4-8 clinically typical, visible, and separate AK lesions 3. Subjects in good health as determined by the investigator based on: Medical History Physical Examination (PE) findings Electrocardiogram (ECG), clinical chemistry, hematology, and urinalysis results 4. Women must be postmenopausal (>45 years of age and amenorrhea for at least 12 months) or surgically sterilized (by hysterectomy, bilateral oophorectomy, or tubal ligation); or, if capable of childbearing, must have used highly effective contraception for at least 30 days or one menstrual cycle, whichever is longer, prior to treatment with KX-01 and agree to continue using highly effective contraception for at least 30 days after the last dose of KX-01. Highly effective contraception includes oral hormonal contraceptives, hormonal contraceptive implants, injections or patches, intrauterine devices, or complete abstinence for 2 weeks prior to treatment and throughout the duration of the study. 5. Non-vasectomized men must agree to use barrier contraception from screening through 90 days after their last dose of KX-01. 6. All subjects must agree not to donate sperm or eggs or conceive from screening until 90 days after their last dose of KX-01. 7. Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to administration of study treatment on Day 1. 8. Willingly avoid direct sun or ultraviolet (UV) light exposure to the face or scalp 9. Able to understand and willing to sign the Informed Consent Form (ICF)

[0240] Exclusion criteria 1. Clinically atypical and / or rapidly changing AK lesions in the treatment area, e.g., hypertrophic, hyperkeratotic, refractory disease (having previously undergone cryosurgery twice) and / or cutaneous keratoses 2. Location of treatment area: Anywhere except the face or scalp Incompletely healed wounds up to 5 cm - Suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) less than 5 cm 3. Have previously been treated with KX-01 4. Anticipated need for hospitalization or inpatient surgery 5. Treatment with 5-fluorouracil (5-FU), imiquimod, ingenol mebutate, diclofenac, photodynamic therapy, or other agents for AK within 2 cm of the treatment site within 8 weeks prior to the screening visit 6. Use of the following treatments and / or medications within 2 weeks prior to the screening visit: Cosmetic or therapeutic procedures within 2 cm of the selected treatment area (e.g., use of liquid nitrogen, surgical excision, curettage, dermabrasion, medium or greater depth chemical peels, laser skin resurfacing) Acid-containing treatments (e.g., salicylic acid or fruit acids, e.g., alpha and beta hydroxyl acids and glycolic acid), topical retinoids, or mild chemical peels within 2 cm of the selected treatment area Topical ointments (non-medicated / non-irritating lotions and creams are acceptable) or topical steroids within 2 cm of the selected treatment area; artificial tanning agents within 5 cm of the selected treatment area 7. Use of the following treatments and / or medications within 4 weeks prior to the screening visit: Treatment with immunomodulatory agents (e.g., azathioprine), cytotoxic agents (e.g., cyclophosphamide, vinblastine, chlorambucil, methotrexate) or interferon / interferon inducers Treatment with systemic drugs that suppress the immune system (e.g., cyclosporine, prednisone, methotrexate, alefacept, infliximab) UVA or UVB treatment / therapy 8. Use of systemic retinoids (e.g., isotretinoin, acitretin, bexarotene) within 6 months prior to the screening visit 9. History of hypersensitivity and / or allergy to any of the components of the investigational drug 10. Any skin disease (e.g., atopic dermatitis, psoriasis, eczema) or condition (e.g., scars, wounds) that in the investigator's opinion may interfere with the conduct or evaluation of the study or where participation in the study would expose the subject to unacceptable risk 11. Any other significant uncontrolled or unstable medical disease or condition for which, in the opinion of the investigator, participation in the study would expose the subject to unacceptable risk 12. Pregnant or breastfeeding women 13. Participation in an investigational drug study in which an investigational drug was administered within 30 days or 5 half-lives of the investigational drug, whichever is longer, prior to dosing

[0241] Activity assessment The investigator or designee will count AK lesions at the treatment sites in all subjects at screening and on days 1 (baseline), 8, 15, 29, and 57.

[0242] Safety assessment Safety will be assessed on Days 1 (baseline), 6, 8, 15, 29, and 57 by recording LSRs, AEs, and serious adverse events (SAEs).

[0243] Laboratory evaluation of hematology, biochemistry, and urinalysis values, measurements of weight, height, and vital signs, evaluation of ECG, and PE will be performed at prespecified time points.

[0244] Subjects will be asked about spontaneously reported AEs at each study visit prior to the LSR assessment. AEs will be reported separately from the LSR.

[0245] Other evaluations The LSR assessment is the investigator's (or trained designee's) assessment of the treatment site for signs of erythema, peeling / scaling, crusting, swelling, vesiculation / pustulation, and erosion / ulceration using a scale ranging from 0=none, 1=mild (slight, barely perceptible), 2=moderate (definitely present), and 3=severe (marked, severe).

[0246] In addition to the LSR, treatment sites are assessed for hypo- and hyperpigmentation and the presence of scarring. Application site reactions not classified as LSR (e.g., pruritus, pain, infection) are reported as adverse events. Investigators are trained in the use of this LSR scale with representative photographs. Standard photographs are taken before dosing on day 1, and on days 6, 8, 15, 29, and 57.

[0247] The primary efficacy endpoint is the rate of complete clearance of AK lesions, defined as the percentage of subjects free of clinically visible AK lesions in treatment sites at day 57. The secondary efficacy endpoint is the rate of partial clearance of AK lesions, defined as the percentage of subjects with a 75% or greater reduction in the number of AK lesions identified on day 1 (baseline) in treatment sites at day 57. The reduction in AK lesion counts from days 1 to 57 is also examined.

[0248] Safety endpoints include evaluation of LSR, pigmentation and scarring, AEs, SAEs, events of special interest, and clinical laboratory data; the results of other safety assessments (vital signs, PE, ECG) will also be evaluated.

[0249] Patient populations included (1) intention-to-treat (ITT) / safety analysis population: all randomized subjects who received at least 1 day of treatment and returned for a follow-up visit, and (2) per-protocol (PP) / evaluable population: all randomized subjects who received at least 4 of 5 doses, followed protocol on entry criteria, were not receiving concomitant medications that could affect efficacy, and returned for the final visit at Day 57. This was the primary efficacy analysis population.

[0250] The primary efficacy endpoint, complete clearance rate, will be compared based on the Cochran-Mantel-Haenszel (CMH) method adjusting for treatment site (face or scalp) between treatment groups. In addition, comparison of complete clearance rate between treatment groups will be performed separately for face and scalp treatment subgroups. Partial clearance rate will be analyzed in the same way as the primary efficacy endpoint (complete clearance rate).

[0251] To show consistency with overall results, complete clearance rates are also tabulated by subgroups such as sex, age (<65 or ≥65 years), study center, baseline lesion count (4, 5, 6 or 7, 8), and skin type (Fitzpatrick I / II or III / IV / V / VI). Outliers will be explained clinically in the study report.

[0252] AK lesion counts at baseline, day 57, and other visits, and changes from baseline in AK lesion counts at each visit will be summarized using descriptive statistics (i.e., mean, standard deviation, median, minimum, and maximum) and then contrasted by treatment group.

[0253] Safety analyses will be performed in the safety analysis population.

[0254] Treatment-emergent AEs (TEAEs) are defined as AEs that develop after administration of a medication or pre-existing AEs that worsen after administration of a medication. For AEs, verbatim terms in case report forms / electronic case report forms (CRF / eCRF) are aligned to preferred terms (PTs) and system organ classes (SOCs) using the Medical Dictionary for Diagnosis and Treatment (MedDRA; v 16.0 or later). Subject incidence of AEs is presented by SOC. Incidence of TEAEs is summarized by treatment group. TEAEs are summarized by severity, relationship to study treatment, and treatment group. Subject incidence of SAEs is also presented by treatment group. Laboratory values ​​are summarized at baseline and at each subsequent time point by treatment group using descriptive statistics. Changes from baseline are also summarized by treatment. In addition, shift tables (i.e., baseline low-normal-high vs. follow-up low-normal-high in a 3 × 3 contingency table) are provided to assess laboratory changes from baseline to follow-up in each treatment group. Investigator-reported local skin reactions, pigmentation, and scarring will be presented and summarized for all subjects by visit and treatment group. Events of special interest will be summarized.

[0255] Example 5 - KX-01 Phase 3 Extension Study Protocol Overview (Relapse Follow-up Protocol) A 12-month prospective long-term follow-up study of complete responders from two Phase 3 studies of KX-01 administered topically in adult subjects with AK on the face or scalp will be conducted at approximately 25 sites in the United States to determine recurrence of actinic keratosis (AK) at the treatment site in subjects who had complete clearance at day 57 in the Phase 3 studies of KX-01 and to investigate adverse events (AEs) at the treatment site.

[0256] Eligibility Criteria 1. Complete clearance defined as 100% clearance of AK lesions at treatment sites at Day 57 in subjects from two Phase 3 studies 2. Willingly avoid direct sun or ultraviolet (UV) light exposure to the face or scalp 3. Able to understand and willingly comply with study procedures and willingly sign the Informed Consent Form (ICF).

[0257] Subjects will not be re-treated with the investigational drug. Subjects will be prohibited from receiving radiation field treatments or treatments that may mask the occurrence of AK lesion recurrence (e.g., topical ingenol mebutate, 5-fluorouracil [5-FU], diclofenac, imiquimod) in or within 2 cm of the treatment site at any time during the study. Treatment of isolated lesions such as cryotherapy or biopsy will be permitted for AK lesions appearing in selected treatment sites. Clinic visits will be conducted 3, 6, 9, and 12 months after the feeder Phase 3 study day 57 visit. The number of AK lesions in the treatment sites will be counted at the visits. If a subject receives lesion-specific treatment (i.e., cryotherapy or biopsy) for a lesion seen in the treatment site, the treated lesion will be considered a recurrence. Information will be collected regarding intercurrent illnesses, treatments that may result in immunosuppression, and treatment with agents known to alter AK. Adverse events and serious adverse events (SAEs) including skin cancer (basal cell carcinoma [BCC] / squamous cell carcinoma [SCC] / melanoma) at or within 5 cm of the treatment site border will be reported. Other AEs and SAEs will be reported if the investigator considers them related to study treatment. Standard photographs will be taken at all visits.

[0258] Efficacy will be assessed for recurrence of AK lesions, defined as any identified AK lesions in selected treatment sites during the 12-month follow-up period in subjects who had achieved complete clearance at the day 57 visit of the Phase 3 study, regardless of previous treatment received. Treated lesions will be considered recurrent if the subject undergoes lesion-specific treatment (i.e., cryotherapy or biopsy) for a lesion found in the treatment area.

[0259] Safety will be assessed for AEs at selected treatment sites over a 12-month follow-up period, as well as other AEs reported by investigators as related to treatment.

[0260] The analysis population will include all subjects who have achieved complete clearance at the Day 57 visit of the feeder Phase 3 study, regardless of prior treatment. Both efficacy and safety analyses will be performed based on this population.

[0261] Analyses by prior treatment group (active treatment vs vehicle control) are contrasted primarily in tables and graphs. Kaplan-Meier recurrence rates with 95% confidence intervals (CI) are estimated by prior treatment at scheduled post-baseline visits (3, 6, 9, and 12 months). Time when lesions were observed is assigned to the corresponding target study date (e.g., 91 days for the 3-month visit). Kaplan-Meier recurrence rates with 95% confidence intervals (CI) are estimated by prior treatment at scheduled post-baseline visits (3, 6, 9, and 12 months). Time when lesions were observed is assigned to the corresponding target study date (e.g., 91 days for the 3-month visit).

[0262] In addition, median time to recurrence (i.e., appearance of new or recurrent lesions at treated sites) based on Kaplan-Meier methods is tabulated by prior treatment. AK lesion counts at treated sites are summarized by prior treatment at each scheduled visit after baseline establishment. In addition, lesion counts (expressed as percentages) at treated sites normalized to the corresponding baseline lesion counts from the Phase 3 study are summarized by prior treatment at each scheduled visit after baseline establishment.

[0263] For AEs collected at treatment sites, case report forms / electronic case report forms (CRF / eCRF) terminology is aligned to preferred terms (PTs) and system organ classes (SOCs) using the Medical Dictionary for Diagnosis and Treatment (MedDRA; v 16.0 or later). Subject incidence of AEs is presented by SOC and PT. Incidence of AEs is summarized by prior therapy. Subject incidence of SAEs is presented by prior therapy. Adverse events reported by investigators as related to treatment are in the same format but assessed individually.

[0264] Example 6 - Comparison of skin reactions with KX-01 to Picato (ingenol mebutate)®, the standard of care for AK Initial data from patients in the studies described herein (e.g., Example 1 and Examples 2a and 2b) indicate that the efficacy of KX-01 for clearing AK lesions may be similar to that of Picato (ingenol mebutate)®, an approved treatment for AK. In addition, treatment with KX-01 results in fewer and less severe skin reactions in subjects compared to Picato (ingenol mebutate)®, i.e., less skin toxicity.

[0265] This is shown in Figures 3A and 3B, which show the skin reaction on the forearm of a subject on days 3 and 5 of treatment with Picato (ingenol mebutate)®, which indicates a severe skin reaction (Figure 3A). In comparison, the forearm of the subject on days 3 and 5 of treatment with KX-01 in subjects who had a 100% response to topical KX-01 treatment had minimal or no adverse skin reaction (Figure 3B).

[0266] Similarly, Figures 4A and 4B show adverse skin reactions on the forehead of a subject on days 4 and 15 of treatment with Picato (ingenol mebutate)®, which indicates a severe skin reaction (Figure 4A). In contrast, the forehead of a subject on days 8 and 57 of treatment with KX-01 in subjects who had a 100% response to topical KX-01 treatment also showed minimal or no adverse skin reactions (Figure 4B).

[0267] Comparisons in Figures 3A, 3B, 4A, and 4B show that no skin toxicity is observed with treatment of AKs with topically administered KX-01 compared to approved therapies for AKs. This is likely to be an important consideration for clinicians and patients, and to the extent that skin toxicity has limited the market for current treatment options for subjects with AKs, KX-01 may significantly expand the market due to its lower skin toxicity.

[0268] Equivalent The disclosure of this application may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore considered in all respects to be illustrative rather than limiting on the disclosure of the application described herein. The scope of the disclosure of this application is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalence of the claims are intended to be embraced therein.

Claims

1. KX-01 for treating and / or preventing actinic keratosis: 【Chemistry 1】 wherein the KX-01 is administered to an affected area of ​​a subject at a dose of 0.1 mg to 10 mg.

2. The affected area is 0.01 cm ２ ~300cm ２ The pharmaceutical composition of claim 1,

3. The affected area is 10cm ２ ~200cm ２ The pharmaceutical composition according to claim 1 or 2,

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the affected area is skin.

5. The affected area is 25cm ２ The pharmaceutical composition according to any one of claims 1 to 4,

6. The affected area is 100cm ２ The pharmaceutical composition according to any one of claims 1 to 4,

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the subject has one affected area.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein the subject has more than one affected area.

9. 9. The pharmaceutical agent of any one of claims 1 to 8, which is administered once a week, once every three days, once every two days, once a day, twice a day, three times a day, or four times a day.

10. The pharmaceutical composition of any one of claims 1 to 9, which is administered for 1, 2, 3, 4 or 5 days.

11. The pharmaceutical composition of any one of claims 1 to 9, which is administered for 1, 2, 3, 4, 5 or 6 days per week.

12. The pharmaceutical agent of any one of claims 1 to 11, which is administered once or twice daily for two or more consecutive days per week, followed by discontinuation of administration for the remainder of the week.

13. The pharmaceutical agent according to any one of claims 1 to 12, which is administered locally.

14. The method of any of claims 1 to 13, wherein the treatment reduces the number and / or severity of local skin reactions or other adverse side effects in the subject compared to other treatments for actinic keratosis.

15. The pharmaceutical composition of any one of claims 1 to 14, which is administered to the affected area of ​​a subject at a dose of 0.2 mg to 5 mg.

16. The pharmaceutical composition of any one of claims 1 to 15, which is administered to the affected area of ​​a subject at a dose of 0.5 mg to 2.5 mg.

17. 16. The pharmaceutical agent of claim 15 administered to an affected area of ​​a subject in a dose of 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 4 mg or 5 mg.

18. 17. The pharmaceutical agent of claim 16 administered to an affected area of ​​a subject at a dose of 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg or 2.5 mg.

19. The pharmaceutical composition of any one of claims 1 to 18, which is administered once a day.

20. The pharmaceutical composition of any one of claims 1 to 19, which is administered for three days.

21. The pharmaceutical composition of any one of claims 1 to 19, which is administered for 5 days.

22. 21. The pharmaceutical composition of any one of claims 1 to 20, administered at a dose of 0.5 mg once a day for three days.

23. 22. The pharmaceutical agent of any one of claims 1 to 19 and 21, administered at a dose of 0.5 mg once a day for 5 days.

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