RU2805929C2 - Methods for treating and/or preventing actinic keratosis - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: treatment of actinic keratosis. Methods for treating actinic keratosis, including administering a therapeutically effective amount of KX-01 at a dose of about 0.025 mg/cm² to about 0.1 mg/cm² or at a dose of about 0.1 mg/cm² to about 10 mg/cm², where the term “approx” refers to the dose of± 5%.

EFFECT: effective treatment of actinic keratosis.

35 cl, 5 dwg, 13 tbl, 6 ex

Description

RELATED APPLICATION

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

BACKGROUND OF THE INVENTION

Actinic keratoses, or solar keratoses, are scaly, hard growths (lesions) caused by damage from the sun's ultraviolet rays. They typically appear on sun-exposed areas such as the face, bald crown of the head, lips, and backs of the hands, and are often raised, have a rough texture, and resemble warts. Most turn red, but some turn brown, pink and/or flesh-colored. If left untreated, up to ten percent of actinic keratoses will develop into squamous cell carcinoma (SCC), which is the most common form of skin cancer. It is estimated that more than 58 million Americans suffer from actinic keratosis. Treatment for actinic keratosis includes cryotherapy, surgical removal, chemical peels, photodynamic therapy, laser resurfacing, and/or medicated gels and creams. Due to the prevalence of actinic keratosis and its ability to develop into skin cancer if not treated properly, the development of further treatments is warranted.

SUMMARY OF THE INVENTION

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

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.1 mg to about 10 mg.

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.2 mg to about 5 mg.

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.5 mg to about 2.5 mg.

In one aspect of the invention, KX-01 is administered to the affected area of the patient 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.

In one aspect of the invention, KX-01 is administered to the affected area of the patient 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.

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.0003 mg/cm ² to about 10 mg/cm ² .

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.001 mg/cm ² to about 0.4 mg/cm ² .

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.005 mg/cm ² to about 0.1 mg/cm ² .

In one aspect of the invention, KX-01 is administered to the affected area of a patient at a dose of from about 0.005 mg/cm ² to about 0.02 mg/cm ² .

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of from about 0.025 mg/cm ² to about 0.1 mg/cm ² .

In one aspect of the invention, KX-01 is administered to the affected area of the patient at a dose of about 0.001 mg/cm ² , about 0.002 mg/cm ² , about 0.003 mg/cm ² , about 0.004 mg/cm ² , about 0.005 mg/cm ² , about 0.006 mg/ ^cm2 , about 0.007 mg/ ^cm2 , about 0.008 mg/ ^cm2 , about 0.009 mg/cm2, about ^0.01 mg/ ^cm2 , about 0.02 mg/ ^cm2 , about 0.03 mg /cm ² , approximately 0.04 mg/cm ² , approximately 0.05 mg/cm ² , approximately 0.06 mg/cm ² , approximately 0.07 mg/cm ² , approximately 0.08 mg/cm ² , approximately 0.09 mg/ ^cm2 , approximately 0.1 mg/ ^cm2 , approximately 0.15 mg/ ^cm2 , approximately 0.2 mg/ ^cm2 , approximately 0.25 mg/ ^cm2 , approximately 0.3 mg/cm2 cm ² , about 0.35 mg/cm ² or about 0.4 mg/cm ² .

In one aspect of the invention, KX-01 is administered to the affected area of a patient at a dose of about 0.005 mg/ ^cm2 , about 0.006 mg/ ^cm2 , about 0.007 mg/ ^cm2 , about 0.008 mg/ ^cm2 , about 0.009 mg/ ^cm2 , about 0.01 mg/ ^cm2 , about 0.015 mg/ ^cm2 , about 0.02 mg/ ^cm2 , about 0.025 mg/ ^cm2 , about 0.03 mg/ ^cm2 , about 0.035 mg/ ^cm2 , about 0 .04 mg/cm ² , approximately 0.045 mg/cm ² , approximately 0.05 mg/cm ² , approximately 0.055 mg/cm ² , approximately 0.06 mg/cm ² , approximately 0.065 mg/cm ² , approximately 0.07 mg/ ^cm2 , about 0.075 mg/ ^cm2 , about 0.08 mg/ ^cm2 , about 0.085 mg/ ^cm2 , about 0.09 mg/ ^cm2 , about 0.095 mg/ ^cm2 or about 0.1 mg/cm2 cm ² .

In one aspect of the invention, the patient's affected area is from about 0.01 cm ² to about 300 cm ² .

In one aspect of the invention, the patient's affected area is from about 1 cm ² to about 200 cm ² , from about 1 cm ² to about 100 cm ² , from about 1 cm ² to about 75 cm ² , from about 1 cm ² to about 50 cm ² or from about 1 cm ² to about 25 cm ² .

In one aspect of the invention, the patient's affected area is from about 10 cm ² to about 200 cm ² , from about 10 cm ² to about 100 cm ² , from about 10 cm ² to about 75 cm ² , from about 10 cm ² to about 50 cm 2 cm ² or from about 10 cm ² to about 25 cm ² .

In one aspect of the invention, the patient's affected area is from about 25 cm ² to about 200 cm ² , from about 25 cm ² to about 100 cm ² , from about 25 cm ² to about 75 cm ² , or from about 25 cm ² to about 50 cm 2 cm ² .

In one aspect of the invention, the patient's affected area is from about 25 cm ² to about 100 cm ² , from about 25 cm ² to about 90 cm ² , from about 25 cm ² to about 80 cm ² , or from about 25 cm 2 to about 70 cm ² cm ² , from about 25 cm ² to about 60 cm ² , from about 25 cm ² to about 50 cm ² , from about 25 cm ² to about 40 cm ² , or from about 25 cm ² to about 30 cm ² .

In one aspect of the invention, the patient's affected area is about 25 cm ² , about 30 cm ² , about 35 cm ² , about 40 cm ² , about 45 cm 2 , about 50 cm ² , about 55 ^{cm 2 ,} about 60 cm ² , about 65 cm ² , about 70 cm ² , about 75 cm ² , about 80 cm ² , about 85 cm ² , about 90 cm ² , about 95 cm ² or about 100 cm ² .

In one aspect of the invention, the affected area of the patient is skin.

In one aspect of the invention, the affected area of the patient is located in one or more locations independently selected from the scalp, forehead, forearm, face, nose, ears, eyelids, lips, neck, arms, hands, torso, legs and feet.

In one aspect, the patient has more than one affected area.

In one aspect of the invention, 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 of the invention, KX-01 is administered once daily or twice daily.

In one aspect of the invention, KX-01 is administered once daily.

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

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

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

In one aspect of the invention, KX-01 is administered for 1, 2, 3, 4, 5 or 6 days per week.

In one aspect of the invention, KX-01 is administered for 2, 3, 4, 5, or 6 days per week.

In one aspect of the invention, KX-01 is administered once or twice daily for more than one day per week, followed by discontinuation of the drug for the remainder of the week.

In one aspect of the invention, KX-01 is administered once or twice daily on alternate days.

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

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

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

In one aspect of the invention, KX-01 is used until actinic keratoses are completely cured.

In one aspect of the invention, KX-01 is applied externally.

In one aspect of the invention, the use of KX-01 reduces the number and/or severity of local skin reactions or other adverse side effects in a patient compared to other treatments for actinic keratosis.

In one aspect of the invention, the use of KX-01 reduces the number of patients who experience local skin reactions or other adverse side effects compared to other treatments for actinic keratosis.

In one aspect, the local skin reaction is selected from the group selected from vesiculation, posturing, erosion, ulceration, redness, swelling, desquamation, scaling, crusting, dryness, suppuration, and blistering.

In one aspect, the other side effect is selected from the group consisting of application site pain, application site itching, application site irritation, application site swelling, application site burning sensation, application site infection, periorbital edema, nasopharyngitis, chills, pain throat, drooping eyelids, swollen eyes, hypopigmentation, hyperpigmentation and headache.

In one aspect of the invention, the present application relates, at least in part, to KX-01 for use (eg, external use) in the treatment and/or prevention of actinic keratosis. In some aspects of the invention, KX-01 is used for use in doses, dosage regimens and/or on one or more affected sites in a patient in need thereof, as described herein.

In one aspect of the invention, the present application relates, at least in part, to the use (eg, external use) of KX-01 in the treatment and/or prevention of actinic keratoses. In some aspects of the invention, KX-01 is used in doses, dosage regimens and/or on one or more affected sites in a patient in need thereof, as described herein.

In one aspect of the invention, 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 of the invention, KX-01 is used in doses, dosage regimens and/or on one or more affected sites in a patient in need thereof, as described herein.

Description of drawings

Figure 1. Mean cumulative LSR score over time - phase 1 study of KX-01 administered externally to the dorsal forearm. ○ Cohort 1 (N=4): 0.5 mg KX-01 was applied topically to a 25 ^cm2 area of 4-8 typical AK lesions daily for 3 consecutive days. ☆ Cohort 2 (N=10): 2.0 mg KX-01 was applied topically to a 100 cm ² area of 8-16 typical AK lesions daily for 3 consecutive days. ρ Cohort 3 (N=8): 0.5 mg KX-01 was applied topically to a ^25cm2 area of 4-8 typical AK lesions daily for 5 consecutive days. □ Cohort 4 (N=8): 2.0 mg KX-01 was applied topically to a ^100cm2 area of 8-16 typical AK lesions daily for 5 consecutive days.

Figure 2. Average Cumulative LSR Score over Time - Phase 2a Study of KX-01 Externally Administered. 0.5 mg KX-01 was applied topically to a 25 cm ² continuous treatment area with 4-8 typical AK lesions for 3 or 5 consecutive days.

Figures 3A and 3B. Comparison of skin reactions on the forearms of patients treated with Picato® (ingenol mebutate) (Figure 3A) versus KX-01 (Figure 3B).

Figures 4A and 4B. Comparison of forehead skin reactions in patients treated with Picato® (ingenol mebutate) (Figure 4A) versus KX-01 (Figure 4B).

Figure 5. Histogram showing the median AK value of the lesion over time (the left column of each pair of bars shows the results of the 5-day treatment, and the right column shows the results of the 3-day treatment).

DETAILED DESCRIPTION

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

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

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

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 10 mg.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.2 mg to about 5 mg.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.5 mg to about 2.5 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 9 mg, from about 0.1 mg to about 8 mg, from 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 , from about 0.1 mg to about 0.7 mg, from about 0.1 mg to about 0.6 mg, from about 0.1 mg to about 0.5 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is administered to the affected area of a patient at a dose of about 0.2 mg to about 10 mg, about 0.2 mg to about 9 mg, from 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, from about 0.2 mg to about 3 mg, from about 0.2 mg to about 2 mg, from about 0.2 mg to about 1 mg, from about 0.2 mg to about 0.9 mg, from 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 , from about 0.2 mg to about 0.4 mg, or from about 0.2 mg to about 0.3 mg,

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.3 mg to about 10 mg, from about 0.3 mg to about 9 mg, from 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, from about 0.3 mg to about 3 mg, from about 0.3 mg to about 2 mg, from about 0.3 mg to about 1 mg, from about 0.3 mg to about 0.9 mg, from 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 from about 0.3 mg to about 0.4 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.4 mg to about 10 mg, from about 0.4 mg to about 9 mg, from 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, from about 0.4 mg to about 3 mg, from about 0.4 mg to about 2 mg, from about 0.4 mg to about 1 mg, from about 0.4 mg to about 0.9 mg, from 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 .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.5 mg to about 10 mg, from about 0.5 mg to about 9 mg, from 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, from about 0.5 mg to about 3 mg, from about 0.5 mg to about 2 mg, from about 0.5 mg to about 1 mg, from about 0.5 mg to about 0.9 mg, from 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.6 mg to about 10 mg, from about 0.6 mg to about 9 mg, from 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, from about 0.6 mg to about 3 mg, from about 0.6 mg to about 2 mg, from about 0.6 mg to about 1 mg, from about 0.6 mg to about 0.9 mg, from about 0.6 mg to about 0.8 mg, or about 0.6 mg to about 0.7 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.7 mg to about 10 mg, from about 0.7 mg to about 9 mg, from 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.8 mg to about 10 mg, from about 0.8 mg to about 9 mg, from 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.9 mg to about 10 mg, from about 0.9 mg to about 9 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is administered to the affected area of a patient 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 approximately 2 mg.

In one embodiment, in any of the methods described herein, KX-01 is administered to the affected area of a patient 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.2 mg to about 10 mg, from about 0.3 mg to about 10 mg, from 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, from about 5 mg to about 10 mg, from about 6 mg to about 10 mg, from about 7 mg to about 10 mg, from about 8 mg to about 10 mg, or from about 9 mg to about 10 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 9 mg, from about 0.2 mg to about 9 mg, from 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 mg, from about 4 mg to about 9 mg, from about 5 mg to about 9 mg, from about 6 mg to about 9 mg, from about 7 mg to about 9 mg, or from about 8 mg to about 9 mg.

In one embodiment, in any of the methods described herein, KX-01 is administered to the affected area of a patient at a dose of about 0.1 mg to about 8 mg, about 0.2 mg to about 8 mg, from 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 mg, from about 4 mg to about 8 mg, from about 5 mg to about 8 mg, from about 6 mg to about 8 mg, or from about 7 mg to about 8 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 7 mg, from about 0.2 mg to about 7 mg, from 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 mg, from about 4 mg to about 7 mg, from about 5 mg to about 7 mg, or from about 6 mg to about 7 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 6 mg, from about 0.2 mg to about 6 mg, from 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 mg, from about 4 mg to about 6 mg, or from about 5 mg to about 6 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 5 mg, from about 0.2 mg to about 5 mg, from 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 mg or from about 4 mg to about 5 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 4 mg, from about 0.2 mg to about 4 mg, from 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 mg.

In one embodiment, in any of the methods described herein, KX-01 is administered to the affected area of a patient 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 2 mg, from about 0.2 mg to about 2 mg, from 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.1 mg to about 1 mg, from about 0.2 mg to about 1 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 3 mg, about 0.2 mg to about 2.9 mg, from about 0.2 mg to about 2.8 mg, from about 0.2 mg to about 2.7 mg, from about 0.2 mg to about 2.6 mg, from about 0.2 mg to about 2.5 mg, from about 0.2 mg to about 2.4 mg, from about 0.2 mg to about 2.3 mg, from about 0.2 mg to about 2.2 mg, from about 0.2 mg to about 2 .1 mg or from about 0.2 mg to about 2.0 mg.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.3 mg to about 3 mg, about 0.3 mg to about 2.9 mg, from about 0.3 mg to about 2.8 mg, from about 0.3 mg to about 2.7 mg, from about 0.3 mg to about 2.6 mg, from about 0.3 mg to about 2.5 mg, from about 0.3 mg to about 2.4 mg, from about 0.3 mg to about 2.3 mg, from about 0.3 mg to about 2.2 mg, from about 0.3 mg to about 2 .1 mg or from about 0.3 mg to about 2.0 mg.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.4 mg to about 3 mg, about 0.4 mg to about 2.9 mg, from about 0.4 mg to about 2.8 mg, from about 0.4 mg to about 2.7 mg, from about 0.4 mg to about 2.6 mg, from about 0.4 mg to about 2.5 mg, from about 0.4 mg to about 2.4 mg, from about 0.4 mg to about 2.3 mg, from about 0.4 mg to about 2.2 mg, from about 0.4 mg to about 2 .1 mg or from about 0.4 mg to about 2.0 mg.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.5 mg to about 3 mg, about 0.5 mg to about 2.9 mg, from about 0.5 mg to about 2.8 mg, from about 0.5 mg to about 2.7 mg, from about 0.5 mg to about 2.6 mg, from about 0.5 mg to about 2.5 mg, from about 0.5 mg to about 2.4 mg, from about 0.5 mg to about 2.3 mg, from about 0.5 mg to about 2.2 mg, from about 0.5 mg to about 2 .1 mg or from about 0.5 mg to about 2.0 mg.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.2 mg to about 3 mg, from about 0.3 mg to about 3 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.9 mg, about 0.3 mg to about 2.9 mg, from about 0.4 mg to about 2.9 mg, from about 0.5 mg to about 2.9 mg, from about 0.6 mg to about 2.9 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.8 mg, about 0.3 mg to about 2.8 mg, from about 0.4 mg to about 2.8 mg, from about 0.5 mg to about 2.8 mg, from about 0.6 mg to about 2.8 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.7 mg, about 0.3 mg to about 2.7 mg, from about 0.4 mg to about 2.7 mg, from about 0.5 mg to about 2.7 mg, from about 0.6 mg to about 2.7 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.6 mg, about 0.3 mg to about 2.6 mg, from about 0.4 mg to about 2.6 mg, from about 0.5 mg to about 2.6 mg, from about 0.6 mg to about 2.6 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.5 mg, about 0.3 mg to about 2.5 mg, from about 0.4 mg to about 2.5 mg, from about 0.5 mg to about 2.5 mg, from about 0.6 mg to about 2.5 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.4 mg, about 0.3 mg to about 2.4 mg, from about 0.4 mg to about 2.4 mg, from about 0.5 mg to about 2.4 mg, from about 0.6 mg to about 2.4 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.3 mg, about 0.3 mg to about 2.3 mg, from about 0.4 mg to about 2.3 mg, from about 0.5 mg to about 2.3 mg, from about 0.6 mg to about 2.3 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.2 mg, about 0.3 mg to about 2.2 mg, from about 0.4 mg to about 2.2 mg, from about 0.5 mg to about 2.2 mg, from about 0.6 mg to about 2.2 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.2 mg to about 2.1 mg, about 0.3 mg to about 2.1 mg, from about 0.4 mg to about 2.1 mg, from about 0.5 mg to about 2.1 mg, from about 0.6 mg to about 2.1 mg, from 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.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.2 mg to about 2 mg, from about 0.3 mg to about 2 mg, from 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient 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 approximately 5 mg.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient 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.

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.0003 mg/cm ² to about 10 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.001 mg/cm ² to about 0.4 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.005 mg/cm ² to about 0.1 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.005 mg/cm ² to about 0.02 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of from about 0.025 mg/cm ² to about 0.1 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.001 mg/cm ² , about 0.002 mg/cm ² , about 0.003 mg/cm ² , about 0.004 mg / ^cm2 , approximately 0.005 mg/ ^cm2 , approximately 0.006 mg/ ^cm2 , approximately 0.007 mg/ ^cm2 , approximately 0.008 mg/cm2, approximately 0.009 mg/ ^{cm2 ,} approximately 0.01 mg/ ^cm2 , approximately 0 .02 mg/cm ² , approximately 0.03 mg/cm ² , approximately 0.04 mg/cm ² , approximately 0.05 mg/cm ² , approximately 0.06 mg/cm ² , approximately 0.07 mg/cm ² , approximately 0.08 mg/ ^cm2 , approximately 0.09 mg/ ^cm2 , approximately 0.1 mg/ ^cm2 , approximately 0.15 mg/ ^cm2 , approximately 0.2 mg/ ^cm2 , approximately 0. 25 mg/cm ² , about 0.3 mg/cm ² , about 0.35 mg/cm ² or about 0.4 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.005 mg/cm ² , about 0.006 mg/cm ² , about 0.007 mg/cm ² , about 0.008 mg / ^cm2 , approximately 0.009 mg/ ^cm2 , approximately 0.01 mg/ ^cm2 , approximately 0.015 mg/cm2, approximately 0.02 mg/ ^cm2 , approximately 0.025 mg/ ^{cm2 ,} approximately 0.03 mg/cm ² , approximately 0.035 mg/ ^cm2 , approximately 0.04 mg/ ^cm2 , approximately 0.045 mg/ ^cm2 , approximately 0.05 mg/ ^cm2 , approximately 0.055 mg/ ^cm2 , approximately 0.06 mg/ ^cm2 , about 0.065 mg/ ^cm2 , about 0.07 mg/ ^cm2 , about 0.075 mg/ ^cm2 , about 0.08 mg/ ^cm2 , about 0.085 mg/ ^cm2 , about 0.09 mg/ ^cm2 , about 0.095 mg/cm ² or about 0.1 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.025 mg/cm ² , about 0.02 mg/cm ² , about 0.015 mg/cm ² , about 0.01 mg/cm ² , about 0.005 mg/cm ² , about 0.002 mg/cm ² , about 0.001 mg/cm 2 , about 0.0005 mg/cm ² , about 0.0002 mg/ ^{cm 2 or} about 0. 0001 mg/ ^cm2 .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.025 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.02 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.015 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of about 0.01 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.005 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.002 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.001 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.0005 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.0002 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to the affected area of the patient at a dose of approximately 0.0001 mg/cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is between about 0.01 cm ² and about 300 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is from about 0.01 cm ² to about 200 cm ² , from about 0.01 cm ² to about 100 cm ² , from about 0.01 cm ² to about 75 cm ² , from about 0.01 cm ² to about 50 cm ² , or from about 0.01 cm ² to about 25 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is from about 0.1 cm ² to about 300 cm ² , from about 0.1 cm ² to about 200 cm ² , from about 0.1 cm ² to about 100 cm ² , from about 0.1 cm ² to about 75 cm ² , from about 0.1 cm ² to about 50 cm ² or from about 0.1 cm ² to approximately 25 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is from about 1 cm ² to about 300 cm ² , from about 1 cm ² to about 200 cm ² , from about 1 cm ² to about 100 cm ² , from about 1 cm ² to about 75 cm ² , from about 1 cm ² to about 50 cm ² , or from about 1 cm ² to about 25 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is from about 10 cm ² to about 300 cm ² , from about 10 cm ² to about 200 cm ² , from about 10 cm ² to about 100 cm ² , from about 10 cm ² to about 75 cm ² , from about 10 cm ² to about 50 cm ² , or from about 10 cm ² to about 25 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is from about 25 cm ² to about 300 cm ² , from about 25 cm ² to about 200 cm ² , from about 25 cm ² to about 100 cm ² , from about 25 cm ² to about 75 cm ² , or from about 25 cm ² to about 50 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion in a patient where the lesion is from about 25 cm ² to about 100 cm ² , from about 25 cm ² to about 90 cm ² , from about 25 cm ² to about 80 cm ² or from about 25 cm ² to about 70 cm ² , from about 25 cm ² to about 60 cm ² , from about 25 cm ² to about 50 cm ² , from about 25 cm ² to about 40 cm ² or from about 25 cm ² to about 30 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is approximately 0.01 cm ² , 0.1 cm ² , 1 cm ² , 2 cm ² , 3 cm ² , 4 cm ² , 5 cm ² , 6 cm ² , 7 cm ² , 8 cm ² , 9 cm ² , 10 cm ² , 15 cm ² , 20 cm ² , 25 cm2, 30 cm ² , 35 cm ² , 40 cm ² , 45 cm ² , 50 cm ² , 55 cm ² , 60 cm ² , 65 cm 2, 70 cm ² , 75 cm ^{2 ,} 80 cm ² , 85 cm ² , 90 cm 2, 95 cm ² or 100 cm ² .

In one embodiment, in any of the methods described herein, KX-01 is applied to a lesion on a patient that is about 25 cm ² , about 30 cm ² , about 35 cm ² , about 40 cm ² , about 45 cm ² , approximately 50 cm ² , approximately 55 cm ² , approximately 60 cm ² , approximately 65 cm ² , approximately 70 cm 2, approximately 75 cm ² , approximately 80 cm ² , approximately 85 cm ² , approximately 90 cm ^{2 ,} approximately 95 cm ² or approximately 100 cm ² .

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to an affected area in a patient, where the affected area is skin.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied to an affected area in a patient where the affected area of skin is located at one or more sites independently selected from the scalp, forehead, forearm, face, nose, ears, eyelids, lips, neck, arms, hands, torso, legs and feet.

In one embodiment of the invention, in any of the methods described herein, the patient has more than one affected area.

In one embodiment, in any of the methods described herein, the patient has more than one affected area located in one or more locations independently selected from the scalp, forehead, forearm, face, nose, ears, eyelids, lips, neck , arms, hands, torso, legs and feet.

In one embodiment, in any of the methods described 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, in any of the methods described herein, KX-01 is administered once daily or twice daily.

In one embodiment, in any of the methods described herein, KX-01 is administered once daily.

In one embodiment, in any of the methods described 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.

In one embodiment, in any of the methods described 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.

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

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

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

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

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

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

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

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

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

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

In one embodiment, in any of the methods described herein, KX-01 is administered once or twice daily for more than one day per week, followed by discontinuation of the drug for the remainder of the week.

In one embodiment, in any of the methods described herein, KX-01 is administered once or twice daily on alternate days.

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

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

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

In one embodiment, in any of the methods described herein, KX-01 is used until the actinic keratosis is completely cured.

In one embodiment, in any of the methods described herein, KX-01 is administered until the actinic keratosis is completely cured, that is, the actinic keratosis disappears from the affected area in the patient.

In one embodiment of the invention, in any of the methods described herein, KX-01 is applied externally.

In one embodiment, in any of the methods described herein, the use of KX-01 reduces the number and/or severity of local skin reactions or other adverse side effects in a patient compared to other treatments for actinic keratosis. In one embodiment of the invention, another treatment for actinic keratoses includes topical application of ingenol mebutate.

In one embodiment, in any of the methods described herein, the use of KX-01 reduces the number of patients who experience local skin reactions or other adverse side effects compared to other treatments for actinic keratosis.

In one embodiment of the invention in any of the methods described herein, the local skin reaction is selected from the group selected from vesiculation, postulation, erosion, ulceration, redness, swelling, desquamation, scaling, hard growths, dryness, suppuration and formation bubbles.

In one embodiment, in any of the methods described herein, the other side effect is selected from the group consisting of application site pain, application site itching, application site irritation, application site swelling, application site burning sensation, infection at the application site, periorbital edema, nasopharyngitis, chills, sore throat, drooping eyelids, swollen eyes, hypopigmentation, hyperpigmentation and headache.

In one aspect, the present application relates, at least in part, to KX-01 for use (eg, external use) in the treatment and/or prevention of actinic keratosis. In some aspects, KX-01 is used for use in doses, dosage regimens and/or on one or more affected sites in a patient in need thereof, as described herein.

In one aspect, the present application relates, at least in part, to the use (eg, topical application) of KX-01 in the treatment and/or prevention of actinic keratoses. In some aspects, KX-01 is used at doses, dosage regimens, and/or on one or more affected sites in a patient 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 keratoses. In some aspects, KX-01 is used at doses, dosage regimens, and/or on one or more affected sites in a patient in need thereof, as described herein.

Unless otherwise expressly stated, the terms "KX-01" and "KX2-391" refer to a base compound, i.e. a "free base", which has the following structure:

The term "KX-01 MSA" refers to the mesylate salt of KX-01, that is, the salt of the compound obtained by reacting KX-01 with methanesulfonic acid.

"KX-01" as used herein may also be called "KX01", "KX2-391" or "KX-2-391".

KX-01 and its salts, eg KX-01 MSA, and their preparation are described in PCT Application Publication Nos. WO 2008/082637, WO 2008/144045 and WO 2010/135429. These publications are incorporated herein by reference in their entirety.

Actinic keratosis, or “AK,” is a common precancerous skin condition caused by overexposure to ultraviolet light. AKs are rough, dry, brown, pink, or red patches (lesions) that often appear on areas of the head, including the face, throat, neck, nose, forehead, ears, or lips. AK can also appear on other parts of the body that are exposed to intense sunlight for a long time, such as the arms, back, and other areas of the torso and legs.

As used herein, the term "torso" refers to a part of the patient that is not an arm, leg, or head.

AKs are most common in people with fair skin, middle age, or the elderly. A patient suffering from AK may have one or more lesions. AK can lead to squamous cell carcinoma.

Clinical variants of AK include: classic (or widespread), hypertrophic (or hyperkeratotic), atrophic, AK with keratoma keratoma, pigmented AK, actinic cheilitis, and bowenoid AK. Unless explicitly stated otherwise, the methods described herein are applicable to all clinical settings, including those listed herein.

Treatment for AK includes cryosurgery, surgical excision and/or curettage of the affected areas, photodynamic therapy, and topical formulations (eg, creams, gels, patches, etc.) containing a steroid, fluorouracil, diclofenac, imiquimod, 5-aminolevulinic acid ( Ameluz®).

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

Skin toxicity associated with the use of other AK treatments such as Picato® (ingenol mebutate) is known to cause unwanted side effects or adverse reactions, i.e. local skin reactions (LSR), which include vesiculation, postulation, erosion, ulceration, redness, swelling, peeling, scaling, crusting, dryness, suppuration and blistering. Other side effects include pain at the application site, itching at the application site, irritation at the application site, swelling at the application site, burning sensation at the application site, infection at the application site, periorbital edema, nasopharyngitis, chills, sore throat, drooping eyelids, swollen eyes, hypopigmentation, hyperpigmentation and headache.

The phrase "until the actinic keratosis goes away" as used herein refers to the case where the lesions in a patient suffering from AK substantially or completely disappear from the treated area of the patient. In one embodiment of the invention, "substantially", as used herein, refers to more than 50% of the AK lesions disappearing from the treated area of the patient. In another embodiment of the invention, "substantially" refers to more than 60% of AK lesions disappearing in the treated area of the patient. In another embodiment of the invention, "substantially" refers to more than 70% of AK lesions disappearing in the treated area of the patient. In another embodiment of the invention, "substantially" refers to more than 80% of AK lesions disappearing in the treated area of the patient. In another embodiment, "substantially" refers to more than 90% of AK lesions disappearing from the treated area of the patient. In another embodiment, "substantially" refers to more than 95% of AK lesions disappearing from the treated area of the patient. In another embodiment, "substantially" refers to more than 99% of AK lesions disappearing from the treated area in the patient.

As used throughout, singular forms include references to the plural unless the context clearly dictates otherwise. Thus, for example, a reference to “method” includes a plurality of such methods, and a reference to “dose” includes a reference to one or more doses and equivalents thereof known to those skilled in the art, and so on.

The term “comprising” is intended to indicate that the method includes the listed elements, but does not exclude others. “Essentially consisting of,” when used to define methods, shall mean the exclusion of other elements essential to the combination when used for their intended purpose. Thus, a method consisting essentially of the elements defined herein does not eliminate essential process steps. “Consists of” means the exclusion of more essential steps of the method. Embodiments defined by each of these transitional terms are within the scope of this application.

Unless expressly stated otherwise, the terms “about” and “approximately” are synonymous. In one embodiment of the invention, "about" and "about" refer to a specified amount, value or duration ±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%. In another embodiment of the invention, "about" and "about" refer to the given amount, value or duration ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1 %, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%. In yet another embodiment of the invention, "about" and "about" refer to a given amount, value, or duration of ±1%. In yet another embodiment of the invention, "about" and "about" refer to the given amount, value, or duration of ±0.5%. In yet another embodiment of the invention, "about" and "about" refer to the given amount, value, or duration of ±0.1%.

The term "patient" includes any living organism that has actinic keratoses or is at risk of developing actinic keratoses. In one embodiment of the invention, the term “patient” refers to a mammal that has actinic keratoses or is at risk of developing actinic keratoses. In one embodiment of the invention, the term patient refers to a person who has actinic keratoses or is at risk of developing actinic keratoses. The term "patient" shall be synonymous with the term "subject" unless otherwise explicitly stated.

The term “therapeutically effective amount” as used herein refers to an amount of a pharmaceutical agent, eg, KX-01, to treat, ameliorate, or prevent an identified disease or condition, eg, AK, or to demonstrate a detectable therapeutic or inhibitory effect. The effect can be detected by any method of analysis known in the art. The exact effective amount for a patient will depend on the patient's weight, size, and health; the nature and extent of the condition; and therapeutic agents or combinations of therapeutic agents selected for use. Therapeutically effective amounts for a given situation can be determined by routine experimentation, which is within the skill and judgment of the attending physician.

For any compound, a therapeutically effective amount can be assessed in animal models, typically rats, mice, rabbits, dogs or pigs. The animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes of administration to humans. Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED ₅₀ (dose therapeutically effective in 50% of the population) and LD ₅₀ (dose lethal in 50% of the population). The dose ratio between toxic and therapeutic effects represents the therapeutic index, and it can be expressed as the ratio LD ₅₀ /ED ₅₀ . The dosage may vary within this range depending on the dosage form used and the sensitivity of the patient.

Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors that may be taken into account include the severity of the disease state, the location of the disease in the patient, the general health of the patient, the age, weight and sex of the patient, nutrition, timing and frequency of use, drug combination, sensitivity of response and tolerance/response to therapy . KX-01 can be administered every day, every other day, every three days, every four days, every five days, every six days, every week, every two weeks, or once every two weeks, depending on the half-life and elimination rate.

For any of the routes described herein, KX-01 can be administered topically, intradermally, intraepidermally, intragingivally, intraocularly, nasally, ophthalmologically, transdermally, periodontally, subconjunctively, sublingually, transmucosally or by the ear route. In one embodiment, KX-01 can be administered externally.

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

Each document cited herein, including any cross-references or related patents or applications, is incorporated herein by reference in its entirety unless expressly excluded or otherwise 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 any combination with any other reference or references, indicates, suggests or discloses any such subject of the invention. In addition, to the extent that any meaning or definition of a term in this document conflicts with the meaning or definition of the same term in a document incorporated by reference, the meaning or definition given to that term is governed by this document.

While specific embodiments of the invention have been illustrated and described, various other changes and modifications may be made without departing from the spirit and scope of the disclosure. The scope of the appended claims includes all such changes and modifications that fall within the scope of the present invention.

Other features and advantages of the present application will be apparent from various examples. The following examples illustrate various components and methods that can be used to practice the present application.

The examples do not limit the stated application. Based on the present invention, one skilled in the art can identify and use other components and methods that can be used to practice the present application.

EXAMPLES

Two clinical studies (detailed in Examples 1 and 2) were conducted to evaluate the activity and safety of KX-01 administered topically to patients with actinic keratosis. Preliminary data from these studies indicate that KX-01 demonstrates clinically significant activity in the treatment of actinic keratoses of the face, scalp and forearm. KX-01, when administered for 5 days, has a very good safety profile with limited systemic exposure. Topical tolerability appears to be very good with local skin reactions (LSRs) consisting primarily of mild to moderate erythema and scaling. KX-01 has been found to be safe.

Example 1 - Phase 1 study of KX-01 administered topically for 3 or 5 days in the forearm

A phase 1, single-center study of the safety, tolerability, and pharmacokinetics of KX-01 was conducted in patients with AK on the dorsal forearm. This was an open-label, uncontrolled, non-randomized, sequential cohort clinical trial conducted at a single study site in the United States. The primary objectives of the study were to evaluate the safety, tolerability, and pharmacokinetics of KX-01 in patients with AK. The secondary objective was to evaluate the activity of KX-01 administered externally to the dorsal forearm in patients with AK.

The following cohorts included adult patients aged 18 years or older with clinically typical AK lesions on the dorsal forearm who met all inclusion criteria and did not meet exclusion criteria.

Cohort 1, N=4, 0.5 mg KX-01 administered externally to a 25 ^cm2 area of 4-8 clinically typical AK lesions on the dorsal forearm, daily for 3 consecutive days.

Cohort 2, N=10, 2.0 mg KX-01 administered externally to a 100 ^cm2 area of 8-16 clinically typical AK lesions on the dorsal forearm, daily for 3 consecutive days.

Cohort 3, N=8, 0.5 mg KX-01 administered externally to a 25 ^cm2 area of 4-8 clinically typical AK lesions on the dorsal forearm, daily for 5 consecutive days.

Cohort 4, N=8, 2.0 mg KX-01 administered externally to a 100 ^cm2 area of 8-16 clinically typical AK lesions on the dorsal forearm, daily for 5 consecutive days.

KX-01 was used externally on treatment days. All patients were screened for safety and tolerability, which included LSR, AE, vital signs, clinical laboratory tests, ECG, and physical examination at baseline and at predetermined time points during treatment and follow-up 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. A standardized photograph of the treatment area was taken. Plasma samples for pharmacokinetics were collected at pre-planned time points on days 1–8.

LSRs (erythema, desquamation/scaling, crusting, edema, vesiculation/pustulation, erosion/ulceration) were scored by the investigator or designee using a 4-point scale according to the protocol. Patient ratings of symptoms (burning/burning sensation, itching) associated with irritation of the treatment area were rated on a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). Patients were asked for spontaneously reported AEs at each visit before the start of the LSR assessment study. LSR and AE were presented separately. All LSRs must be regulated and stabilized.

A total of 30 patients were enrolled and 29 patients completed the study. The patient population consisted of 19 men and 11 women. The overall mean age was 63.1 years and the mean weight was 194.9 pounds. All but one patient were white. All were non-Hispanic or Latino. Demographic data and baseline characteristics by cohort are shown in Table 1.

Table 1. Patient demographics and baseline characteristics Demographics and baseline characteristics Cohort 1 (N=4)
0.5 mg KX-01/25 cm2 daily × 3 days Cohort 2 (N=10)
2 mg KX-01/100 cm2 daily x 3 days Cohort 3 (N=8)
0.5 mg KX-01/25 cm2 daily × 5 days Cohort 4 (N=8)
2 mg KX-01/100 cm2 daily × 5 days Average age (years) 63.0 61.8 63.0 64.9 Gender (m/f) 3/1 6/4 5/3 5/3 Race
white
other 4
0 9
1 8
0 8
0 Average weight (lbs) 200.8 180.2 215.0 190.3 Number of initial AK lesions - median (range) 5.0 (4-5) 11.5 (8-16) 6.0 (5-6) 11.0 (10-16) m=male; f=female.

Local tolerability was acceptable. All 30 patients had investigator-assessed LSRs. LSRs typically appeared on day 2, typically peaked around day 5 for the 3-day treatment cohorts (cohorts 1 and 2) and around day 10 for the 5-day treatment cohorts (cohorts 3 and 4). ) before returning to or close to the original level. No patients had an LSR score of 4 in any category. No patients had vesicles or pustules. Fifteen patients had erythema and/or desquamation/flaking with a score of 1 or 2 at day 45, which was observed until resolution or stabilization. The maximum LSR values are displayed by category and group in Table 2.

At each visit, patients were specifically asked about burning, burning, and itching sensations at the application site. The maximum scores for each symptom are shown in Table 2. Symptoms typically began as early as day 2, peaked in severity and frequency on days 8 and 10, and resolved by day 45. Two patients (one in group 2 and one in group 4) who had mild to moderate symptoms were monitored for resolution or stabilization. There was one patient in Group 3 who had severe pruritus on day 17, which subsided to mild severity at the next visit on day 31, without requiring concomitant treatment.

Table 2. Number of patients (%) with maximum LSR score by LSR category and by cohort LSR Cohort 1 (N=4)
0.5 mg KX-01
25 cm ² daily×3 days Cohort 2 (N=10)
2 mg KX-01
100 cm ² daily×3 days Cohort 3 (N=8)
0.5 mg KX-01
25 cm ² daily×5 days Cohort 4 (N=8)
2 mg KX-01
100 cm ² daily×5 days Max. point 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 Max. LSR score as assessed by the investigator Erythema 0 2 (50%) 1 (25%) 1 (25%) 0 0 6 (60%) 2 (20%) 2 (20%) 0 0 2
(25%) 4 (50%) 2 (25%) 0 0 2 (25%) 4 (50%) 2 (25%) 0 Peeling/flaking 0 3
(75%) 0 1 (25%) 0 1 (10%) 2 (20%) 1 (10%) 6 (60%) 0 0 2
(25%) 2 (25%) 4 (50%) 0 0 2 (25%) 4 (50%) 2 (25%) 0 Crusting 4 (100%) 0 0 0 0 5 (50%) 5 (50%) 0 0 0 1
(13%) 7
(88%) 0 0 0 4 (50%) 4 (50%) 0 0 0 Swelling 4 (100%) 0 0 0 0 8 (80%) 2 (20%) 0 0 0 4
(50%) 1
(13%) 0 3 (38%) 0 1 (13%) 6 (75%) 1 (13%) 0 0 Blisters/pustules 4 (100%) 0 0 0 0 10 (100%) 0 0 0 0 8 (100%) 0 0 0 0 8 (100%) 0 0 0 0 Erosion/ulceration 4 (100%) 0 0 0 0 10 (100%) 0 0 0 0 8 (100%) 0 0 0 0 7 (88%) 1 (13%) 0 0 0 Max. patient-rated LSR score Burning 3 (75%) 1 (25%) 0 0 8 (80%) 2 (20%) 0 0 6
(75%) 1 (13%) 1 (13%) 0 5 (63%) 3 (38%) 0 0 Burn 4 (100%) 0 0 0 6 (60%) 3 (30%) 1 (10%) 0 4
(50%) 3
(38%) 1 (13%) 0 4 (50%) 4 (50%) 0 0 Itching 3 (75%) 1 (25%) 0 0 4 (40%) 6 (60%) 0 0 2
(25%) 4
(50%) 1 (13%) 1 (13%) 0 4 (50%) 4 (50%) 0 LSR=local skin reaction; Max = maximum.
Investigator rating of LSR, 5-point LSR rating scale: 0=absent, 1=minimal, 2=weak, 3=moderate, 4=strong.
Patient assessment of LSR, 4-point LSR rating scale: 0=absent, 1=weak, 2=moderate, 3=strong.

As a retrospective analysis of LSR, total scores were calculated by adding the scores from the 6 LSR categories for each patient, which were determined by the investigator at each examination visit. The range of possible total scores is 0-24. Figure 1 shows the mean total scores over time by group.

Four of 30 patients reported 10 treatment-emergent adverse events (TEAEs). All TEAEs were mild to moderate and responded to treatment when provided. No TEAEs were reported for cohort 1. One patient in cohort 2 had a mild upper respiratory tract infection on days 38–44 that was not related to the study drug. One patient in Cohort 3 experienced headache on day 2, back pain on days 4–5, and urinary tract infection on days 6–14; these AEs were mild in severity and were considered possibly related to the study drug. The same patient had mild arthralgia on days 16–49, moderate osteoarthritis on days 16–49, and moderate pain from a platelet-rich plasma injection for osteoarthritis on days 43–44, which was considered unrelated to the study drug. In cohort 4, one patient had basal cell carcinoma, not in the treatment area, of moderate severity on days 3–25, which was considered unrelated to the study drug; was surgically removed. Another patient reported mild muscle weakness and myositis, which was not related to the study drug but was related to fenofibrate, which was taken for hyperlipidemia. Fenofibrate was discontinued. At follow-up, the muscle weakness had resolved and the myositis had improved, but was still present.

There were no serious adverse events (SAEs) or deaths in the study. No one stopped treatment or monitored for side effects. One participant in Cohort 2 withdrew consent for personal reasons after 1 day of study drug use.

Clinical activity:

All 4 cohorts showed a decrease in the mean baseline number of AK lesions over time, and some patients demonstrated complete clearance at day 45 (Table 3).

Table 3. Complete/Partial Clearance by Cohort and Summary of Median (Range) Number of AK Lesions by Visit and Cohort, in KX01-AK-01-US Activity Cohort 1 (N=4)
0.5 mg KX-01
25 cm2 daily×3 days Cohort 2 (N=10)
2 mg KX-01
100 cm2 daily×3 days Cohort 3 (N=8)
0.5 mg KX-01
25 cm2 daily×5 days Cohort 4 (N=8)
2 mg KX-01
100 cm2 daily×5 days Full cleanse on day 45a 1/4 (25%) 0/10 4/8 (50%) 1/8 (13%) Partial cleanse for day 45b 2/4 (50%) 3/10 (30%) 5/8 (63%) 4/8 (50%) Summary of median (min, max) number of AK lesions by visit by cohort Day 1 (initial) 5.0 (4.5) 11.5 (8, 16) 6.0 (5, 6) 11.0 (10, 16) Day 4 5.0 (4.5) 9.0 (6, 16) Didn't do it Didn't do it Day 10 5.0 (4.5) 7.0 (6, 11) 5.0 (5, 6) 10.0 (10, 10) Day 17 4.5 (3.5) 7.0 (5, 15) 5.0 (4.6) 10.0 (10, 11) Day 31 3.5 (1.5) 7.0 (1.15) 1.0 (0.6) 6.0 (0.11) Day 45 2.5 (0.4) 4.0 (1, 10) 0.5 (0.4) 4.5 (0.12) a Complete clearance - 100% reduction in AK lesions on day 45 compared to baseline.
b Partial clearance - ≥75% reduction in AK lesions at day 45 compared to baseline.

This study provided preliminary data on the clinical activity of topical KX-01 for the treatment of AK. Data also suggest that the 5-day regimen may provide better potency than the 3-day regimen, as demonstrated by higher rates of complete and partial AK clearance in patients treated for 5 days. Local skin reactions were mostly mild. The safety and activity results of this study prompted an extension to a larger multicenter study.

Example 2a - Phase 2a Study of KX-01 Applied Topically to the Face or Scalp

This document describes an ongoing, open-label, multicenter, phase 2a study of the activity and safety of KX-01 administered topically to patients with AK on the face or scalp. The primary objective is to evaluate the activity of KX-01 applied topically to the face or scalp in patients with AK by determining the overall response rate, defined as 100% clearance at day 57. Secondary objectives are to evaluate the activity of KX-01 applied topically for 1-57 days based on reduction in the number of AK lesions compared to baseline, evaluate safety and tolerability and pharmacokinetics, and compare dosing regimens (5-day treatment versus 3-day treatment). daytime treatment) in terms of activity and safety in patients with AK on the face or scalp. This uncontrolled, non-randomized study is being conducted at 16 study sites in the United States. Enrollment is sequential for 2 cohorts of 80 patients each. Enrollment stopped for Cohort 1 and continued for Cohort 2. Results for the two treatment cohorts are shown below:

Cohort 1: 0.5 mg KX-01 applied topically to a 25 ^cm2 continuous treatment area with 4-8 clinically typical AK lesions for 5 consecutive days.

Cohort 2: 0.5 mg KX-01 applied topically to a 25 ^cm2 continuous treatment area with 4-8 clinically typical AK lesions for 3 consecutive days.

On treatment days, study staff administer 0.5 mg KX-01 topically to a 25 ^cm2 area of the face or scalp. All patients are monitored for safety and tolerability, which include LSR, hyperpigmentation, hypopigmentation, scarring, AE, vital signs, clinical laboratory tests, ECG, and physical examinations at baseline at predetermined time points during treatment and follow-up days 1, 2, 3, 4, 5, 8, 15, 29 and 57. The number of AK lesions is recorded at the beginning of the study, on days 8, 15, 29 and 57. Those who achieve complete AK clearance on day 57 monitored for AK lesion counts, LSRs, and AEs at 3, 6, 9, and 12 months after day 57 during the follow-up period for relapse. Standardized photography of the treatment area is performed at baseline, day 8, and day 57. Plasma samples are collected at pre-planned time points on days 1 and 5 for cohort 1 and on days 1 and 3 for cohort 2.

LSRs (erythema, desquamation/scaling, crusting, edema, vesiculation/pustulation, erosion/ulceration) are scored by the investigator or designee using a grading scale from 0 (not present) to 4 (worst) based on protocol-defined LSR scoring criteria. The absence or presence of hyperpigmentation, hypopigmentation and scarring are also assessed. Application site reactions not classified as LSRs are reported as AEs. Patients were asked for spontaneously reported AEs at each visit before the start of the LSR assessment study. LSR and AE were presented separately. All LSR, pigmentation and scars in the treatment area are accompanied by resolution and stabilization.

82 eligible patients were enrolled in Cohort 1. Patient demographics and baseline characteristics are shown in Table 4. The study was not stopped until day 57. Since this study is ongoing, the data presented should be considered preliminary. Data for cohort 2 (3-day dosing) are not yet available.

Table 4. Demographics and baseline characteristics of patients in cohort 1 Demographics and baseline characteristics Cohort 1 (N=82)
0.5 mg KX-01, 25 cm2 daily × 5 days Average age (years) 69.0 Gender: male/female 74/8 Race - white 82 Ethnicity - Hispanic or Latino/Non-Hispanic or Latino 2/80 Skin type I/II/III/IV/V/VI 11/37/26/7/1/0 Number of AK lesions at baseline - median (min., max.) 6.0 (4.8) Average weight (lbs) 194.07

Of the 67 patients who had a 57-day visit, 7 had no LSR in the treatment area throughout the study. The majority of patients had erythema (60/67, 90%) and desquamation/scaling (47/67, 70%). The majority of these LSRs were graded as 1 and 2. Crusting was observed in 26/67 (39%) patients and was mostly graded as 1. Edema was noted in 14/67 (21%) patients. All swellings were graded as 1 except for two patients, one had a grade of 2 and the other a grade of 3. Three patients had vesiculation/pustulation and 9 patients had erosion/ulceration. LSRs were generally observed from day 3 and peaked on days 5 and 8 and then decreased to or near baseline on days 29 and 57. Of the 60 patients who had LSRs, all but 8 patients had LSRs return to baseline by day 57. These 8 patients had erythema of 1 or 2, desquamation/scaling, and/or crusting of 1, and were followed until resolution or stabilization by the investigators.

A detailed description of the local skin reactions (LSR) in this KX01-AK-002 study is provided below in Table 5.

Table 5. Summary of Local Skin Reactions by Visit Assessments in Cohort 1 Attendance Degree Erythema Peeling/Scaling Crusting Swelling Vesiculation/pustulization Erosion/ulceration Day 1, n (%) 0 56/67 (84) 55/67 (82) 62/67 (93) 67/67 (100) 67/67 (100) 67/67 (100) 1 11/67 (16) 12/67 (18) 5/67 (7) 0 0 0 2 0 0 0 0 0 0 3 0 0 0 0 0 0 4 0 0 0 0 0 0 Day 2, n (%) 0 44/67 (66) 51/67 (76) 64/67 (96) 67/67 (100) 67/67 (100) 67/67 (100) 1 20/67 (30) 15/67 (22) 2/67 (3) 0 0 0 2 3/67 (4) 1/67 (1) 1/67 (1) 0 0 0 3 0 0 0 0 0 0 4 0 0 0 0 0 0 Day 3, n (%) 0 32/67 (48) 46/67 (69) 63/67 (94) 67/67 (100) 67/67 (100) 66/67 (99) 1 24/67 (36) 14/67 (21) 3/67 (4) 0 0 1/67 (1) 2 10/67 (15) 5/67 (7) 1/67 (1) 0 0 0 3 1/67 (1) 2/67 (3) 0 0 0 0 4 0 0 0 0 0 0 Day 4, n (%) 0 19/67 (28) 43/67 (64) 61/67 (91) 65/67 (97) 66/67 (99) 65/67 (97) 1 26/67 (39) 16/67 (24) 4/67 (6) 2/67 (3) 1/67 (1) 2/67 (3) 2 17/67 (25) 5/67 (7) 2/67 (3) 0 0 0 3 5/67 (7) 3/67 (4) 0 0 0 0 4 0 0 0 0 0 0 Day 5, n (%) 0 12/67 (18) 35/67 (52) 56/67 (84) 58/67 (87) 65/67 (97) 61/67 (91) 1 19/67 (28) 21/67 (31) 9/67 (13) 7/67 (10) 2/67 (3) 6/67 (9) 2 27/67 (40) 9/67 (13) 2/67 (3) 1/67 (1) 0 0 3 9/67 (13) 2/67 (3) 0 1/67 (1) 0 0 4 0 0 0 0 0 0 Day 8, n (%) 0 14/67 (21) 26/67 (39) 51/67 (76) 64/67 (96) 67/67 (100) 65/67 (97) 1 24/67 (36) 18/67 (27) 15/67 (22) 3/67 (4) 0 1/67 (1) 2 25/67 (37) 15/67 (22) 1/67 (1) 0 0 1/67 (1) 3 4/67 (6) 8/67 (12) 0 0 0 0 4 0 0 0 0 0 0 Day 15, n (%) 0 27/67 (40) 39/67 (58) 63/67 (94) 67/67 (100) 67/67 (100) 66/67 (99) 1 25/67 (37) 14/67 (21) 4/67 (6) 0 0 1/67 (1) 2 13/67 (19) 9/67 (13) 0 0 0 0 3 2/67 (3) 5/67 (7) 0 0 0 0 4 0 0 0 0 0 0 Day 29, n (%) 0 45/67 (67) 51/67 (76) 65/67 (97) 66/67 (99) 67/67 (100) 67/67 (100) 1 18/67 (27) 13/67 (19) 2/67 (3) 1/67 (1) 0 0 2 4/67 (6) 2/67 (3) 0 0 0 0 3 0 1/67 (1) 0 0 0 0 4 0 0 0 0 0 0 Day 57, n (%) 0 53/67 (79) 57/67 (85) 63/67 (94) 67/67 (100) 67/67 (100) 67/67 (100) 1 12/67 (18) 10/67 (15) 4/67 (6) 0 0 0 2 2/67 (3) 0 0 0 0 0 3 0 0 0 0 0 0 4 0 0 0 0 0 0

Note 1: Cohort 1=25 cm ² treatment area /5 consecutive days of treatment/0.5 mg KX-01 administered topically.

2: Data are presented as the ratio of number of patients with specific results/number of patients assessed at each visit. The calculated percentage is shown in parentheses.

Table 6 presents the maximum post-dose LSR score and the maximum LSR score obtained in the phase 3 combination registration trial of Picato® (ingenol mebutate) in the treatment of AK of the face and scalp. The findings suggest that a 5-day treatment with topical KX-01 may have a more favorable local safety profile compared with data obtained for Picato® (ingenol mebutate).

Table 6. Summary of maximum local skin reactions after baseline for Picato® (ingenol mebutate) Local skin reactions Degree Gel Pep005 0.015%a
N=274 KX-01b
N=67 Erythema 0 eleven%) 7 (10%) 1 25 (9%) 16 (24%) 2 56 (20%) 32 (48%) 3 125 (46%) 12 (18%) 4 66 (24%) 0 (0%) Peeling/Scaling 0 7 (3%) 20 (30%) 1 52 (19%) 14 (21%) 2 91 (33%) 20 (30%) 3 98 (36%) 13 (19%) 4 25 (9%) 0 (0%) Crusting 0 44 (16%) 41 (61%) 1 85 (31%) 20 (30%) 2 64 (23%) 6 (9%) 3 64 (23%) 0 (0%) 4 16 (6%) 0 (0%) Swelling 0 56 (20%) 53 (79%) 1 88 (32%) 12 (18%) 2 67 (25%) eleven%) 3 48 (18%) eleven%) 4 14 (5%) 0 (0%) Vesiculation/pustulization 0 119 (43%) 64 (96%) 1 36 (13%) 3 (4%) 2 53 (19%) 0 (0%) 3 50 (18%) 0 (0%) 4 15 (6%) 0 (0%) Erosion/ulceration 0 186 (68%) 57 (85%) 1 55 (20%) 9 (13%) 2 26 (10%) eleven%) 3 5 (2%) 0 (0%) 4 eleven%) 0 (0%) a Source of information: NDA statistical review and evaluation of Pep005 (ingenol mebutate) gel, 0.015%; table 9.
b Values represent the number of patients in the evaluable sample classified by their maximum post-baseline LSR score. Percentages are based on the number of patients.

As a retrospective analysis of LSR, total scores were calculated by adding the scores from the 6 LSR categories for each patient, which were determined by the investigator at each examination visit. The range of possible total scores is 0-24. Figure 2 shows the mean total scores over time in Cohort 1.

All 82 patients included in cohort 1 were included in the AE analysis. Twenty-six of 82 patients in cohort 1 reported 54 TEAEs. All TEAEs were mild to moderate, except for one severe case of small bowel obstruction, which was noted as an SAE (discussed below). Seven patients reported 12 TEAEs thought to be related to KX-01. There were 6 cases of application site reactions, which included 1 mild sensitivity, 2 mild tingling, and 3 mild itching. Other treatment-related AEs included 2 mild dizziness, 1 mild darkening of hair color near the treatment area, and 1 mild headache. There was a case of “worsening of elevated alanine transaminase” from a baseline of 58 IU/mL to 61 IU/mL on day 22. A case of mild conjunctivitis near the treatment area was reported on day 4 and continued until day 5. The patient explained that only mucus is released from the eye due to the use of contact lenses. There was no associated redness, itching, pain, or swelling, and KX-01 did not enter the eye.

There were 3 SAEs that occurred in 2 patients, none of which were considered related to the study drug. All SAEs required hospitalization. One was an 84-year-old man who had small bowel obstruction on day 56, transurethral resection of the prostate (TURP) for benign prostatic hypertrophy (BPH) on day 67, and postoperative cardiac ischemia on day 72. After this he recovered. The other patient was a 67-year-old white man who was admitted for TURP for BPH on day 17. He recovered without complications.

There was one case of cancer that was not associated with the study drug - a 61-year-old man who was diagnosed with squamous cell carcinoma that was absent from the treatment area on day 3 and was subsequently removed. This AE was not considered serious.

Among the enrolled patients, 67 reached day 57 of the visit. Twenty-four of 67 patients (36%, 95% CI: 24%-47%) met the primary endpoint defined as 100% clearance of AK lesions in the treatment area at day 57. Of the 35 patients treated on the face, 15 (43%, 95% CI: 26%-59%) achieved 100% clearance, while 9 of 32 patients (28%, 95% CI: 13%-59%) achieved 100% clearance. 44%) who received treatment on the scalp achieved 100% cleansing.

Thirty-four of 67 patients (51%, 95% CI: 39%-63%) had at least a 75% reduction in AK lesions at day 57 compared with baseline; 21/35 (60%, 95% CI: 44%-76%) who received treatment on the face and 13/32 (41%, 95% CI: 24%-58%) who received treatment on the scalp. These data are shown in Table 7.

Table 7. Day 57 Clearance Analysis - Evaluable Sample in Cohort 1 Cleansing (a) Treatment area Number of patients with specific cleansing on day 57 Total number of patients per day 57 Binomial proportion Wald 95% lower confidence limit Wald 95% upper confidence limit 100% Face 15 35 0.43 0.26 0.59 Scalp 9 32 0.28 0.13 0.44 General 24 67 0.36 0.24 0.47 >=75% Face 21 35 0.60 0.44 0.76 Scalp 13 32 0.41 0.24 0.58 General 34 67 0.51 0.39 0.63 Note 1: Data cut-off date is Oct 12. 2016.
2: Cohort 1=25 cm ² treatment area /5 consecutive days of treatment/0.5 mg KX-01 administered topically.
(a) Clearance is calculated relative to the score on day 1 of the visit.

The activity of KX-01 in terms of reducing the number of AK lesions is presented in Table 8. Over the 57-day observation period, there was a gradual decrease in the average number of lesions from 6.0 to 2.0.

Table 8. Summary of number of AK lesions by visit in Cohort 1, KX01-AK-002 Number of AK hits Day 1 Day 8 Day 15 Day 29 Day 57 N 67 60a 63a 67 67 Median 6.0 5.0 4.0 2.0 2.0 Min., max. 4, 8 0, 10 0.9 0.8 0.9

KX-01, applied topically once daily for 5 days, appears to be safe and well tolerated. There were few treatment-related side effects and no severe or serious treatment-related side effects.

The 5-day dosing regimen of KX-01 was associated with mild and reversible LSRs consisting primarily of erythema and desquamation/flaking. In this study, no grade 4 LSRs were observed after 5 days of KX-01 treatment.

Preliminary results (Example 1, Example 2a and Example 2b) indicate that KX-01, applied topically once daily for up to 5 days, demonstrates clinically significant activity in the treatment of AK of the dorsal forearm, as well as the face and scalp. Data suggest that the 5-day regimen of KX-01 has greater potency than the 3-day regimen.

Crossover studies with results published for Picato® (ingenol mebutate) suggest that the activity of a 5-day regimen of topical KX-01 may be comparable to that observed in the phase 3 studies of Picato® (ingenol mebutate). (Table 9).

Table 9. Complete Clearance Cross Study Table - KX-01 and Picato® (ingenol mebutate) KX-01 3-day topical dosing regimen KX-01 5-day topical dosing regimen Gel Picatob Gel Picatob Anatomical location Shoulder (area 25 ^cm2 ) 1/4 (25%) 4/8 (50%) Study 3 Study 4 22/84 (26%) 27/59 (46%) Face TBD 15/35 (43%) Study 1 Study 2 46/109 (42%) 58/111 (52%) Scalp TBD 9/32 (28%) Study 1 Study 2 4/26 (15%) 9/31 (29%) a Studies KX01-AK-01-US and KX01-AK-002, data cut-off date 12 Oct. 2016.
b Picato® (ingenol mebutate), instructions for use of the drug, September 2016.

Pharmacokinetic results after 5 days of KX-01 treatment showed low systemic exposure (<1 ng/mL) and limited drug accumulation in most patients. The data obtained indicate that 5 days of topical application of KX-01 has optimal activity and safety.

Example 2a - Phase 2a Study of KX-01 Applied Topically to the Face or Scalp

Phase 2a, described in Example 2a, was completed with 84 eligible patients enrolled in each of two cohorts: one cohort was treated for 5 consecutive days and the other cohort was treated for 3 consecutive days. The results are described below and presented in Figure 5.

Table 10. AK clearance in two cohorts at day 57 after treatment

Cohort AK cleanse on day 57 Responders/total number (%) Face Scalp Total 5 days 100% 23/44 (52%) 13/40 (33%) 36/84 (43%) ≥ 75% 29/44 (66%) 18/40 (45%) 47/84 (56%) 3 days 100% 20/66 (30%) 7/18 (39%) 27/84 (32%) ≥ 75% 35/66 (53%) 9/18 (50%) 44/84 (52%)

Table 11. Summary of maximum local skin reactions after baseline for Picato® (ingenol mebutate)

Local skin reactions Degree Gel Pep005 0.015%a N=274 KX-01b (5-day) N=84 KX-01b (3-day) N=84 Erythema 0 eleven%) 15 (18%) 30 (36%) 1 25 (9%) 16 (19%) 22 (26%) 2 56 (20%) 35 (42%) 26 (31%) 3 125 (46%) 17 (20%) 6 (7%) 4 66 (24%) eleven%) 0 (0%) Peeling/
flake formation 0 7 (3%) 33 (39%) 39 (46%) 1 52 (19%) 10 (12%) 18 (21%) 2 91 (33%) 24 (29%) 19 (23%) 3 98 (36%) 16 (19%) 8 (10%) 4 25 (9%) eleven%) 0 (0%) Crusting 0 44 (16%) 51 (61%) 58 (69%) 1 85 (31%) 25 (30%) 16 (19%) 2 64 (23%) 8 (10%) 9 (11%) 3 64 (23%) 0 (0%) eleven%) 4 16 (6%) 0 (0%) 0 (0%) Swelling 0 56 (20%) 66 (79%) 76 (90%) 1 88 (32%) 16 (19%) 8 (10%) 2 67 (25%) eleven%) 0 (0%) 3 48 (18%) eleven%) 0 (0%) 4 14 (5%) 0 (0%) 0 (0%) Vesiculation/
pustulization 0 119 (43%) 80 (95%) 83 (99%) 1 36 (13%) 4 (5%) 0 (0%) 2 53 (19%) 0 (0%) eleven%) 3 50 (18%) 0 (0%) 0 (0%) 4 15 (6%) 0 (0%) 0 (0%) Erosion/ulceration 0 186 (68%) 71 (85%) 79 (94%) 1 55 (20%) 12 (14%) 5 (6%) 2 26 (10%) eleven%) 0 (0%) 3 5 (2%) 0 (0%) 0 (0%) 4 eleven%) 0 (0%) 0 (0%)

a. Source of information: NDA 202833; statistical review and evaluation of Pep005 (ingenol mebutate) gel, 0.015%; table 9.

b. Values represent the number of patients in the evaluable sample classified by their maximum post-baseline LSR score. Percentages are based on the number of patients.

Example 3 - Summary of PK Study Results for Examples 1 and 2

KX-01 was tested in adult patients with actinic keratoses of the dorsal forearm (Example 1) and actinic keratoses of the face or scalp (Examples 2a and 2b). In Example 1, plasma pharmacokinetics (PK) of KX-01 following topical administration was assessed by collecting plasma on days 1 and 3 for 3-day treatment regimens and on days 1 and 5 for 5-day treatment regimens (Table 12). In Examples 2a and 2b, plasma samples were collected on days 1 and 5 from cohort 1 (Table 13). Plasma samples at identical time points were collected on days 1 and 3 from 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.

Table 12. Example 1 - Treatment regimens and time to obtain PK data

Cohort KX-01 quantity Dosage regimen PK data acquisition time (hour) 1 0.5 mg per 25 cm ² Once within 3 days Day 1: before using the drug, 0.5, 1, 2, 4, 6, 8 and 12 after using the drug
Day 2: before using the drug (24 after using the drug Day 1)
Day 3: before using the drug, 0.5, 1, 2, 4, 6, 8, 24, 48 and 120 after using the drug 2 2 mg per 100 cm ² Once within 3 days Day 1: before using the drug, 0.5, 1, 2, 4, 6, 8, 12 after using the drug
Day 2: before using the drug (24 hours after using the drug Day 1)
Day 3: before using the drug, 0.5, 1, 2, 4, 6, 8, 24, 48 and 120 after using the drug 3 0.5 mg per 25 cm ² Once within 5 days Day 1: before using the drug, 0.5, 1, 2, 4, 6 after using the drug
Day 2: before using the drug (24 hours after using the drug Day 1)
Day 5: before using the drug, 0.5, 1, 2, 4, 6 and 72 after using the drug 4 2 mg per 100 cm ² Once within 5 days Day 1: before using the drug, 0.5, 1, 2, 4, 6 after using the drug
Day 2: before using the drug (24 hours after using the drug Day 1)
Day 5: before using the drug, 0.5, 1, 2, 4, 6 and 72 after using the drug

Table 13. Examples 2a and 2b - Treatment regimens and timing of PK data acquisition

Cohort KX-01 quantity Dosage regimen PK data acquisition time (hour) 1 0.5 mg per 25 cm ² Once within 5 days Day 1: before using the drug, 0.5, 1 and 4 after using the drug
Day 5: before using the drug, 0.5, 1 and 4 after using the drug 2 0.5 mg per 25 cm ² Once within 3 days Day 1: before using the drug, 0.5, 1 and 4 after using the drug
Day 3: before using the drug, 0.5, 1 and 4 after using the drug

Examination of the PK data in these studies suggests that some plasma concentration data may be misleading. 75% of concentrations in both studies were below the level of quantitation (BLQ).

In study KX01-AK-002, PK data are available for 84 patients in cohort 1 treated once daily for 5 days and for 84 patients in cohort 2 treated once daily for 3 days at 0.5 mg KX-01 to a 25 ^cm2 dosing area on the face or scalp. Of a total of 336 plasma samples analyzed from these 84 patients after 1 day of treatment, 15 samples (~4%) were above the limit of quantitation. Before dosing on days 5 and 8, 84 (~9%) patients had quantifiable KX-01 concentrations. On day 5 of dosing, measurable plasma concentrations were detected in 42 of 84 patients 4 hours after dosing. All measured plasma concentrations were below 0.7 ng/mL except for three aberrant samples.

Two of the three PK aberrant samples had plasma concentrations of 44 and 23 ng/mL occurring at 1 and 0.5 hours postdose in two different patients on day 5. These primary PK samples were reanalyzed with comparable results. Analysis of reserve PK samples resulted in concentrations of 0.351 ng/mL and BLQ, respectively. These results are more consistent with plasma concentrations of KX-01 from the other 82 patients and other samples obtained from these patients. One PK sample from the patient had an apparent plasma concentration greater than 12,500 ng/mL, but the backup sample had a plasma concentration of 30 ng/mL. The most likely reason for these aberrant results is cross-contamination, and the results do not represent actual plasma concentrations of KX-01. All sites in Study KX01-AK-002 were double-checked for proper collection, processing and storage of PK samples.

In summary, the PK results from these studies showed that after 5 consecutive days of topical administration of KX-01, there was low systemic exposure (less than 1 ng/mL) and limited drug accumulation.

Example 4 - Phase 3 Study KX-01

A Phase 3, double-blind, placebo-controlled, randomized, parallel-group, multicenter study of the efficacy and safety of KX2-391 in adult patients with AK of the face or scalp will be conducted at approximately 25 sites in the United States to study the following:

efficacy of topical KX-01 applied daily for 5 consecutive days compared with placebo control in terms of 100% clearance on day 57 in the treatment of adults with actinic keratosis (AK) when applied to a continuous 25 ^cm2 area of the face or scalp,

safety of topical KX-01 daily for 5 consecutive days based on local skin reactions (LSR) and other safety assessments such as adverse events (AE) and laboratory assessments,

Partial response rates were defined as at least 75% clearance of AK lesions in the treatment area of the face or scalp on day 57 between the KX-01-treated group and the placebo-treated group.

Topical KX treatment daily for 5 consecutive days will demonstrate more complete clearance (defined as 100% clearance of clinically typical and visible AK lesions on day 57) than daily placebo for 5 consecutive days in adults with actinic keratoses of the face or skin heads.

Registration will be regulated so that approximately two thirds of registered patients will have the face treated and approximately one third of registered patients will have the scalp treated. Eligible patients will be centrally randomized to treatment in a 1:1 ratio (KX-01 or placebo) in each treatment area subgroup. In other words, in the subgroup of individuals having either the face or scalp treated, half of the subjects will randomly receive the active treatment and the other half will randomly receive placebo.

The treatment area will be marked at study sites with a permanent marker on Day 1. Patients will be given daily single doses to be administered at home for the next 5 days. Patients in both groups will be instructed to wash their hands and treatment area, then dry the treatment area before applying KX-01. A small amount of KX-01 should be applied to the fingertip and gently rubbed over the entire 25 cm ² treatment area. Patients will be instructed to wash their hands after applying KX-01 and to avoid washing the treatment area for at least 8 hours, and to avoid getting KX-01 in the eyes. Patients return for safety follow-up, LSR, and activity assessment (number of AK lesions) at predetermined time points through day 57. All patients who have unresolved LSR hypo- or hyperpigmentation, scarring, or treatment-related AEs at day 57 will return for post-study follow-up every 7 to 28 days until resolved or deemed stable by the investigators. Patients who achieve 100% clearance of AK lesions in the treatment area at day 57 will be asked to enroll in a continuation protocol to determine relapse rates and safety for up to 12 months.

Enough patients will be screened to randomize approximately 300 patients. Each site will randomize a minimum of 10 patients and a maximum of 20 patients.

Each patient will be on the study for up to 85 days: assessed 28 days before Day 1, treated for 5 consecutive days, and monitored until Day 57. The use of any non-investigational medications to treat AK lesions in the treatment area is prohibited until day 57.

Inclusion criteria for the study

1. Men and women aged ≥18 years

2. Treatment area on the face or scalp that:

is a continuous area with an area of 25 cm ²

contains 4 to 8 clinically typical, visible and discrete AK lesions

3. Patients who, in the opinion of the investigator, are in good general health based on:

medical history

physical examination (PE) results

electrocardiogram (ECG), clinical chemistry, hematology and urinalysis results

4. Women must be postmenopausal (age >45 years with at least 12 months of amenorrhea), surgically sterile (hysterectomy, bilateral oophorectomy, or tubal ligation); or, if fertile, must use highly effective contraception for at least 30 days or 1 menstrual cycle, whichever is longer, before starting KX01 treatment and must agree to continue using highly effective contraception for at least 30 days after use last dose of KX01. Highly effective contraception includes oral hormonal contraceptives, hormonal contraceptive implants, injections or patches, intrauterine contraceptives, or complete abstinence from sexual intercourse for 2 weeks before dosing and for the duration of the study.

5. Men who have not had a vasectomy must agree to use barrier contraception after screening 90 days after the last dose of KX-01.

6. All patients must agree not to donate sperm or eggs or attempt to conceive after screening 90 days after the last dose of KX-01.

7. Women of childbearing potential should have a negative serum pregnancy test at screening and a negative urine pregnancy test on day 1 before starting treatment.

8. Agree to avoid direct exposure to sunlight or ultraviolet (UV) light on the face or scalp

9. Ability to understand and willingness to sign the Informed Consent Form (ICF)

Study exclusion criteria

1. Clinically atypical and/or rapidly changing AK lesions in the treated area, e.g. hypertrophic, hyperkeratotic, recurrent disease (cryosurgery on two previous occasions) and/or keratoma keratoma

2. Location of treatment area:

Anywhere except the face or scalp

Within 5 cm of an incompletely healed wound

Within 5 cm of suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)

3. Previous treatment with KX-01

4. Anticipated need for inpatient hospitalization or inpatient surgery

5. Treatment with 5-fluorouracil (5-FU), imiquimod, ingenol mebutate, diclofenac, photodynamic therapy, or other treatments for AK within 2 cm of the treatment area, for 8 weeks before the screening visit

6. Use of the following treatments and/or medications for 2 weeks before your screening visit:

Cosmetic or therapeutic procedures (eg, liquid nitrogen, surgical excision, curettage, dermabrasion, moderate or deeper chemical peels, laser resurfacing) within 2 cm of the selected treatment area

Acid-containing therapeutic products (such as salicylic acid or fruit acids such as alpha and beta hydroxyl acids and glycolic acids), topical retinoids, or light chemical peels within 2 cm of the chosen treatment area

Topical balms (non-drug/non-irritating lotion and cream are acceptable) or topical steroids within 2 cm of the chosen treatment area; tanning creams within 5 cm of the selected treatment area

7. Use of the following treatments and/or medications within 4 weeks before your screening visit:

Treatment with immunomodulators (eg, azathioprine), cytotoxic drugs (eg, cyclophosphamide, vinblastine, chlorambucil, methotrexate), or interferon/interferon inducers

Treatment with systemic drugs that suppress the immune system (eg, cyclosporine, prednisone, methotrexate, alefalept, infliximab)

Treatment/therapy with UVA or UVB

8. Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene) for 6 months before the screening visit

9. History of sensitivity and/or allergy to any of the ingredients in the study drug

10. Skin disease (eg, atopic dermatitis, psoriasis, eczema) or condition (eg, scarring, open wounds) that, in the opinion of the investigator, may affect the conduct or evaluation of the study or which exposes the patient to an unacceptable risk from participating in the study

11. Other serious uncontrolled or unstable medical diseases or conditions that, in the opinion of the investigator, may place the patient at an unacceptable risk by participating in the study

12. Pregnant and breastfeeding women

13. Participated in a drug trial in which the study drug was administered for 30 days or 5 half-lives of the study drug, whichever is longer, prior to dosing

Activity rating

The investigator or designee will perform AK counts of treatment site lesions on all patients at screening and on days 1 (baseline), 8, 15, 29, and 57.

Security assessment

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

Laboratory evaluation of hematology, biochemistry and urinalysis readings, weight, height and vital signs measurements, ECG and PE assessments will be performed at predetermined time points.

Patients will be asked for spontaneously reported AEs at each visit before the start of the LSR assessment study. AEs will be reported separately from LSRs.

Other ratings

The LSR assessment is the investigator's (or trained designee's) assessment of the following signs in the treatment area: erythema, desquamation/scaling, crusting, edema, vesiculation/pustulation, and erosion/ulceration. These signs will be scored using a rating scale: 0=absent, 1=mild (mild, barely noticeable), 2=moderate (clearly present), and 3=severe (pronounced, intense).

In addition to LSR, hypo- and hyperpigmentation and scarring in the treatment area will be assessed as present or absent. Application site reactions not classified as LSRs (eg, itching, pain, infection) will be reported as adverse events. Researchers will be trained in the use of this LSR scale using representative photographs. Standardized photography will be performed on Day 1 before dosing, and on Days 6, 8, 15, 29, and 57.

The primary efficacy endpoint is the complete AK lesion clearance rate, defined as the proportion of patients at day 57 without clinically visible AK lesions in the treatment area. The secondary efficacy endpoint is partial clearance of AK lesions, defined as the proportion of patients at day 57 with a 75% or greater reduction in the number of AK lesions in the treatment area detected on day 1 (baseline). Reducing the number of AK lesions during days 1-57 will also be considered.

Safety endpoints include assessment of LSR, pigmentation and scarring, AE, SAE, cases of special interest, and clinical laboratory data; The results of other safety assessments (vital signs, PE, ECG) will also be assessed.

Patient populations include (1) the intent-to-intervention (ITT)/safety population: all randomized patients who received at least one day of treatment and returned for a follow-up visit, and (2) the patient population whose data compliant with protocol (PP)/evaluable: all randomized patients who received at least 4 of 5 doses met the protocol regarding study inclusion criteria, were not receiving concomitant medications that may affect efficacy, and returned for a follow-up visit at day 57. This is the main effectiveness population.

The primary efficacy endpoint, complete clearance rate, will be compared based on the Cochran-Mantel-Haenszel (CMH) method controlling for treatment areas (face or scalp) between treatment groups. In addition, full comparisons of clearance rates between treatment groups will be performed in the face and scalp subgroups independently of each other. Partial clearance will be analyzed in the same way as the primary efficacy endpoint (complete clearance).

To show consistency with the overall results, the full clearance rate will also be tabulated and displayed graphically, as well as by subgroups such as sex, age (˂65 or ≥65 years), study site, baseline number of lesions (4, 5, 6 or 7, 8), skin type (I/II or III/IV/V/VI according to Fitzpatrick). Outliers in experimental values will be clinically explained in the clinical study report.

The number of AK lesions at baseline, day 57, and other visits and changes from baseline in the number of AK lesions at each visit will be summarized using descriptive statistics (ie, mean, standard deviation, median, minimum, and maximum), and then comparisons for each treatment group.

A safety analysis will be conducted in a population to assess safety.

Treatment emergent AEs (TEAEs) are defined as those AEs that occur after dosing or those that were pre-existing that worsen after dosing. For AE, verbatim terms on the Case Report Form/Electronic Case Report Form (CRF/eCRF) will be mapped to Preferred Terms (PT) and System Organ Classes (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA; v 16.0 or higher). The occurrence rate of AE will be displayed by SOC and PT. TEAE cases will be summarized by treatment group. TEAEs will also be summarized by severity, relationship with study treatment, and treatment group. The incidence of SAEs will also be displayed by treatment group. Laboratory parameters will be summarized using descriptive statistics at baseline and at each subsequent time point by treatment group. Changes from baseline will also be summarized by treatment group. In addition, offset tables (ie, low-normal-high at baseline versus low-normal-high at follow-up as a 3 by 3 contingency table) will be provided to assess changes in laboratory values from baseline to follow-up. in each treatment group. Local skin reactions, pigmentation, and scarring as reported by the investigator will be displayed and summarized by visit and treatment group for all patients. Cases of particular interest will be summarized.

Example 5 - KX-01 Phase 3 Extension Study Protocol Set (Repeat Continuation Protocol)

A prospective 12-month follow-up study of complete responders from two phase 3 studies of KX-01 administered topically in adult patients 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) in the area treatment of patients who had complete clearance at day 57 in the phase 3 studies of KX-01, and to examine treatment-related adverse events (AEs).

Eligibility Criteria

1. Complete clearance, defined as 100% clearance of AK lesions in the treatment area on day 57 in patients from two phase 3 studies

2. Agreement to avoid direct exposure to sunlight or ultraviolet (UV) light on the face or scalp

3. Ability to understand and willingness to comply with study procedures and sign an informed consent form (ICF)

No patient will be re-treated with the study drug. Patients will be prohibited from receiving radiation therapy or treatments that may mask the recurrence rate of AK lesions (eg, topical ingenol mebenate, 5-fluorouracil [5-FU], diclofenac, imiquimod) within or within 2 cm of the treatment area at any time during the treatment research. Treatment of isolated lesions, such as cryotherapy or biopsy, will be permitted for the treatment of AK lesions arising in the selected treatment area. Clinic visits will occur at 3, 6, 9, and 12 months after the 57th day of the pivotal phase 3 study visit. The number of AK lesions in the treatment area will be counted at each visit. If a patient receives lesion-specific treatment (ie, cryotherapy or biopsy) for a lesion that appears in the treatment area, the treated lesion will be considered a relapse. Information will be collected regarding intercurrent illnesses, therapeutic agents that may lead to immunosuppression, and treatment with agents known to alter AK. Adverse events and serious adverse events (SAEs) have been reported, including skin cancer (basal cell carcinoma [BCC]/squamous cell carcinoma [SCC]/melanoma) in the treatment area or within 5 cm of the treatment area border. Other AEs and SAEs will be reported if the investigator believes they are related to the study treatment. Standard photography will be taken at all visits.

For efficacy, recurrence of AK lesions will be assessed, which is defined as any identified AK lesion in the targeted treatment area during the 12-month follow-up period for patients who achieved complete clearance on day 57 of the phase 3 study visit, regardless of what treatment they received previously. If a patient receives lesion-specific treatment (ie, cryotherapy or biopsy) for a lesion that appears in the treatment area, the treated lesion is considered a recurrence.

For safety reasons, AEs in the selected treatment area will be assessed over a 12-month follow-up period. Other AEs that investigators report are related to treatment will also be evaluated.

The analysis population included all patients who achieved complete clearance on day 57 of the pivotal phase 3 study visit, regardless of what treatment they had previously received. Efficacy and safety analyzes will be conducted based on this population.

The results of the analysis by previous treatment groups (active treatment versus placebo control) will be primarily compared using tables and graphs. Relapse rates will be estimated using the Kaplan-Meier method with 95% confidence intervals (CI) at routine visits after the baseline visit (3, 6, 9, and 12 months) for prior treatment. The time at which the lesion(s) are observed will be imputed to the corresponding study target day (eg, day 91 for the 3-month visit). Relapse rates will be estimated using the Kaplan-Meier method with 95% confidence intervals (CI) at routine visits after the baseline visit (3, 6, 9, and 12 months) for prior treatment. The time at which the lesion(s) are observed will be imputed to the corresponding study target day (eg, day 91 for the 3-month visit).

In addition, based on the Kaplan-Meier method, the mean time to recurrence (i.e., the appearance of a new or recurrent lesion in the treatment area) will be displayed graphically at the previous treatment. The number of AK lesions in the treatment area will be summed at each scheduled visit after the baseline visit for the previous treatment. In addition, the number of lesions in the treatment area, normalized by the corresponding baseline numbers of lesions from the phase 3 studies (expressed as a percentage), will be summed at each routine visit after the baseline visit for the previous treatment.

For AEs that are collected in the treatment area, verbatim terms on the Case Report Form/Electronic Case Report Form (CRF/eCRF) will be mapped to Preferred Terms (PT) and System Organ Classes (SOC) using the Medical Dictionary for Regulatory Activities ( MedDRA; v 16.0 or higher). The occurrence rate of AE will be displayed by SOC and PT. AE cases will be summarized by previous treatment. SAE incidence will be displayed by previous treatment. Adverse events reported by the investigators to be treatment-related will be assessed in the same way, but separately.

Example 6 - Comparison of Skin Response to KX-01 Versus Response to Picato® (ingenol mebutate), Standard of Care AK Treatment

Baseline patient data in the studies described herein (eg, Example 1 and Examples 2a and 2b) demonstrate that the effectiveness of KX-01 for clearing AK lesions may be similar to Picato® (ingenol mebutate), an approved therapy for AK. In addition, treatment with KX-01 results in fewer and less severe patient skin reactions, i.e., less skin toxicity, compared to Picato® (ingenol mebutate).

This is shown in Figures 3A and 3B, which demonstrate a skin reaction on the patient's forearm on days 3 and 5 of treatment with Picato® (ingenol mebutate), which shows severe skin reactions (Figure 3A). In comparison, the patient's forearm on days 3 and 5 of KX-01 treatment in a patient who had a 100% response to topical KX-01 treatment demonstrated minimal or no adverse skin reactions (Figure 3B).

Likewise, Figures 4A and 4B illustrate an adverse skin reaction on the patient's forehead on days 4 and 15 of treatment with Picato® (ingenol mebutate), which shows severe skin reactions (Figure 4A). In comparison, the patient's forehead on days 8 and 57 of KX-01 treatment in a patient who had a 100% response to topical KX-01 treatment also demonstrated minimal or no adverse skin reactions (Figure 4B).

Comparisons in Figures 3A, 3B, 4A and 4B illustrate the lack of skin toxicity observed with topical KX-01 treatment of AK compared to approved AK therapy. This is likely an important consideration for clinicians and patients, and since skin toxicity limits the market for existing treatment options for patients suffering from AK, KX-01 could significantly expand the market as a result of less skin toxicity.

EQUIVALENTS

The specification of the application may be embodied in other specific forms without departing from the essence or essential characteristics thereof. Therefore, the above embodiments are to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, expressed by the appended claims and not by the above description, and all changes that come within the meaning and range of equivalence of the claims are intended to be covered thereby.

Claims (39)

1. A method of treating actinic keratosis, comprising administering to a subject with actinic keratosis a therapeutically effective amount of KX-01: at a dose of approximately 0.025 mg/cm² up to approximately 0.1 mg/cm^2,Where the term “about” refers to a dose of ±5%. 2. The method of claim 1, wherein KX-01 is administered to the affected area of the subject at a dose of about 0.1 mg to about 10 mg, about 0.2 mg to about 5 mg, or about 0.5 mg to about 2 .5 mg. 3. The method of claim 1, 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. 4. The method according to claim 1, where KX-01 is administered to the affected area of the patient at a dose of approximately 0.03 mg/ ^cm2 , approximately 0.04 mg/ ^cm2 , approximately 0.05 mg/ ^cm2 , approximately 0.06 mg/cm ² , about 0.07 mg/cm ² , about 0.08 mg/cm ² , about 0.09 mg/cm ² or about 0.1 mg/cm ² . 5. Method according to any one of paragraphs. 1-4, where the area of the affected area is from about 0.01 cm ² to about 300 cm ² , from about 1 cm ² to about 200 cm ² , from about 1 cm ² to about 100 cm ² , from about 1 cm ² to about 75 cm ² , from about 1 cm ² to about 50 cm ² _, from about 1 cm ² to about 25 cm ² , from about 10 cm ² to about 200 cm ² , from about 10 cm ² to about 100 cm ² , from about 10 cm ² to about 75 cm ² , from about 10 cm ² to about 50 cm ² , from about 10 cm ² to about 25 cm ² , from about 25 cm ² to about 200 cm ² , from about 25 cm ² to about 100 cm ² , from about 25 cm ² to about 75 cm ² , from about 25 cm ² to about 50 cm ² , from about 25 cm ² to about 90 cm ² , from about 25 cm ² to about 80 cm ² , from about 25 cm ² to about 70 cm ² , from about 25 cm ² to about 60 cm ² , from about 25 cm ² to about 40 cm ² , or from about 25 cm ² to about 30 cm ² . 6. Method according to any one of paragraphs. 1-4, where the area of the affected area is about 25 cm ² , about 30 cm ² , about 35 cm ² , about 40 cm ² , about 45 cm 2, about 50 cm ² , about 55 ^{cm 2 ,} about 60 cm ² , about 65 cm ² , about 70 cm ² , about 75 cm ² , about 80 cm ² , about 85 cm ² , about 90 cm ² , about 95 cm ² or about 100 cm ² . 7. Method according to any one of paragraphs. 1-4, where the area of the affected area is from about 1 cm ² to about 25 cm ² . 8. Method according to any one of paragraphs. 1-4, where the area of the affected area is from about 10 cm ² to about 25 cm ² . 9. A method of treating actinic keratosis, comprising administering to the affected area of a subject with actinic keratosis a therapeutically effective amount of KX-01: at a dose of approximately 0.1 mg/cm² up to approximately 10 mg/cm^2,Where the term “about” refers to a dose of ±5%. 10. The method of claim 9, wherein KX-01 is administered to the affected area of the subject at a dose of from about 0.2 mg to about 5 mg. 11. The method of claim 9, wherein KX-01 is administered to the affected area of the subject at a dose of from about 0.2 mg to about 2.5 mg. 12. The method of claim 9, wherein KX-01 is administered to the affected area of the subject at a dose of from about 0.3 mg to about 2.5 mg. 13. The method of claim 9, wherein KX-01 is administered to the affected area of the subject at a dose of from about 0.4 mg to about 2.5 mg. 14. The method of claim 9, wherein KX-01 is administered to the affected area of the subject at a dose of from about 0.5 mg to about 2.5 mg. 15. The method of claim 9, wherein KX-01 is administered to the affected area of the patient 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. 16. Method according to any one of paragraphs. 1-15, where the affected area is the skin. 17. The method according to claim 16, where the affected area is located in one or more places independently selected from the scalp, forehead, forearm, face, nose, ears, eyelids, lips, neck, arms, hands, torso, legs and feet . 18. The method of claim 17, wherein the subject has more than one affected area. 19. Method according to any one of paragraphs. 1-18, 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. 20. Method according to any one of paragraphs. 1-18, where KX–01 is administered during 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days. 21. Method according to any one of paragraphs. 1-18, where KX-01 is administered for 1, 2, 3, 4 or 5 days. 22. Method according to any one of paragraphs. 1-18, where KX-01 is administered for 1, 2, 3, 4, 5 or 6 days per week. 23. Method according to any one of paragraphs. 1-18, where KX-01 is administered once or twice daily continuously for more than one day per week, followed by discontinuation of the drug for the remainder of the week. 24. Method according to any one of paragraphs. 1-18, where KX-01 is administered once or twice daily, every other day, every three days, every four days, every five days, every six days, or every seven days. 25. Method according to any one of paragraphs. 1-18, where KX-01 is administered once or twice daily for two consecutive days, every three days, every four days, every five days, every six days, or every seven days. 26. Method according to any one of paragraphs. 1-18, where KX-01 is administered once or twice daily for three consecutive days, every four days, every five days, every six days, or every seven days. 27. Method according to any one of paragraphs. 1-18, where KX-01 is administered once or twice daily for four consecutive days, every five days, every six days, or every seven days. 28. Method according to any one of paragraphs. 1-18, where KX-01 is administered until actinic keratosis is completely cured. 29. Method according to any one of paragraphs. 1-28, where KX–01 is administered externally. 30. Method according to any one of paragraphs. 1-29, wherein administration of KX-01 reduces the number and/or severity of local skin reactions or the number of subjects who have local skin reactions or other adverse side effects compared to other treatments for actinic keratosis. 31. The method of claim 30, wherein the local skin reaction is selected from the group selected from vesiculation, postulation, erosion, ulceration, redness, swelling, desquamation, scaling, crusting, dryness, suppuration and blistering. 32. The method of claim 30, wherein the other adverse side effect is selected from the group consisting of pain at the application site, itching at the application site, irritation at the application site, swelling at the application site, burning sensation at the application site, infection at the application site, periorbital edema, nasopharyngitis, chills, sore throat, drooping eyelids, swollen eyes, hypopigmentation, hyperpigmentation and headache. 33. Method according to any one of paragraphs. 1-32, where the compound is administered once daily. 34. Method according to any one of paragraphs. 1-32, where the compound is administered over three days. 35. Method according to any one of paragraphs. 1-32, where the compound is administered for 5 days.

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