Methods of reducing mammographic breast density and/or breast cancer risk

• US 10,471,073 B2
• Filed: 04/18/2017
• Issued: 11/12/2019
• Est. Priority Date: 04/19/2016
• Status: Active Grant

• Current Assignee: Havah Therapeutics Pty., Ltd.
• Original Assignee: Havah Therapeutics Pty., Ltd.
• Inventors: Birrell, Stephen Nigel
• Primary Examiner(s): Puttlitz, Karl J
• Application Number:
  US15/490,309
• Publication Number:
  US 20170319597A1
• Time in Patent Office: 938 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: A61P 5/32 Antioestrogens

Abstract

The present disclosure is directed to generally methods and/or compositions for treating mammographic breast density and/or breast stiffness in a patient in need thereof, such as a pre-menopausal, a peri-menopausal or a post-menopausal patient, comprising the administration of an effective amount of androgenic agent and an effective amount of an aromatase inhibitor. The present disclosure is also directed to methods and/or compositions for reducing breast pain. The present disclosure is also directed to method and/or compositions for reducing elasticity and/or decreasing mechano-transduction on the genome of breast cells. The present disclosure is also directed to methods and/or compositions for stabilizing and/or increasing the levels of androgen receptor expression in breast tissue.

Claims

1. A method of reducing mammographic breast density and/or breast stiffness in a patient, comprising administering to the patient:

i) an effective amount of a selective androgen receptor modulator selected from the group consisting of;

(2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide;

(7R,7aS)-2-Chloro-4-(7-hydroxy-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile;

4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-trifluoromethyl)benzonitrile;

4-(3-Hydroxy-8-aza-bicyclo[3.2.1]octyl)-naphthalene-1-carbonitrile;

JNJ-28330835;

6-(bis-(2,2,2-trifluoroethyl)amino)-4-trifluoromethyl-1H-quinolin-2-one;

9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one;

2-[4-(dimethylamino)-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl]-2-methylpropan-1-ol; and

(2S)—

N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluoro-4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide;

or pharmaceutically acceptable salts thereof; and

ii) an effective amount of an aromatase inhibitor selected from the group consisting of;

exemestane, formestane, anastrozole, letrozole, vorozole, and fadrozole.

2. The method of claim 1, wherein the patient has, or is diagnosed with having, a breast with:

i) a mammographic breast density of 7.5% or greater;

ii) an area breast density percentage (ABD %) of 7.5% or greater;

iii) a volume breast density percentage (VBD %) of 7.5% or greater; and

/or

iv) a BIRADS score of 3 or 4 (or c or d).

3. The method of claim 1, wherein the patient is premenopausal, peri-menopausal, or post-menopausal.

4. The method of claim 1, wherein:

i) the reduction in mammographic breast density is in the range of between 5% to 25% or 10% to 25% after 1 year, 2 years, 3 years, 4 years or 5 years of treatment;

ii) the method reduces the VBD % or absolute volume breast density (AVBD) of the patient'"'"'s breast between one or more annual intervening mammographic detections; and

/or

iii) the method reduces the ABD % or absolute area breast density (AABD) of the patient'"'"'s breast between one or more annual intervening mammographic detections.

5. The method of claim 1, wherein the breast stiffness reduces by at least 10% after 1 year, 2 years, 3 years, 4 years or 5 years of treatment.

6. The method of claim 1, wherein the method increases or improves the patient'"'"'s fat to breast tissue ratio from 1:

19 to 19;

1 over a 3 month period, over a 6 month period, over a 9 month period, over a 1 year period, or over a 5 year period.

7. The method of claim 1, wherein the method reduces the treated patient'"'"'s risk of developing breast cancer between one or more annual intervening mammographic detections.

8. The method of claim 1, wherein the method provides one or more of the following:

i) enhances mammographic detection due to reduced breast density enabling the mammogram to visualize malignancy at an earlier and/or less aggressive stage;

ii) enhances the ability to achieve better mammographic compression due at least in part due to reduced pain;

iii) enhances the ability to achieve better patient compliance in having regular mammographic check-ups;

iv) enhances the ability to treat the patient and at the same time not causing perturbations in the hypothalamic-pituitary axis and/or other endocrine axis;

v) reduces breast pain in a patient;

vi) reduces breast elasticity in a patient;

vii) decrease mechano-transduction on the genome of a cell in order to reduce the risk of malignant transformation in a patient;

viii) increases ratio of fibro-glandular and adipose tissue in a patient;

ix) increases CD36 in a patient;

x) stabilizes and/or an increase in levels of androgen receptor expression in breast tissue of a patient;

xi) increases the level of GCDFP15 in a patient;

xii) reduces BPE in an MRI breast image of a patient;

xiii) improves detection of breast abnormalities due to reduced BPE in an MRI breast image of a patient; and

xiv) reduces cysts in size and/or quantity in a patient'"'"'s breast.

9. The method of claim 1, wherein the method reduces or reverses peri-menopausal symptoms.

10. The method of claim 1, wherein the selective androgen receptor modulator is (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide.

11. The method of claim 1, wherein the aromatase inhibitor is anastrozole.