阅读说明：本技术 治疗和/或预防光化性角化病的方法 (Method for treating and/or preventing actinic keratosis ) 是由 M-F.R.关 J.Y-N.刘 E.D.克莱默 D.L.卡特勒 J.方 于 2018-03-12 设计创作，主要内容包括：本申请涉及治疗和/或预防光化性角化病的方法,包括向需要的受试者给予治疗有效量的式(I)的KX-01。<Image he="234" wi="700" file="DDA0002260832880000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present application relates to a method for the treatment and/or prevention of actinic keratosis comprising administering to a subject in need thereof a therapeutically effective amount of KX-01 of formula (I).)

1. A method for the treatment and/or prevention of actinic keratosis comprising administering to a subject in need thereof a therapeutically effective amount of KX-01:

2. the method of claim 1, wherein the following doses of KX-01 are administered to the affected area of the subject: from about 0.1mg to about 10 mg.

3. The method of any one of claims 1-2, wherein the following doses of KX-01 are administered to the affected area of the subject: from about 0.2mg to about 5 mg.

4. The method of any of the above claims, wherein the following doses of KX-01 are administered to the affected area of the subject: from about 0.5mg to about 2.5 mg.

5. The method of any one of claims 1-3, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, about 1.7mg, about 1.8mg, about 1.9mg, about 2.0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3mg, about 4mg, or about 5 mg.

6. The method of any of the above claims, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, about 1.7mg, about 1.8mg, about 1.9mg, about 2.0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, or about 2.5 mg.

7. The method of any of the above claims, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.0003mg/cm²To about 10mg/cm²。

8. The method of any of the above claims, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.001mg/cm²To about 0.4mg/cm²。

9. The method of any one of claims 1-8, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.005mg/cm²To about 0.1mg/cm²。

10. The method of any one of claims 1-8, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.005mg/cm²To about 0.02mg/cm²。

11. The method of any one of claims 1-8, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.025mg/cm²To about 0.1mg/cm²。

12. The method of any one of claims 1-8, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.001mg/cm²About 0.002mg/cm²About 0.003mg/cm²About 0.004mg/cm²About 0.005mg/cm²About0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.02mg/cm²About 0.03mg/cm²About 0.04mg/cm²About 0.05mg/cm²About 0.06mg/cm²About 0.07mg/cm²About 0.08mg/cm²About 0.09mg/cm²About 0.1mg/cm²About 0.15mg/cm²About 0.2mg/cm²About 0.25mg/cm²About 0.3mg/cm²About 0.35mg/cm²Or about 0.4mg/cm²。

13. The method of any one of claims 1-8, wherein the following doses of KX-01 are administered to the affected area of the subject: about 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.015mg/cm²About 0.02mg/cm²About 0.025mg/cm²About 0.03mg/cm²About 0.035mg/cm²About 0.04mg/cm²About 0.045mg/cm²About 0.05mg/cm²About 0.055mg/cm²About 0.06mg/cm²About 0.065mg/cm²About 0.07mg/cm²About 0.075mg/cm²About 0.08mg/cm²About 0.085mg/cm²About 0.09mg/cm²About 0.095mg/cm²Or about 0.1mg/cm²。

14. The method of any one of claims 2-13, wherein the diseased area is about 0.01cm²To about 300cm²。

15. The method of any one of claims 2-13, wherein the diseased area is about 1cm²To about 200cm²About 1cm, of²To about 100cm²About 1cm, of²To about 75cm²About 1cm, of²To about 50cm²Or about 1cm²To about 25cm²。

16. The method of any one of claims 2-13, wherein the diseased area is about 10cm²To about 200cm²About 10cm, of²To about 100cm²About 10cm, of²To about 75cm²About 10cm, of²To about 50cm²Or about 10cm²To about 25cm²。

17. The method of any one of claims 2-13, wherein the diseased area is about 25cm²To about 200cm²About 25cm, of²To about 100cm²About 25cm, of²To about 75cm²Or about 25cm²To about 50cm²。

18. The method of any one of claims 2-13, wherein the diseased area is about 25cm²To about 100cm²About 25cm, of²To about 90cm²About 25cm, of²To about 80cm²Or about 25cm²To about 70cm²About 25cm, of²To about 60cm²About 25cm, of²To about 50cm²About 25cm, of²To about 40cm²Or about 25cm²To about 30cm²。

19. The method of any one of claims 2-13, wherein the diseased area is about 25cm²About 30cm, from the bottom²About 35cm, from the bottom²About 40cm²About 45cm, of²About 50cm²About 55cm²About 60cm²About 65cm, from the center²About 70cm²About 75cm²About 80cm²About 85cm, from the center²About 90cm, from the center of the tube²About 95cm, from the center of the sample²Or about 100cm²。

20. The method of any one of claims 2-19, wherein the affected area is skin.

21. The method of any one of claims 2-20, wherein the diseased area is located at one or more locations independently selected from the group consisting of: scalp, forehead, forearm, face, nose, ear, eyelid, lips, neck, arm, hand, torso, leg, and foot.

22. The method of any one of claims 1-21, wherein the subject has more than one diseased area.

23. The method of any one of claims 1-21, wherein KX-01 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.

24. The method of any one of claims 1-21, wherein KX-01 is administered once a day or twice a day.

25. The method of any one of claims 1-21, wherein KX-01 is administered once a day.

26. The method of any one of claims 1-21, 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.

27. The method of any one of claims 1-21, wherein KX-01 is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

28. The method of any one of claims 1-21, wherein KX-01 is administered for 1, 2, 3, 4, 5, 6, or 7 days.

29. The method of any one of claims 1-21, wherein KX-01 is administered for 1, 2, 3, 4, or 5 days.

30. The method of any one of claims 1-21, wherein KX-01 is administered weekly for 1, 2, 3, 4, 5, or 6 days.

31. The method of any one of claims 1-21, wherein KX-01 is administered weekly for 2, 3, 4, 5, or 6 days.

32. The method of any one of claims 1-21, wherein KX-01 is administered once or twice daily for more than one day per week and then is discontinued for the remainder of the week.

33. The method of any one of claims 1-21, wherein KX-01 is administered every other day, once or twice a day.

34. The method of any one of claims 1-21, wherein KX-01 is administered once or twice daily every three days, four days, five days, six days, or seven days.

35. The method of any one of claims 1-21, wherein KX-01 is administered every three days, every four days, every five days, every six days, or every seven days for two consecutive days, once or twice daily.

36. The method of any one of claims 1-21, wherein KX-01 is administered every four days, every five days, every six days, or every seven days for three consecutive days, once or twice daily.

37. The method of any one of claims 1-21, wherein KX-01 is administered every five, six or seven days for four consecutive days, once or twice daily.

38. The method according to any of the preceding claims, wherein KX-01 is administered until actinic keratosis is completely treated.

39. The method of any of the preceding claims, wherein KX-01 is administered topically.

40. The method of any one of claims 1-39, wherein the 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.

41. The method of any one of claims 1-39, wherein the administration of KX-01 reduces the number of subjects with a localized skin reaction or other adverse side effect compared to other treatments for actinic keratosis.

42. The method of claim 40 or 41, wherein the local skin reaction is selected from the group consisting of vesiculation, pustule formation, erosion, ulcer, redness, swelling, scaling, desquamation, hard mass, dryness, pus, and blisters.

43. The method of claim 42, wherein the other side effects are selected from the group consisting of pain at the site of administration, itching at the site of administration, irritation at the site of administration, swelling at the site of administration, burning sensation at the site of administration, infection at the site of administration, edema around the eye, nasopharyngitis, chills, sore throat, drooping eyelids, edema in the eye, hypopigmentation, hyperpigmentation, and headache.

Use of KX-01:

for use in the treatment and/or prevention of actinic keratosis in a subject in need thereof.

45. The use of claim 44, wherein KX-01 is for administration to an affected area of a subject at a dose of: from about 0.1mg to about 10 mg.

46. The use of any one of claims 44-45, wherein KX-01 is for administration to the affected area of a subject at a dose of: from about 0.2mg to about 5 mg.

47. The use of any one of claims 44-46, wherein KX-01 is for administration to an affected area of a subject at a dose of: from about 0.5mg to about 2.5 mg.

48. The use of any one of claims 44-46, wherein KX-01 is for administration to an affected area of a subject at a dose of: about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, about 1.7mg, about 1.8mg, about 1.9mg, about 2.0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3mg, about 4mg, or about 5 mg.

49. The use of any one of claims 44-48, wherein KX-01 is for administration to an affected area of a subject at a dose of: about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, about 1.7mg, about 1.8mg, about 1.9mg, about 2.0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, or about 2.5 mg.

50. The use of any one of claims 44-49, wherein KX-01 is for administration to an affected area of a subject at a dose of: about 0.0003mg/cm²To about 10mg/cm²。

51. The use of any one of claims 44-50, wherein KX-01 is for administration to an affected area of a subject at a dose of: about 0.001mg/cm²To about 0.4mg/cm²。

52. The use of any one of claims 44-51, wherein KX-01 is for administration to the affected area of a subject at a dose of: about 0.005mg/cm²To about 0.1mg/cm²。

53. The use of any one of claims 44-51, wherein KX-01 is for administration to the affected area of a subject at a dose of: about 0.005mg/cm²To about 0.02mg/cm²。

54. The use of any one of claims 44-51, wherein KX-01 is for administration to the affected area of a subject at a dose of: about 0.025mg/cm²To about 0.1mg/cm²。

55. The use of any one of claims 44-51, wherein KX-01 is for administration to the affected area of a subject at a dose of: about 0.001mg/cm²About 0.002mg/cm²About 0.003mg/cm²About 0.004mg/cm²About 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.02mg/cm²About 0.03mg/cm²About 0.04mg/cm²About 0.05mg/cm²About 0.06mg/cm²About 0.07mg/cm²About 0.08mg/cm²About 0.09mg/cm²About 0.1mg/cm²About 0.15mg/cm²About 0.2mg/cm²About 0.25mg/cm²About 0.3mg/cm²About 0.35mg/cm²Or about 0.4mg/cm²。

56. The use of any one of claims 44-51, wherein KX-01 is for administration to the affected area of a subject at a dose of: about 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.015mg/cm²About 0.02mg/cm²About 0.025mg/cm²About 0.03mg/cm²About 0.035mg/cm²About 0.04mg/cm²About 0.045mg/cm²About 0.05mg/cm²About 0.055mg/cm²About 0.06mg/cm²About 0.065mg/cm²About 0.07mg/cm²About 0.075mg/cm²About 0.08mg/cm²About 0.085mg/cm²About 0.09mg/cm²About 0.095mg/cm²Or about 0.1mg/cm²。

57. The use of any one of claims 45-56, wherein the diseased area is about 0.01cm²To about 300cm²。

58. The use of any one of claims 45-56, wherein the diseased area is about 1cm²To about 200cm²About 1cm, of²To about 100cm²About 1cm, of²To about 75cm²About 1cm, of²To about 50cm²Or about 1cm²To about 25cm²。

59. The use of any one of claims 45-56, wherein the diseased area is about 10cm²To about 200cm²About 10cm, of²To about 100cm²About 10cm, of²To about 75cm²About 10cm, of²To about 50cm²Or about 10cm²To about 25cm²。

60. The use of any one of claims 45-56, wherein the diseased area is about 25cm²To about 200cm²About 25cm, of²To about 100cm²About 25cm, of²To about 75cm²Or about 25cm²To about 50cm²。

61. The use of any one of claims 45-56, wherein the diseased area is about 25cm²To about 100cm²About 25cm, of²To about 90cm²About 25cm, of²To about 80cm²Or about 25cm²To about 70cm²About 25cm, of²To about 60cm²About 25cm, of²To about 50cm²About 25cm, of²To about 40cm²Or about 25cm²To about 30cm²。

62. The use of any one of claims 45-56, wherein the diseased area is about 25cm²About 30cm, from the bottom²About 35cm, from the bottom²About 40cm²About 45cm, of²About 50cm²About 55cm²About 60cm²About 65cm, from the center²About 70cm²About 75cm²About 80cm²About 85cm, from the center²About 90cm, from the center of the tube²About 95cm, from the center of the sample²Or about 100cm²。

63. The use of any one of claims 45-62, wherein the affected area is skin.

64. The use of any one of claims 45-63, wherein the diseased region is located at one or more positions independently selected from the group consisting of: scalp, forehead, forearm, face, nose, ear, eyelid, lips, neck, arm, hand, torso, leg, and foot.

65. The use of any one of claims 44-64, wherein the subject has more than one diseased area.

66. The use of any one of claims 44-64, wherein KX-01 is for administration to an affected area of a subject 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.

67. The use of any one of claims 44-64, wherein KX-01 is for administration to an affected area of a subject once a day or twice a day.

68. The use of any one of claims 44-64, wherein KX-01 is for once-a-day application to an affected area of a subject.

69. The use of any one of claims 44-64, wherein KX-01 is for administration to an affected area of a 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.

70. The use of any one of claims 44-64, wherein KX-01 is for application to an affected area of a subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

71. The use of any one of claims 44-64, wherein KX-01 is for administration to an affected area of a subject for 1, 2, 3, 4, 5, 6, or 7 days.

72. The use of any one of claims 44-64, wherein KX-01 is for administration to an affected area of a subject for 1, 2, 3, 4, or 5 days.

73. The use of any one of claims 44-64, wherein KX-01 is for weekly administration to an affected area of a subject for 1, 2, 3, 4, 5, or 6 days.

74. The use of any one of claims 44-64, wherein KX-01 is for weekly administration to an affected area of a subject for 2, 3, 4, 5, or 6 days.

75. The use of any one of claims 44-64, wherein KX-01 is for administration to the affected area of the subject once or twice daily for more than one day per week, followed by discontinuation of the administration for the remainder of the week.

76. The use of any one of claims 44-64, wherein KX-01 is for administration to the affected area of the subject every other day, once or twice daily.

77. The use of any one of claims 44-64, wherein KX-01 is for administration to the affected area of the subject every three days, every four days, every five days, every six days, or every seven days, once or twice daily.

78. The use of any one of claims 44-64, wherein KX-01 is for administration to the affected area of the subject every three days, every four days, every five days, every six days, or every seven days for two consecutive days, once or twice daily.

79. The use of any one of claims 44-64, wherein KX-01 is for administration to the affected area of the subject every four days, every five days, every six days, or every seven days, for three consecutive days, once or twice daily.

80. The use of any one of claims 44-64, wherein KX-01 is for administration to the affected area of the subject every five, six or seven days for four consecutive days, once or twice daily.

81. The use of any one of claims 43-80, wherein KX-01 is for application to the affected area of the subject until actinic keratosis is completely treated.

82. The use of any one of claims 43-80, wherein KX-01 is for topical application to an affected area of a subject.

83. The use of any one of claims 43-82, wherein 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.

84. The use of any one of claims 43-82, wherein KX-01 reduces the number of subjects with a localized skin reaction or other adverse side effect compared to other treatments for actinic keratosis.

85. The use of claim 83 or 84, wherein the topical skin reaction is selected from the group consisting of vesiculation, pustule formation, erosion, ulcer, redness, swelling, scaling, desquamation, hard mass, dryness, pus, and blisters.

86. The use of claim 85, wherein the other side effects are selected from the group consisting of pain at the site of administration, itching at the site of administration, irritation at the site of administration, swelling at the site of administration, burning sensation at the site of administration, infection at the site of administration, edema around the eye, nasopharyngitis, chills, sore throat, drooping eyelids, edema of the eye, hypopigmentation, hyperpigmentation, and headache.

Background

Actinic keratosis or solar keratosis is the growth of squamous scleroderma (lesions) caused by solar ultraviolet damage. They are usually present in areas exposed to sunlight, such as the face, bald scalp, lips and back of the hand, and often bulge, are rough in texture and resemble warts. Most turn red, but some turn tan, pink and/or flesh. Up to ten percent of actinic keratosis, if left untreated, progresses to Squamous Cell Carcinoma (SCC), the second most common form of skin cancer. In rare cases, actinic keratosis may also turn into basal cell carcinoma, the most common form of skin cancer. It is estimated that more than 5800 million Americans suffer from actinic keratosis. Methods of treatment of actinic keratosis include cryotherapy, surgical resection, chemical dissection, photodynamic therapy, laser skin replacement and/or medicated gels and creams. In view of the prevalence of actinic keratosis, which can become skin cancer if not properly treated, there is a need to develop further treatments.

Disclosure of Invention

In one aspect, the present application is directed, at least in part, to a method of treating and/or preventing actinic keratosis comprising administering to a subject in need thereof a therapeutically effective amount of KX-01:

in one aspect, KX-01 is administered to the affected area of the subject at the following doses: from about 0.1mg to about 10 mg.

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: from about 0.2mg to about 5 mg.

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: from about 0.5mg to about 2.5 mg.

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

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

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.0003mg/cm²To about 10mg/cm²。

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.001mg/cm²To about 0.4mg/cm²。

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.005mg/cm²To about 0.1mg/cm²

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.005mg/cm²To about 0.02mg/cm²。

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.025mg/cm²To about 0.1mg/cm²。

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.001mg/cm²About 0.002mg/cm²About 0.003mg/cm²About 0.004mg/cm²About 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.02mg/cm²About 0.03mg/cm²About 0.04mg/cm²About 0.05mg/cm²About 0.06mg/cm²About 0.07mg/cm²About 0.08mg/cm²About 0.09mg/cm²About 0.1mg/cm²About 0.15mg/cm²About 0.2mg/cm²About 0.25mg/cm²About 0.3mg/cm²About 0.35mg/cm²Or about 0.4mg/cm²。

In one aspect, KX-01 is administered to the affected area of the subject at the following doses: about 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.015mg/cm²About 0.02mg/cm²About 0.025mg/cm²About 0.03mg/cm²About 0.035mg/cm²About 0.04mg/cm²About 0.045mg/cm²About 0.05mg/cm²About 0.055mg/cm²About 0.06mg/cm²About 0.065mg/cm²About 0.07mg/cm²About 0.075mg/cm²About 0.08mg/cm²About 0.085mg/cm²About 0.09mg/cm²About 0.095mg/cm²Or about 0.1mg/cm²。

In one aspect, the diseased area of the subject is about 0.01cm²To about 300cm²。

In one aspect, the diseased area of the subject is about 1cm²To about 200cm²About 1cm, of²To about 100cm²About 1cm, of²To about 75cm²About 1cm, of²To about 50cm²Or about 1cm²To about 25cm²。

In one aspect, the diseased area of the subject is about 10cm²To about 200cm²About 10cm, of²To about 100cm²About 10cm, of²To about 75cm²About 10cm, of²To about 50cm²Or about 10cm²To about 25cm²。

In one aspect, the diseased area of the subject is about 25cm²To about 200cm²About 25cm, of²To about 100cm²About 25cm, of²To about 75cm²Or about 25cm²To about 50cm²。

In one aspect, the subject isThe affected area is about 25cm²To about 100cm²About 25cm, of²To about 90cm²About 25cm, of²To about 80cm²Or about 25cm²To about 70cm²About 25cm, of²To about 60cm²About 25cm, of²To about 50cm²About 25cm, of²To about 40cm²Or about 25cm²To about 30cm²。

In one aspect, the diseased area of the subject is about 25cm²About 30cm, from the bottom²About 35cm, from the bottom²About 40cm²About 45cm, of²About 50cm²About 55cm²About 60cm²About 65cm, from the center²About 70cm²About 75cm²About 80cm²About 85cm, from the center²About 90cm, from the center of the tube²About 95cm, from the center of the sample²Or about 100cm²。

In one aspect, the affected area of the subject is the skin.

In one aspect, the diseased area of the subject is located at one or more locations independently selected from: scalp, forehead, forearm, face, nose, ear, eyelid, lips, neck, arm, hand, torso, leg, and foot.

In one aspect, the subject has more than one diseased area.

In one aspect, KX-01 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.

In one aspect, KX-01 is administered once a day or twice a day.

In one aspect, KX-01 is administered once a day.

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.

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

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

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

In one aspect, KX-01 is administered weekly for 1, 2, 3, 4, 5, or 6 days.

In one aspect, KX-01 is administered weekly for 2, 3, 4, 5 or 6 days.

In one aspect, KX-01 is administered once or twice daily for more than one day per week, and then administration is discontinued for the remainder of the week.

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

In one aspect, KX-01 is administered once or twice daily every three days, four days, five days, six days, or seven days.

In one aspect, KX-01 is administered every three, four, five, six or seven days for two consecutive days, once or twice daily.

In one aspect, KX-01 is administered every four, five, six or seven days for three consecutive days, once or twice daily.

In one aspect, KX-01 is administered every five, six or seven days for four consecutive days, once or twice daily.

In one aspect, KX-01 is administered until actinic keratosis is completely treated.

In one aspect, KX-01 is administered topically.

In one aspect, 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.

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 of actinic keratosis.

In one aspect, the local skin reaction is selected from the group consisting of vesiculation, pustulation, erosion, ulcer, redness, swelling, scaling, desquamation, hard mass, dryness, pus, and blister.

In one aspect, the additional side effect is selected from the group consisting of pain at the site of administration, itching at the site of administration, irritation at the site of administration, swelling at the site of administration, burning sensation at the site of administration, infection at the site of administration, edema around the eye, nasopharyngitis, chills, sore throat, drooping eyelids, puffiness of the eye, hypopigmentation, hyperpigmentation, and headache.

In one aspect, the present application is directed, at least in part, to KX-01 for use (e.g., topically) in the treatment and/or prevention of actinic keratosis. In some aspects, KX-01 is used at the dosages, dosing schedules, and/or at one or more diseased areas in a subject in need thereof as described herein.

In one aspect, the present 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 some aspects, KX-01 is used at the dosages, dosing schedules, and/or at one or more diseased areas in a subject in need thereof as described herein.

In one aspect, 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 some aspects, KX-01 is used at the dosages, dosing schedules, and/or at one or more diseased areas in a subject in need thereof as described herein.

Drawings

Figure 1 mean LSR composite score versus time-phase 1 study with local application of KX-01 on dorsal forearm (dorsal foream) ○ group 1(N ═ 4) 0.5mg KX-01 was administered locally daily to 25cm with 4-8 common AK lesions²Regional, 3 consecutive days of administration. Star group 2 (N-10) 2.0mg of KX-01 were administered topically daily to 100cm with 8-16 common AK lesions²Regional, 3 consecutive days of administration. Delta group 3(N ═ 8) 0.5mg KX-01 was administered topically daily to 25cm with 4-8 common AK lesions²Regional, 5 consecutive days of administration. □ group 4(N ═ 8): 2.0mg KX-01 was administered topically daily to 100cm with 8-16 common AK lesions²Regional, 5 consecutive days of administration.

Figure 2 mean LSR composite score versus time phase 2a study of locally administered KX-01. 0.5mg of KX-01 was topically administered to 25cm with 4-8 common AK lesions for 3 or 5 consecutive days²A continuous treatment zone.

FIGS. 3A and 3B.Picato

(FIG. 3A) comparison of forearm skin response of patients treated with KX-01 (FIG. 3B).

Picato, FIGS. 4A and 4B

(fig. 4A) comparison of forehead skin reactions of patients treated compared to KX-01 (fig. 4B).

Figure 5-bar graph shows median AK lesion counts over time (left bar of each pair of bars shows results from 5 days of treatment and right bar shows results from 3 days of treatment).

Detailed Description

The present application relates, at least in part, to methods of treating and/or preventing actinic keratosis comprising administering to a subject in need thereof a therapeutically effective amount of KX-01:

the present application relates, at least in part, to a method of treating actinic keratosis comprising administering to a subject in need thereof a therapeutically effective amount of KX-01:

the present application relates, at least in part, to a method of preventing actinic keratosis comprising administering to a subject in need thereof a therapeutically effective amount of KX-01:

in one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: from about 0.1mg to about 10 mg.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: from about 0.2mg to about 5 mg.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: from about 0.5mg to about 2.5 mg.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.0003mg/cm²To about 10mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.001mg/cm²To about 0.4mg/cm²。

In one embodiment, KX-01 is as described for any of the methods disclosed hereinThe following doses were administered to the affected area of the subject: about 0.005mg/cm²To about 0.1mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.005mg/cm²To about 0.02mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.025mg/cm²To about 0.1mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.001mg/cm²About 0.002mg/cm²About 0.003mg/cm²About 0.004mg/cm²About 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.02mg/cm²About 0.03mg/cm²About 0.04mg/cm²About 0.05mg/cm²About 0.06mg/cm²About 0.07mg/cm²About 0.08mg/cm²About 0.09mg/cm²About 0.1mg/cm²About 0.15mg/cm²About 0.2mg/cm²About 0.25mg/cm²About 0.3mg/cm²About 0.35mg/cm²Or about 0.4mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.005mg/cm²About 0.006mg/cm²About 0.007mg/cm²About 0.008mg/cm²About 0.009mg/cm²About 0.01mg/cm²About 0.015mg/cm²About 0.02mg/cm²About 0.025mg/cm²About 0.03mg/cm²About 0.035mg/cm²About 0.04mg/cm²About 0.045mg/cm²About 0.05mg/cm²About 0.055mg/cm²About 0.06mg/cm²About 0.065mg/cm²About 0.07mg/cm²About 0.075mg/cm²About 0.08mg/cm²About 0.085mg/cm²About 0.09mg/cm²About 0.095mg/cm²Or about 0.1mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.025mg/cm²About 0.02mg/cm²About 0.015mg/cm²About 0.01mg/cm²About 0.005mg/cm²About 0.002mg/cm²About 0.001mg/cm²About 0.0005mg/cm²About 0.0002mg/cm²Or about 0.0001mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.025mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.02mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.015mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.01mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.005mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.002mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.001mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.0005mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.0002mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject at the following dose: about 0.0001mg/cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 0.01cm²To about 300cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 0.01cm²To about 200cm²About 0.01cm²To about 100cm²About 0.01cm²To about 75cm²About 0.01cm²To about 50cm²Or about 0.01cm²To about 25cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 0.1cm²To about 300cm²About 0.1cm²To about 200cm²About 0.1cm²To about 100cm²About 0.1cm²To about 75cm²About 0.1cm²To about 50cm²Or about 0.1cm²To about 25cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 1cm²To about 300cm²About 1cm, of²to about 200cm²About 1cm, of²To about 100cm²About 1cm, of²To about 75cm²About 1cm, of²To about 50cm²Or about 1cm²To about 25cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 10cm²To about300cm²About 10cm, of²To about 200cm²About 10cm, of²To about 100cm²About 10cm, of²To about 75cm²About 10cm, of²To about 50cm²Or about 10cm²To about 25cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 25cm²To about 300cm²About 25cm, of²To about 200cm²About 25cm, of²To about 100cm²About 25cm, of²To about 75cm²Or about 25cm²To about 50cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 25cm²To about 100cm²About 25cm, of²To about 90cm²About 25cm, of²To about 80cm²Or about 25cm²To about 70cm²About 25cm, of²To about 60cm²About 25cm, of²To about 50cm²About 25cm, of²To about 40cm²Or about 25cm²To about 30cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about 0.01cm²，0.1cm²，1cm²，2cm²，3cm²，4cm²，5cm²，6cm²，7cm²，8cm²，9cm²，10cm²，15cm²，20cm²，25cm²，30cm²，35cm²，40cm²，45cm²，50cm²，55cm²，60cm²，65cm²，70cm²，75cm²，80cm²，85cm²，90cm²，95cm²Or 100cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, the affected area being about25cm²About 30cm, from the bottom²About 35cm, from the bottom²About 40cm²About 45cm, of²About 50cm²About 55cm²About 60cm²About 65cm, from the center²About 70cm²About 75cm²About 80cm²About 85cm, from the center²About 90cm, from the center of the tube²About 95cm, from the center of the sample²Or about 100cm²。

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to an affected area of the subject, wherein the affected area is skin.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered to the affected area of the subject, wherein the affected area of the skin is located at one or more positions independently selected from the group consisting of: scalp, forehead, forearm, face, nose, ear, eyelid, lips, neck, arm, hand, torso, leg, and foot.

In one embodiment, for any of the methods disclosed herein, the subject has more than one diseased area.

In one embodiment, for any of the methods disclosed herein, the subject has more than one diseased area located at one or more positions independently selected from the group consisting of: scalp, forehead, forearm, face, nose, ear, eyelid, lips, neck, arm, hand, torso, leg, and foot.

In one embodiment, for any of the methods disclosed herein, KX-01 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.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered once a day or twice a day.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered once a day.

In one embodiment, 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 for any of the methods disclosed herein.

In one embodiment, 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 for any of the methods disclosed herein.

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

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

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

In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 1 day.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 2 days.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered for 3 days.

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

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

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

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

In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily for more than one day per week, and then administration is discontinued for the remainder of the week.

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

In one embodiment, for any of the methods disclosed herein, KX-01 is administered once or twice daily every three days, every four days, every five days, every six days, or every seven days.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered every three days, every four days, every five days, every six days, or every seven days for two consecutive days, once or twice daily.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered every four days, every five days, every six days, or every seven days for three consecutive days, once or twice daily.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered every five, six or seven days for four consecutive days, once or twice daily.

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

In one embodiment, for any of the methods disclosed herein, KX-01 is administered until actinic keratosis is completely treated, i.e., actinic keratosis is cleared from the diseased area of the subject.

In one embodiment, for any of the methods disclosed herein, KX-01 is administered topically.

In one embodiment, for any of the methods disclosed herein, administering 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. In one embodiment, another treatment of actinic keratosis includes topical administration of ingenol mebutate.

In one embodiment, for any of the methods disclosed herein, administering KX-01 reduces the number of subjects with a localized skin reaction or other adverse side effect compared to other treatments for actinic keratosis.

In one embodiment, for any of the methods disclosed herein, the local skin response is selected from the group consisting of vesicle formation, pustule formation, erosion, ulcer, redness, swelling, scaling, desquamation, hard mass, dryness, pus, and blister.

In one embodiment, for any of the methods disclosed herein, the additional side effect is selected from the group consisting of pain at the site of administration, itching at the site of administration, irritation at the site of administration, swelling at the site of administration, burning sensation at the site of administration, infection at the site of administration, edema around the eye, nasopharyngitis, chills, sore throat, drooping eyelids, puffiness of the eye, hypopigmentation, hyperpigmentation, and headache.

In one aspect, the present application is directed, at least in part, to KX-01 for use (e.g., topically) in the treatment and/or prevention of actinic keratosis. In some aspects, KX-01 is used at the dosages, dosing schedules, and/or at one or more diseased areas in a subject in need thereof as described herein.

In one aspect, the present 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 some aspects, KX-01 is used at the dosages, dosing schedules, and/or at one or more diseased areas in a subject in need thereof as described herein.

In one aspect, 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 some aspects, KX-01 is used at the dosages, dosing schedules, and/or at one or more diseased areas in a subject in need thereof as described herein.

Unless otherwise specifically indicated, the terms "KX-01" and "KX 2-391" refer to the base form of the compound, i.e., "free base," which has the following structure:

the term "KX-01 MSA" refers to the mesylate salt of KX-01, i.e., the salt compound resulting from the reaction of KX-01 with methanesulfonic acid.

"KX-01", as described herein, may also be referred to as "KX 01", "KX 2-391", or "KX-2-391".

KX-01, and salts thereof, e.g., KX-01MSA, and their preparation are disclosed in PCT application publication Nos. WO 2008/082637, WO 2008/144045, and WO 2010/135429. These disclosures are incorporated herein by reference in their entirety.

Actinic keratosis, also known as "AK", is a common precancerous skin condition caused by excessive exposure to ultraviolet light. AK is a rough, dry, tan, pink or red scar (lesion) that often appears on the head (including the face, throat, neck, nose, forehead, ears or lips). AK may also occur on other body parts that are subjected to intense sunlight for extended periods of time, such as the hands, back, and other areas of the torso and legs.

The term "torso" as used herein refers to parts of a subject other than the arms, legs, or head.

AK is most commonly found in middle-aged or elderly people with very white skin. A subject with AK may have a single lesion or multiple lesions. AK can cause squamous cell carcinoma.

Clinical variants of AK include: traditional (or common) AK, hypertrophic (or hyperkeratotic) AK, atrophic AK, AK with skin angle, pigmented AK, actinic cheilitis, and bowenoid AK (bowenoid AK). Unless otherwise explicitly indicated, the methods described herein are applicable to all clinical variants, including those listed herein.

Treatments for AK include cryosurgery and surgical excision and/or curettage of the affected area, photodynamic therapy and treatment of diseases involving steroids, fluorouracil (fluorouricil), diclofenac (diclofenac), imiquimod (imiquimod), 5-aminolevulinic acid

For topical application (e.g., creams, gels, patches, etc.).

Approved treatment for AK is Picato

A gel contains ingenol mebutate (0.015% or 0.05%). The gel was applied once daily (0.015%) to the affected area on the face or scalp for three consecutive days or once daily (0.05%) to the affected area on the trunk or limbs for two consecutive days.

Other AK treatments are known and used (such as using Picato)

) The associated skin toxicity produces undesirable side effects or adverse reactions, namely Local Skin Reactions (LSR), which include vesiculation, pustule formation, erosion, ulceration, redness, swelling, flaking, desquamation, hard mass, dryness, pus, and blisters. Other side effects include pain at the site of application, itching at the site of application, irritation at the site of application, swelling at the site of application, burning sensation at the site of application, infection at the site of application, edema around the eye, nasopharyngitis, chills, sore throat, drooping eyelids, puffiness of the eye, hypopigmentation, hyperpigmentation, and headache.

The phrase "until actinic keratosis clears" as used herein refers to a condition in which a lesion on a subject with AK substantially or completely disappears from the treatment area of the subject. In one embodiment, "substantially" in this context means that more than 50% of the AK lesions have disappeared from the treated area of the subject. In another embodiment, "substantially" refers to more than 60% of the AK lesions disappearing from the treated area of the subject. In another embodiment, "substantially" refers to more than 70% of the AK lesions disappearing from the treated area of the subject. In another embodiment, "substantially" refers to more than 80% of the AK lesions disappearing from the treated area of the subject. In another embodiment, "substantially" refers to more than 90% of the AK lesions disappearing from the treated area of the subject. In another embodiment, "substantially" refers to more than 95% of the AK lesions disappearing from the treated area of the subject. In another embodiment, "substantially" refers to more than 99% of the AK lesions disappearing from the treated area of the subject.

As used throughout this disclosure, the singular forms "a," "an," 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 dose" includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.

The term "comprising" is intended to mean that the method includes the recited elements, but not excluding other elements. When used to define a method, "consisting essentially of … …" shall mean that other elements having any of the basic meanings of the combination are excluded when used for the intended purpose. Thus, a process consisting essentially of the elements defined herein does not exclude substantial process steps. "consisting of … …" means that a number of substantial method steps are excluded. Embodiments defined by each of these transition terms are within the scope of the present application.

The terms "about" and "about" are synonymous unless expressly indicated otherwise. In one embodiment, "about" 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 amount, value, or duration. In another embodiment, "about" and "about" refer to the listed amounts, values, or durations plus or minus 2.5%, + -2%, + -1.75%, + -1.5%, + -1.25%, + -1%, + -0.9%, + -0.8%, + -0.7%, + -0.6%, + -0.5%. In another embodiment, "about" and "approximately" refer to ± 1% of the listed amount, value, or duration. In another embodiment, "about" and "approximately" refer to ± 0.5% of the listed amount, value, or duration. In another embodiment, "about" and "approximately" refer to ± 0.1% of the listed amount, value, or duration.

The term "subject" includes any living organism that has, or is 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 synonymous with "subject" unless explicitly indicated otherwise.

As used herein, the term "therapeutically effective amount" refers to an amount of an agent, e.g., KX-01, that is used to treat, ameliorate, or prevent a diagnosed disease or condition, e.g., AK, or that exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The exact effective amount of the subject depends on the weight, size and health of the subject; the nature and extent of the disorder; and selecting the therapeutic agent or combination of therapeutic agents for administration. A therapeutically effective amount for a given situation can be determined by routine experimentation within the abilities and judgment of the clinician.

For any compound, a therapeutically effective amount can be estimated in an animal model, typically rat, mouse, rabbit, dog, or pig. Animal models can 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 by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. ED₅₀(dose therapeutically effective in 50% of the population) and LD₅₀(dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as LD₅₀/ED₅₀The ratio of. The dosage may vary within this range depending upon the dosage form employed and the sensitivity of the subject.

The dosage and administration are adjusted to provide a sufficient level of the active ingredient or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the location of the disease on the subject, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, response sensitivity and tolerance/response to treatment. KX-01 may be administered daily, every other day, every third day, every fourth day, every fifth day, every sixth day, weekly, twice weekly or once every two weeks, depending on half-life and clearance.

For any of the methods described herein, KX-01 can be administered topically, intradermally, interperitoneally, intragingivally, intraocularly, nasally, ocularly, transdermally, periodontal, subconjunctivally, sublingually, transmucosally, or otically. In one embodiment, KX-01 may be administered topically.

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

Each document cited herein, including any cross-referenced or related patent or application, is hereby incorporated by reference in its entirety unless expressly excluded or otherwise limited. 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 any combination with any other reference, teaches, suggests or discloses any such subject matter. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

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. The scope of the appended claims includes all such changes and modifications as fall within the true spirit and scope of the disclosure.

Other features and advantages of the present application will be apparent from the various embodiments. The examples provided illustrate the different components and methods useful in practicing the present application.

These examples do not limit the claimed application. Based on the disclosure, the skilled artisan can identify and employ other components and methods useful in practicing the present application.

Examples

Two clinical studies (detailed in examples 1 and 2) were performed to evaluate the activity and safety of topical administration of KX-01 in subjects with actinic keratosis. Preliminary data from these studies indicate that KX-01 has clinically relevant activity in the treatment of actinic keratosis of the face and scalp and forearm. After 5 days of administration, the safety profile of KX-01 was very good and systemic exposure was limited. Local tolerability appeared very good, with Local Skin Reactions (LSR) consisting mainly of mild to moderate erythema and desquamation. KX-01 was found to be safe.