COMPOSITIONS AND METHODS FOR THE TREATMENT OF ESTROGEN-DEPENDENT DISORDERS
20230067378 · 2023-03-02
Inventors
Cpc classification
A61K31/519
HUMAN NECESSITIES
A61K31/57
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
A61K31/513
HUMAN NECESSITIES
A61K31/565
HUMAN NECESSITIES
A61K31/57
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K31/567
HUMAN NECESSITIES
A61K31/585
HUMAN NECESSITIES
A61P15/00
HUMAN NECESSITIES
International classification
A61K31/519
HUMAN NECESSITIES
A61K31/567
HUMAN NECESSITIES
A61K31/585
HUMAN NECESSITIES
A61K31/57
HUMAN NECESSITIES
Abstract
The present disclosure provides compositions and methods for treating estrogen-dependent disorders, such as disorders of the female reproductive system, including uterine fibroids and endometriosis, among others. Compounds described herein that may be used to treat such indications include gonadotropin-releasing hormone (GnRH) antagonists. Suitable GnRH antagonists useful in conjunction with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid and the choline salt thereof, among others. Using the compositions and methods described herein, GnRH antagonists may be periodically administered to a patient, such as one or more times per day, week, or month, in combination with periodic add-back therapy, thereby preventing bone mineral density loss that may otherwise accompany estrogen depletion effectuated by GnRH antagonist activity. Advantageously, using the dosing schedules of the present disclosure, the periodic administration the GnRH antagonist and add-back therapy may commence together, such as on the same day.
Claims
1. A method of treating an estrogen-dependent disease in a human patient in need thereof, the method comprising periodically administering to the patient therapeutically effective amounts of a gonadotropin-releasing hormone (GnRH) antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
2. The method of claim 1, wherein the estrogen-dependent disease is uterine fibroids.
3. A method of reducing the volume of menstrual blood loss a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
4. A method of inducing amenorrhea in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
5. A method of reducing the volume of one or more uterine fibroids in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
6. The method of claim 1, wherein the estrogen-dependent disease is endometriosis.
7. A method of reducing the volume of one or more endometriosis nodes in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
8. A method of reducing pelvic pain in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
9. A method of reducing dysmenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
10. A method of reducing dyspareunia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
11. A method of reducing dyschezia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
12. A method of reducing uterine bleeding in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
13. A method of inducing amenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
14. The method of claim 1, wherein the estrogen-dependent disease is adenomyosis.
15. A method of reducing uterine volume in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
16. A method of reducing the thickness of the anterior and/or posterior region of the uterine myometrium in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
17. A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
18. A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
19. A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
20. A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
21. A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
22. A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
23. A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
24. The method of claim 1, wherein the estrogen-dependent disease is rectovaginal endometriosis.
25. A method of reducing the volume of one or more rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
26. A method of reducing the volume of one or more type III rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
27. A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
28. A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
29. A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
30. A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
31. A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
32. A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.
33. The method of any one of claims 1-32, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00582## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
34. The method of claim 33, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00583##
35. The method of claim 33 or 34, wherein m is 1.
36. The method of claim 35, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00584##
37. The method of any one of claims 33-36, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.
38. The method of claim 37, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
39. The method of any one of claims 33-38, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.
40. The method of claim 39, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00585##
41. The method of any one of claims 33-40, wherein n is 2.
42. The method of claim 41, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00586##
43. The method of any one of claims 33-42, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.
44. The method of claim 43, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
45. The method of any one of claims 33-44, wherein U is a single bond.
46. The method of any one of claims 33-45, wherein X is a group represented by —O-L-Y.
47. The method of any one of claims 33-46, wherein L is a methylene group.
48. The method of any one of claims 33-47, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00587## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.
49. The method of claim 48, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00588##
50. The method of claim 33, wherein the compound is represented by formula (Ia) ##STR00589## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.3 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.
51. The method of claim 50, wherein the compound is represented by formula (Ib) ##STR00590##
52. The method of claim 51, wherein the compound is represented by formula (Ic) ##STR00591## or a pharmaceutically acceptable salt thereof.
53. The method of claim any one of claims 33-52, wherein the compound is represented by formula (VI) ##STR00592## or a pharmaceutically acceptable salt thereof.
54. The method of claim 53, wherein the compound is administered to the patient in the form of the choline salt of (VI), choline 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylate.
55. The method of claim 54, wherein the compound is in a crystalline state.
56. The method of claim 55, wherein the compound exhibits characteristic X-ray powder diffraction (XRPD) peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2θ.
57. The method of claim 55 or 56, wherein the compound exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm.
58. The method of any one of claims 55-57, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.
59. The method of any one of claims 33-58, wherein the compound is orally administered to the patient.
60. The method of any one of claims 33-59, wherein the compound is administered to the patient one or more times per day, week, or month.
61. The method of claim 60, wherein the compound is administered to the patient one or more times daily.
62. The method of claim 61, wherein the compound is administered to the patient once daily.
63. The method of any one of claims 60-62, wherein the compound is administered to the patient in an amount of from about 25 mg per day to about 400 mg per day.
64. The method of claim 63, wherein the compound is administered to the patient in an amount of from about 35 mg to about 65 mg per day.
65. The method of claim 64, wherein the compound is administered to the patient in an amount of about 50 mg per day.
66. The method of claim 63, wherein the compound is administered to the patient in an amount of from about 60 mg per day to about 90 mg per day.
67. The method of claim 66, wherein the compound is administered to the patient in an amount of about 75 mg per day.
68. The method of claim 63, wherein the compound is administered to the patient in an amount of from about 85 mg to about 115 mg per day.
69. The method of claim 68, wherein the compound is administered to the patient in an amount of about 100 mg per day.
70. The method of claim 63, wherein the compound is administered to the patient in an amount of from about 185 mg to about 215 mg per day.
71. The method of claim 70, wherein the compound is administered to the patient in an amount of about 200 mg per day.
72. The method of any one of claims 60-71, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least four weeks.
73. The method of claim 72, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least eight weeks.
74. The method of claim 73, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least 10 weeks.
75. The method of claim 74, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least 12 weeks.
76. The method of claim 75, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least 24 weeks.
77. The method of any one of claims 60-71, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about four weeks to about 48 months.
78. The method of claim 77, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about five weeks to about 36 months.
79. The method of claim 78, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about six weeks to about 24 months.
80. The method of claim 79, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about seven weeks to about 12 months.
81. The method of claim 80, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about eight weeks to about six months.
82. The method of any one of claims 60-71, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about four weeks to about 12 months.
83. The method of claim 82, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about five weeks to about 24 weeks.
84. The method of claim 83, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about six weeks to about 18 wees.
85. The method of claim 84, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about seven weeks to about 14 weeks.
86. The method of claim 85, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about eight weeks to about 12 weeks.
87. The method of any one of claims 1-32, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.
88. The method of claim 87, wherein the GnRH antagonist is elagolix.
89. The method of claim 88, wherein the GnRH antagonist is orally administered to the patient.
90. The method of claim 88 or 89, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.
91. The method of claim 90, wherein the GnRH antagonist is administered to the patient one or more times daily.
92. The method of claim 91, wherein the GnRH antagonist is administered to the patient once daily.
93. The method of any one of claims 88-92, wherein the GnRH antagonist is administered to the patient in an amount of from about 100 mg to about 600 mg per day.
94. The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day.
95. The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day.
96. The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 200 mg per dose.
97. The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 300 mg per dose.
98. The method of claim 87, wherein the GnRH antagonist is relugolix.
99. The method of claim 98, wherein the GnRH antagonist is orally administered to the patient.
100. The method of claim 98 or 99, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.
101. The method of claim 100, wherein the GnRH antagonist is administered to the patient one or more times daily.
102. The method of claim 101, wherein the GnRH antagonist is administered to the patient once daily.
103. The method of any one of claims 98-102, wherein the GnRH antagonist is administered to the patient in an amount of from about 10 mg to about 60 mg per day.
104. The method of claim 103, wherein the GnRH antagonist is administered to the patient in an amount of from about 20 mg to about 50 mg per day.
105. The method of claim 104, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day.
106. The method of any one of claims 1-105, wherein the add-back therapy is administered to the patient one or more times daily.
107. The method of claim 106, wherein the add-back therapy is administered to the patient once daily, concurrently with the GnRH antagonist.
108. The method of claim 106, wherein the add-back therapy is administered to the patient once daily, prior to administration of the GnRH antagonist.
109. The method of claim 106, wherein the add-back therapy is administered to the patient once daily, following administration of the GnRH antagonist.
110. The method of claim 107, wherein the add-back therapy is administered to the patient in the form of a pharmaceutical composition comprising the GnRH antagonist.
111. The method of any one of claims 1-110, wherein the add-back therapy comprises an estrogen.
112. The method of claim 111, wherein the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens.
113. The method of claim 112, wherein the estrogen is β17-estradiol.
114. The method of claim 113, wherein the β17-estradiol is administered to the patient in an amount of about 1.0 mg/day.
115. The method of claim 113, wherein the β17-estradiol is administered to the patient in an amount of about 0.5 mg/day.
116. The method of claim 112, wherein the estrogen is ethinyl estradiol.
117. The method of claim 116, wherein the ethinyl estradiol is administered to the patient in an amount of about 5.0 μg/day.
118. The method of claim 116, wherein the ethinyl estradiol is administered to the patient in an amount of about 2.5 μg/day.
119. The method of claim 112, wherein the estrogen is a conjugated estrogen.
120. The method of claim 119, wherein the conjugated estrogen is administered to the patient in an amount of about 0.625 mg/day.
121. The method of claim 119, wherein the conjugated estrogen is administered to the patient in an amount of about 0.45 mg/day.
122. The method of claim 119, wherein the conjugated estrogen is administered to the patient in an amount of about 0.3 mg/day
123. The method of any one of claims 1-122, wherein the add-back therapy comprises a progestin.
124. The method of claim 123, wherein the progestin is selected from the group consisting of norethindrone or an ester thereof, progesterone, norgestimate, medroxyprogesterone, and drospirenone.
125. The method of claim 124, wherein the progestin is norethindrone or norethindrone acetate.
126. The method of claim 125, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 1.0 mg/day.
127. The method of claim 125, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.5 mg/day.
128. The method of claim 125, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.1 mg/day.
129. The method of claim 124, wherein the progestin is progesterone.
130. The method of claim 129, wherein the progesterone is administered to the patient in an amount of about 200 mg/day.
131. The method of claim 129, wherein the progesterone is administered to the patient in an amount of about 100 mg/day.
132. The method of claim 124, wherein the progestin is norgestimate.
133. The method of claim 132, wherein the norgestimate is administered to the patient in an amount of about 0.09 mg/day.
134. The method of claim 124, wherein the progestin is medroxyprogesterone.
135. The method of claim 134, wherein the medroxyprogesterone is administered to the patient in an amount of about 5 mg/day.
136. The method of claim 134, wherein the medroxyprogesterone is administered to the patient in an amount of about 2.5 mg/day.
137. The method of claim 134, wherein the medroxyprogesterone is administered to the patient in an amount of about 1.5 mg/day.
138. The method of claim 124, wherein the progestin is drospirenone.
139. The method of claim 138, wherein the drospirenone is administered to the patient in an amount of about 0.5 mg/day.
140. The method of claim 138, wherein the drospirenone is administered to the patient in an amount of about 0.25 mg/day.
141. The method of any one of claims 1-140, wherein the add-back therapy comprises about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.
142. The method of any one of claims 1-140, wherein the add-back therapy comprises about 0.5 mg of β17-estradiol and about 0.1 mg of norethindrone acetate.
143. The method of any one of claims 1-142, wherein the patient is a pre-menopausal female of from about 18 to about 48 years of age.
144. The method of any one of claims 1-143, wherein the patient exhibits a serum concentration of follicle-stimulating hormone (FSH) of about 20 IU/L or less prior to administration of the GnRH antagonist to the patient.
145. The method of any one of claims 1-144, wherein the patient exhibits a rectal (type II) and/or vaginal (type III) endometriosis node of at least 2 cm prior to administration of the GnRH antagonist to the patient.
146. The method of claim 145, wherein the length of the type II and/or type III endometriosis node is assessed by way of magnetic resonance imaging (MRI).
147. The method of any one of claims 1-146, wherein the patient exhibits a junctional-zone width of about 12 mm or more prior to administration of the GnRH antagonist to the patient.
148. The method of claim 147, wherein the junctional-zone width is assessed by way of MRI.
149. The method of any one of claims 1-148, wherein the patient exhibits a reduction in serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or β17-estradiol (E2) following administration of the GnRH antagonist to the patient.
150. The method of claim 149, wherein the patient exhibits the reduction in serum concentration of LH, FSH, and/or E2 within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
151. The method of any one of claims 1, 2, 5-11, 14-21, 24-30, and 33-150, wherein the patient exhibits a reduction in uterine bleeding following administration of the GnRH antagonist to the patient.
152. The method of claim 151, wherein the patient exhibits the reduction in uterine bleeding within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
153. The method of any one of claims 3, 4, 12, 13, 22, 23, 31, 32, 151, and 152, wherein the reduction in uterine bleeding is assessed by way of an alkaline hematin method.
154. The method of any one of claims 1-3, 5-12, 14-22, 24-31, and 33-153, wherein the patient exhibits amenorrhea following administration of the GnRH antagonist to the patient.
155. The method of claim 154, wherein the patient exhibits the amenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the amenorrhea within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
156. The method of any one of claims 1-24 and 27-155, wherein the patient exhibits a reduction in the volume of one or more rectovaginal endometiosis nodes following administration of the GnRH antagonist to the patient.
157. The method of claim 156, wherein the patient exhibits the reduction in volume of the one or more rectovaginal endometriosis nodes within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
158. The method of any one of claims 26, 156, and 157, wherein the reduction in volume of the one or more rectovaginal endometriosis nodes is assessed by way of MRI or TVUS.
159. The method of any one of claims 1-158, wherein the patient exhibits a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient.
160. The method of claim 159, wherein the patient exhibits the reduction in bowel involvement of the one or more type III endometriosis nodes within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
161. The method of any one of claims 1-7, 9-16, 18-26, and 28-160, wherein the patient exhibits a reduction in pelvic pain following administration of the GnRH antagonist to the patient.
162. The method of claim 161, wherein the patient exhibits the reduction in pelvic pain within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
163. The method of any one of claims 8, 17, 27, 161, and 162, wherein the reduction in pelvic pain is assessed by way of a modified Biberoglu & Behrman (mB&B) score, Numerical Rating Scale (NRS) score, or Verbal Rating Scale (VRS) score.
164. The method of any one of claims 1-8, 10-17, 19-27, and 29-163, wherein the patient exhibits a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient.
165. The method of claim 164, wherein the patient exhibits the reduction in dysmenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
166. The method of any one of claims 9, 18, 28, 164, and 165, wherein the reduction in dysmenorrhea is assessed by way of an mB&B score, NRS score, or VRS score.
167. The method of any one of claims 1-9, 11-18, 20-28, and 30-166, wherein the patient exhibits a reduction in dyspareunia following administration of the GnRH antagonist to the patient.
168. The method of claim 167, wherein the patient exhibits the reduction in dyspareunia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
169. The method of any one of claims 10, 19, 29, 167, and 168, wherein the reduction in dyspareunia is assessed by way of an mB&B score, NRS score, or VRS score.
170. The method of any one of claims 1-10, 12-19, 21-29, and 31-169, wherein the patient exhibits a reduction in dyschezia following administration of the GnRH antagonist to the patient.
171. The method of claim 170, wherein the patient exhibits the reduction in dyschezia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
172. The method of any one of claims 11, 20, 30, 170, and 171, wherein the reduction in dyschezia is assessed by way of an mB&B score, NRS score, or VRS score.
173. The method of any one of claims 1-14 and 16-172, wherein the patient exhibits a reduction in uterine volume following administration of the GnRH antagonist to the patient.
174. The method of claim 173, wherein the patient exhibits the reduction in uterine volume within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
175. The method of any one of claims 15, 173, and 174, wherein the reduction in uterine volume is assessed by way of MRI or transvaginal ultrasound (TVUS).
176. The method of any one of claims 1-15 and 17-175, wherein the patient exhibits a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient.
177. The method of claim 176, wherein the patient exhibits the reduction in thickness of the anterior and/or posterior region of the uterine myometrium within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
178. The method of any one of claims 1-20 and 22-177, wherein the patient exhibits a reduction in uterine tenderness following administration of the GnRH antagonist to the patient.
179. The method of claim 178, wherein the patient exhibits the reduction in uterine tenderness within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
180. The method of any one of claims 1-179, wherein the patient exhibits a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient.
181. The method of claim 180, wherein the patient exhibits the reduction in the diameter of the junctional zone of adenomyosis within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
182. The method of anyone of claims 1-181, wherein the patient exhibits an improvement in Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient.
183. The method of claim 182, wherein the patient exhibits the improvement in the EHP-30 score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the improvement within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
184. The method of any one of claims 1-183, wherein the patient exhibits a positive Patient Global Impression of Change (PGIC) score core following administration of the GnRH antagonist to the patient.
185. The method of claim 184, wherein the patient exhibits the positive PGIC score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the positive PGIC score within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.
186. The method of any one of claims 1-185, wherein the patient does not exhibit a reduction in bone mineral density (BMD) of greater than 5% following administration of the GnRH antagonist to the patient.
187. The method of claim 186, wherein the patient does not exhibit a reduction in BMD of greater than 3% following administration of the GnRH antagonist to the patient.
188. The method of claim 187, wherein the patient does not exhibit a reduction in BMD of greater than 2% following administration of the GnRH antagonist to the patient.
189. The method of claim 188, wherein the patient does not exhibit a reduction in BMD of greater than 1% following administration of the GnRH antagonist to the patient.
190. The method of any one of claims 186-189, wherein the BMD is assessed by dual energy X-ray absorptiometry.
191. The method of claim 190, wherein the BMD is assessed in the spine or femur of the patient.
192. The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of bone specific alkaline phosphatase (BAP) in a sample isolated from the patient following the administration to the concentration of BAP in a sample isolated from the patient prior to the administration.
193. The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of deoxypyridinoline (DPD) in a sample isolated from the patient following the administration to the concentration of DPD in a sample isolated from the patient prior to the administration.
194. The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of type I collagen C-terminal telopeptide (CTX) in a sample isolated from the patient following the administration to the concentration of CTX in a sample isolated from the patient prior to the administration.
195. The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of procollagen 1 N-terminal peptide (P1NP) in a sample isolated from the patient following the administration to the concentration of P1NP in a sample isolated from the patient prior to the administration.
196. A kit comprising a GnRH antagonist and a package insert instructing a user of the kit to administer the GnRH antagonist to a human patient in accordance with the method of any one of claims 1-195.
197. The kit of claim 196, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00593## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and Wa may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
198. The kit of claim 197, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00594##
199. The kit of claim 197 or 198, wherein m is 1.
200. The kit of claim 199, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00595##
201. The kit of any one of claims 197-200, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.
202. The kit of claim 201, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
203. The kit of any one of claims 197-202, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.
204. The kit of claim 203, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00596##
205. The kit of any one of claims 197-204, wherein n is 2.
206. The kit of claim 205, wherein ring B is represented by a formula selected from the group consisting of: ##STR00597##
207. The kit of any one of claims 197-206, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.
208. The kit of claim 207, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
209. The kit of any one of claims 197-208, wherein U is a single bond.
210. The kit of any one of claims 197-209, wherein X is a group represented by —O-L-Y.
211. The kit of any one of claims 197-210, wherein L is a methylene group.
212. The kit of any one of claims 197-211, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00598## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.
213. The kit of claim 212, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00599##
214. The kit of claim 196, wherein the compound is represented by formula (Ia) ##STR00600## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.
215. The kit of claim 214, wherein the compound is represented by formula (Ib) ##STR00601##
216. The kit of claim 215, wherein the compound is represented by formula (Ic) ##STR00602## or a pharmaceutically acceptable salt thereof.
217. The kit of any one of claims 197-216, wherein the compound is represented by formula (VI) ##STR00603## or a pharmaceutically acceptable salt thereof.
218. The kit of claim 217, wherein the compound is the choline salt of the compound represented by formula (VI).
219. The kit of claim 196, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.
Description
BRIEF DESCRIPTION OF THE FIGURES
[0402]
[0403]
[0404]
[0405]
[0406]
DETAILED DESCRIPTION
[0407] The compositions and methods of the present disclosure can be used to treat a variety of estrogen-dependent disorders, including uterine fibroids and endometriosis, among others. For example, using the compositions and methods described herein, a patient, such as a female human patient, may be administered a gonadotropin-releasing hormone (GnRH) antagonist in order to not only treat the cause of the estrogen-dependent pathology, but also to alleviate one or more symptoms associated these conditions. Exemplary disease that are induced by elevated estrogen production, and that can be treated using the compositions and methods described herein, include, without limitation, uterine fibroids, endometriosis (e.g., rectovaginal endometriosis), and adenomyosis, among others.
[0408] GnRH antagonists that may be used for the treatment of an estrogen-dependent disorder as described herein include optionally substituted thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or the choline salt thereof. Other GnRH antagonists useful in conjunction with the compositions and methods of the disclosure include optionally substituted 3-aminoalkyl pyrimidine-2,4(1H,3H)-dione derivatives, such as sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, also referred to as elagolix, or the carboxylic acid conjugate thereof. In some embodiments, the GnRH antagonist is an optionally substituted thieno[2,3d]pyrimidine derivative, such as N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, also referred to as relugolix, or a pharmaceutically acceptable salt thereof. In some embodiments, the GnRH antagonist is an optionally substituted propane-1,3-dione derivative, such as (2R)—N-{5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorobenzene-1-sulfonyl}-2-hydroxypropanimidamide, also referred to as opigolix or ASP-1707. Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include SK12670 and BAY-784, as well as derivatives and variants thereof, among others.
[0409] Estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis), and adenomyosis, among others described herein, may be effectuated by circulating concentrations of β17-estradiol (E2) in excess of 50 pg/ml. Using the compositions and methods described herein, a GnRH antagonist may be administered to the patient so as to suppress E2 production to healthy levels, such as a concentration of from about 20 pg/ml to about 50 pg/ml, in order to correct the underlying physiological cause of the disease and ameliorate one or more symptoms associated therewith. However, excessive depletion of endogenous E2 (for example, to levels of less than 20 pg/ml) may lead to undesirable side effects, such as a reduction in bone mineral density. To prevent hypoestrogenemia, the GnRH antagonists of the disclosure may be administered to a patient in combination with add-back therapy, which provides the patient with an exogenous source of estrogen. Dual administration of a GnRH antagonist and add-back therapy may thus have the effect of partially compensating for the reduction in endogenous E2 induced by the GnRH antagonist. In this way, endogenous E2 can be reduced to a level sufficient to treat an estrogen-dependent disease (e.g., uterine fibroids, endometriosis, such as rectovaginal endometriosis, and adenomyosis, among others) without permitting bone mineral density loss.
[0410] The compositions and methods of the disclosure are based, in part, on the surprising discovery that the simultaneous onset of GnRH antagonist administration and add-back therapy administration reduces endogenous E2 levels to a greater extent than dosing schedules in which the patent is first treated with a GnRH antagonist alone before receiving add-back therapy. In uterine fibroids patients, the enhanced reduction in E2 achieved by concurrent onset of GnRH antagonist and add-back therapy administration manifests as a marked improvement in uterine bleeding pattern. One of the discoveries underlying the present disclosure is the unexpected observation that patients administered a GnRH antagonist for the treatment of uterine fibroids with a concurrent onset of the antagonist and add-back therapy exhibit substantially diminished uterine blood loss relative to patients that are pre-treated with the GnRH antagonist alone before receiving add-back therapy. It has been observed that patients pre-treated with a GnRH antagonist for several weeks have endogenous E2 concentrations that mirror those of post-menopausal subjects (Pohl et al., J Clin Endocrinol Metab. 103:497-504 (2018)). When post-menopausal subjects are administered add-back therapy, the uterine blood loss exhibited by these subjects remains low (Archer et al., Fertil. Steril. 108:152-160 (2017)). Thus, one might conclude that subjects pre-treated with a GnRH antagonist before receiving add-back therapy would similarly exhibit minimal uterine bleeding. The present disclosure is based, in part, on the surprising discovery that subjects that are provided a simultaneous onset of GnRH antagonist administration and add-back therapy administration actually exhibit significantly less uterine bleeding relative to subjects that are pre-treated with a GnRH antagonist alone before initiating add-back therapy.
[0411] The sections that follow provide a detailed description of GnRH antagonists and add-back therapy agents that may be used in conjunction with the compositions and methods of the disclosure, as well as a description of various estrogen-dependent diseases that may be treated using these therapeutics.
[0412] GnRH Antagonists
Thieno[3,4d]pyrimidines
[0413] GnRH antagonists for use with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives and variants, such as those described in U.S. Pat. No. 9,040,693, the disclosure of which is incorporated herein by reference in its entirety. Exemplary GnRH antagonists include those represented by formula (I)
##STR00040##
[0414] wherein ring A is a thiophene ring;
[0415] each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
[0416] m is an integer from 0 to 3;
[0417] ring B is an aryl group or a monocyclic heteroaryl group;
[0418] each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
[0419] n is an integer from 0 to 2;
[0420] U is a single bond;
[0421] X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group;
[0422] Y is a group represented by Z or —NW.sup.7W.sup.6, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.6 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
[0423] Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group;
[0424] or a pharmaceutically acceptable salt thereof.
[0425] In some embodiments, the ring A is a thiophene ring represented by formula (IIa)
##STR00041##
[0426] In some embodiments, m is 1 or 2. In some embodiments, m is 1. For instance, the ring A may be an optionally substituted thiophene ring represented by formula (IIb)
##STR00042##
[0427] Each R.sup.A may independently be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group. In some embodiments, each R.sup.A is COOH or pharmaceutically acceptable salt thereof.
[0428] In some embodiments, ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring. For instance, ring B may be represented by a formula selected from the group consisting of:
##STR00043##
[0429] In some embodiments, n is 1 or 2. For instance, in some embodiments, n is 1. Ring B may be, for example, represented by a formula selected from the group consisting of:
##STR00044##
[0430] In some embodiments, each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group. For instance, each R.sup.B may be independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.
[0431] In some embodiments, U is a single bond. X may be, for example, a group represented by —O-L-Y. L may be, for example, a methylene group. In some embodiments, Y is an optionally substituted benzene ring represented by formula (V)
##STR00045##
[0432] wherein each R is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9 wherein each W.sup.8 is independently a hydrogen atom or an optionally substituted lower alkyl group; and
[0433] p is an integer from 0 to 3.
[0434] In some embodiments, Y is a substituted benzene ring represented by formula (Va)
##STR00046##
[0435] For example, GnRH antagonists that may be used for the treatment of the endometrial growth disorders described herein include those thieno[3,4d]pyrimidine compounds described in Table 1, below. The synthesis and characterization of these compounds is reported, for instance, in U.S. Pat. No. 9,040,693, incorporated herein by reference.
TABLE-US-00001 TABLE 1 Exemplary Thieno[3,4d]pyrimidine GnRH Antagonists Useful for the Treatment of Estrogen-Dependent Diseases No. Compound Reported .sup.1H NMR spectral properties 1
[0436] For example, the GnRH antagonist may be 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof. The salt may be, for instance, the choline salt thereof, represented by formula (VIa), below.
##STR00475##
[0437] Compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof (compound (VIa)), can be synthesized, for example, using the methodology described in WO 2014/042176, the disclosure of which is incorporated herein by reference in its entirety. An exemplary synthetic scheme that may be used for the preparation of compound (VI) and the choline salt thereof is shown in Scheme 1, below.
##STR00476##
[0438] wherein R.sub.1 and R.sub.2 are independently C.sub.1-6 alkoxy groups; LG is a nucleofugal leaving group, such as chlorine or bromine, among others; R.sub.3 represents an optional substituent, such as halogen, acyl group, C.sub.1-6 alkyl group, or a nitro substituent; DMAP denotes N-dimethylaminopyridine; and TEA denotes trimethylamine.
[0439] Crystalline compound (VIa) has been characterized spectroscopically, for instance, in U.S. Pat. No. 9,169,266, the disclosure of which is incorporated herein by reference in its entirety. The foregoing crystalline form has been shown to exhibit characteristic X-ray powder diffraction peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ. Additionally, this crystalline form exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm. This crystalline form further exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.
[0440] Compound (VI), as well as pharmaceutically acceptable salts thereof, such as the choline salt thereof, exhibit a high affinity for human GnRH receptor (27.4 nM). Using the compositions and methods described herein, a patient that is presenting with or has been diagnosed as having an estrogen-dependent disease (e.g., uterine fibroids, endometriosis, such as rectovaginal endometriosis, and/or adenomyosis, among others described herein) may be administered a compound of formula (VI), or a pharmaceutically acceptable salt thereof, such as the choline salt thereof, to treat the disease or ameliorate one or more symptoms of the disease. Exemplary doses of compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof, include doses of from 25 mg to 500 mg daily, such as doses of 100 mg per day and 200 mg per day. Additional dosing information is provided below. 3-Aminoalkyl pyrimidine-2,4(1H,3H)-diones
[0441] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted 3-aminoalkyl pyrimidine-2,4(1H,3H)-dione derivatives, such as compounds represented by formula (VII)
##STR00477##
[0442] wherein R.sub.1a, R.sub.1b and R.sub.1c are the same or different and are each independently hydrogen, halogen, C.sub.1-4alkyl, hydroxy or alkoxy, or R.sub.1a and R.sub.1b taken together form —OCH.sub.2O— or —OCH.sub.2CH.sub.2—;
[0443] R.sub.2a and R.sub.2b are the same or different and are each independently hydrogen, halogen, trifluoromethyl, cyano or —SO.sub.2CH.sub.3;
[0444] R.sub.3 is hydrogen or methyl;
[0445] R.sub.4 is phenyl or C.sub.3-7alkyl;
[0446] R.sub.5 is hydrogen or C.sub.1-4alkyl;
[0447] R.sub.6 is —COOH or an acid isostere; and
[0448] X is C.sub.1-6alkanediyl optionally substituted with from 1 to 3 C.sub.1-6alkyl groups;
[0449] or a pharmaceutically acceptable salt thereof.
[0450] For example, the GnRH antagonist may be the conjugate acid of elagolix, which is represented by formula (VIII),
##STR00478##
[0451] or a pharmaceutically acceptable salt thereof. In some embodiments, the GnRH antagonist is the sodium salt of the compound represented by formula (VIII), which is represented by formula (IX), below.
##STR00479##
Compound (IX), also referred to as sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, is known as elagolix. Other GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 7,056,927, the contents of which are incorporated herein by reference. Exemplary GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the present disclosure include the compounds set forth in Table 2, below.
TABLE-US-00002 TABLE 2 Exemplary 3-Aminoalkyl pyrimidine-2,4(1H,3H)-dione GnRH Antagonists Useful for the Treatment of Estrogen-Dependent Diseases No. Compound Reported spectral properties 1
Thieno[2,3d]pyrimidines
[0452] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted thieno[2,3d]pyrimidine derivatives, such as compounds represented by formula (X)
##STR00491##
[0453] wherein R.sup.a is a hydrogen atom, an optionally substituted aryl group (such as an aryl group that may have 1 to 5 substituents selected from halogen, nitro, cyano, amino, a carboxyl group that may be esterified or amidated, an alkylenedioxy, alkyl, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl), an optionally substituted cycloalkyl group, or an optionally substituted heterocyclic group;
[0454] R.sup.b is an optionally substituted nitrogen-containing heterocyclic group;
[0455] R.sup.c is an optionally substituted amino group;
[0456] R.sup.d is an optionally substituted aryl group;
[0457] p is an integer from 0 to 3; and
[0458] q is an integer from 0 to 3;
[0459] or a pharmaceutically acceptable salt thereof.
[0460] In some embodiments, the GnRH antagonist is a thieno[2,3d]pyrimidine compound represented by formula (XI)
##STR00492##
[0461] wherein R.sup.1 is C.sub.1-4alkyl;
[0462] R.sup.2 is (1) a C.sub.1-6alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C.sub.1-4alkoxy, (3′) a C.sub.1-4alkoxy-carbonyl, (4′) a di-C.sub.1-4alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C.sub.1-4alkyl-carbonyl and (7′) a halogen, (2) a C.sub.3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C.sub.1-4alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C.sub.1-4alkyl and (4′) a C.sub.1-4alkoxy, (4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C.sub.1-4alkoxy-C.sub.1-4alkyl, (3′) a mono-C.sub.1-4alkyl-carbamoyl-C.sub.1-4alkyl, (4′) a C.sub.1-4alkoxy and (5′) a mono-C.sub.1-4alkylcarbamoyl-C.sub.1-4alkoxy, or (5) a C.sub.1-4alkoxy;
[0463] R.sup.3 is C.sub.1-4alkyl;
[0464] R.sup.4 is (1) hydrogen, (2) C.sub.1-4alkoxy, (3) C.sub.6-10aryl, (4)N—C.sub.1-4alkyl-N—C.sub.1-4alkylsulfonylamino, (5) hydroxyl, or (6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C.sub.1-4alkyl, (3′) a hydroxy-C.sub.1-4alkyl, (4′) a C.sub.1-4alkoxy-carbonyl, (5′) a mono-C.sub.1-4alkyl-carbamoyl and (6′) a C.sub.1-4alkylsulfonyl; and
[0465] n is an integer from 1 to 4;
optionally provided that when R.sup.2 is a phenyl which may have a substituent, R.sup.4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) hydroxy-C.sub.1-4alkyl, (3) C.sub.1-4alkoxy-carbonyl, (4) mono-C.sub.1-4alkyl-carbamoyl and (5) C.sub.1-4alkylsulfonyl; [0466] or a pharmaceutically acceptable salt thereof. For example, the GnRH antagonist may be a compound represented by formula (XII), below.
##STR00493##
Compound (XII), also referred to as N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, is known as relugolix. Other GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 7,300,935, the contents of which are incorporated herein by reference. Exemplary GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the present disclosure include the compounds set forth in Table 3, below.
TABLE-US-00003 TABLE 3 Exemplary Thieno[2,3d]pyrimidine GnRH Antagonists Useful for the Treatment of Estrogen-Dependent Diseases No. Compound Reported spectral properties 1
Propane-1,3-diones
[0467] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted propane-1,3-dione derivatives, such as (2R)—N-{5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorobenzene-1-sulfonyl}-2-hydroxypropanimidamide, also referred to as opigolix or ASP-1707. Other GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 6,960,591, the contents of which are incorporated herein by reference.
Add-Back Therapy
[0468] Among the potential side-effects of GnRH antagonist therapy is a reduction in bone mineral density due to excessive depletion of estrogen (Newhall-Perry et al., American Journal of Obstetrics and Gynecology 173:824-829 (1995)). To combat this potential side effect, a patient undergoing GnRH antagonist therapy using the compositions and methods described herein can be administered add-back therapy. Add-back therapy may contain an estrogen (such as β17-estradiol, ethinyl estradiol, or a conjugated estrogen, such as a conjugated equine estrogen) optionally in combination with a progestin (such as norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent such as progesterone, norgestimate, medroxyprogesterone, or drospirenone).
[0469] Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 μg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Circulating estrogens modulate the pituitary secretion of the gonadotropins, LH and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
[0470] Progestin compounds, such as norethindrone and esters thereof (e.g., norethindrone acetate), as well as progesterone, norgestimate, medroxyprogesterone, and drospirenone, enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone. Progestins may be included in combination with estrogen in add-back therapy. For instance, according to the methods described herein, one can administer estrogen (e.g., E2) in conjunction with a progestin (e.g., norethindrone or an ester thereof, such as norethindrone acetate) to a patient undergoing GnRH antagonist therapy as to counteract the hypoestrogenemia that may be induced by the antagonist. In this way, add-back therapy can be used to mitigate or prevent potentially deleterious side effects, such as a reduction in bone mineral density.
[0471] Add-back therapy may be formulated for oral administration. For instance, add-back therapy administered in conjunction with the compositions and methods described herein may be formulated as a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, such as β17-estradiol, and a progestin, such as norethindrone or norethindrone acetate. The estrogen and progestin may be administered separately or admixed in a single composition, such as a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.
[0472] For example, add-back therapy may feature a co-formulation containing estrogen (e.g., in the form of E2) and an additional agent such as a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate). In some embodiments, add-back therapy is administered to a patient in the form of a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension that contains both estrogen (e.g., in the form of E2) and a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate). In some embodiments, add-back therapy is administered as a fixed dose combination containing a GnRH antagonist, estrogen, and one or more additional agents, such as a progestin, in a single pharmaceutical composition. For instance, add-back therapy may be administered as a fixed dose combination of a GnRH antagonist, estrogen (e.g., in the form of E2) and a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate) in the form of a single pharmaceutical composition, such as a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.
Methods of Treating Estrogen-Dependent Diseases
[0473] Using the compositions and methods described herein, a patient having an estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis), and/or adenomyosis, among others, may be administered a GnRH antagonist as described herein. Additional examples of estrogen-dependent diseases that may be treated using the compositions and methods of the disclosure include, without limitation, benign prostatic hypertrophy, precocious puberty, premenstrual syndrome, polycystic ovary syndrome, hirsutism, short stature, a sleep disorder, acne, baldness, and irritable bowel syndrome.
[0474] A variety of methods known in the art and described herein can be used to determine whether a patient is responding favorably to GnRH antagonist treatment. For instance, beneficial clinical results in response to GnRH antagonist therapy include, without limitation, alleviation of symptoms of the endometrial growth disorder. Indications of successful treatment of a uterine fibroids patient include, for example, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in uterine blood loss following administration of the GnRH antagonist to the patient, (iii) elimination of heavy menstrual bleeding following administration of the GnRH antagonist to the patient, and (iv) induction of amenorrhea in the patient following administration of the GnRH antagonist to the patient.
[0475] Similarly, clinical indicators of successful treatment of an endometriosis patient (e.g., a rectovaginal endometriosis patient) that is administered a GnRH antagonist include, without limitation, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in the volume of one or more endometriosis nodes (e.g., rectovaginal endometriosis nodes) following administration of the GnRH antagonist to the patient, (iii) a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (ix) achievement of amenorrhea following administration of the GnRH antagonist to the patient; and (x) an improvement in the patient's overall well-being as determined by an improvement in the patient's Endometriosis Health Profile questionnaire (EHP-30)score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.
[0476] Exemplary indicia of successful treatment of an adenomyosis patient that is administered a gonadotropin-releasing hormone (GnRH) antagonist include, without limitation, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in uterine volume following administration of the GnRH antagonist to the patient, (iii) a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine tenderness following administration of the GnRH antagonist to the patient; (ix) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (x) achievement of amenorrhea following administration of the GnRH antagonist to the patient; (xi) a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient; and (xii) an improvement in the patient's overall well-being as determined by an improvement in the patient's EHP-30 score following administration of the GnRH antagonist to the patient and/or by way of a positive PGIC score following administration of the GnRH antagonist to the patient.
Modified Biberoglu and Behrman Symptom Severity Scale
[0477] Exemplary methods for assessing a patient's response to GnRH antagonist therapy for the treatment of estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein, include administration of a modified Biberoglu and Behrman questionnaire, as described herein. An exemplary mB&B questionnaire for use in conjunction with the compositions and methods described herein is shown in Table 4, below.
Endometriosis Health Profile Questionnaire
[0478] Additional methods for assessing patient respond to GnRH antagonist therapy for the treatment of estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein, include analyzing the patient's score on an Endometriosis Health Profile questionnaire. An exemplary Endometriosis Health Profile questionnaire for use in conjunction with the compositions and methods described herein is the EHP-30 questionnaire shown in Table 5, below.
Patient Global Impression of Change Score
[0479] Additional methods for assessing patient response to GnRH antagonist therapy for the treatment of an estrogen-dependent disease described herein, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis, and/or adenomyosis, among others) include analyzing the patient's score on a Patient Global Impression of Change (PGIC) scale. An exemplary PGIC questionnaire for use in conjunction with the compositions and methods described herein is shown in Table 6, below.
Quantitation of Uterine Blood Loss by the Alkaline Hematin Method
[0480] Techniques for quantifying uterine blood loss are known in the art and include, for instance, the alkaline hematin method, as described, for instance, in Hallberg et al., Scand. J. Clin. Lab. Invest. 16:244-248 (1964), the disclosure of which is incorporated herein by reference as it pertains to techniques for assessing the volume of blood lost by a patient. In the alkaline hematin approach, uterine blood soaked into, for example, a sanitary napkin, vaginal tampon, or cotton pad, is reconstituted in a basic aqueous solution, such as a solution of 5% (w/v) sodium hydroxide. This incubation enables (i) extraction of the iron-containing porphyrin of hemoglobin and (ii) oxidation of the ferrous ion to a hydroxy-coordinated ferric ion in each chelate, thus forming hematin. Hematin is a detectable chromophore, absorbing light at between 550 and 546 nm. By comparing the concentration of hematin obtained from incubation of a soaked menstrual blood sample with aqueous sodium hydroxide to the concentration of hematin obtained from incubation of a sample of venous blood with aqueous sodium hydroxide, one can stoichiometrically determine the volume of menstrual blood lost by a patient, such as a patient having an estrogen-dependent disease. Improvements to the original alkaline hematin method are known in the art and are described, for example, in Newton et al., Contraception 16:269-282 (1977), and in van Eijkeren et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 22:345-351 (1986), the disclosures of each of which are incorporated herein by reference as they pertain to methods of determining the volume of blood lost by a patient.
Routes of Administration and Dosing of GnRH Antagonists
[0481] The GnRH antagonists described herein may be administered to a patient in need thereof (e.g., a patient suffering from an estrogen-dependent disease, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein) by a variety of routes of administration. For instance, the GnRH antagonists described herein may be formulated for oral administration, among other routes. Exemplary non-oral routes of administration of the GnRH antagonists described herein include, without limitation, intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, and intradermal administration, among others.
[0482] In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(VIa), above, and is administered to the patient in an amount of from about 25 mg to about 500 mg per dose, and may be administered in one or more doses per day, for example, in accordance with a dosing schedule described above. For instance, the GnRH antagonist may a compound of any one of formulas (I)-(VIa), above, and may be administered to the patient in an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose, and may be administered in one or more doses per day (e.g., in a single daily dose). In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(VIa), above, and is administered to the patient once daily in an amount of from 100 mg to 300 mg, per dose, such as from 105 mg to 295 mg, 110 mg to 290 mg, 115 mg to 285 mg, 120 mg to 280 mg, 125 mg to 275 mg, 130 mg to 270 mg, 135 mg to 265 mg, 140 mg to 260 mg, 145 mg to 255 mg, 150 mg to 250 mg, 155 mg to 245 mg, 160 mg to 240 mg, 165 mg to 235 mg, 170 mg to 230 mg, 175 mg to 225 mg, 180 mg to 220 mg, 185 mg to 215 mg, 190 mg to 210 mg, or 195 mg to 205 mg, per dose. In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(VIa), above, and is administered to the patient once daily in an amount of about 100 mg per dose or 200 mg per dose.
[0483] The GnRH antagonists described herein may be administered to a patient a plurality of times over the course of a treatment period. For instance, the GnRH antagonists described herein may be administered to a patient periodically over a treatment period of at least two weeks (e.g., a treatment period of from about two weeks to about six months, about three weeks to about five months, about four weeks to about four months, or about one month to about three months). The GnRH antagonist may be administered to the patient, for example, over a treatment period of from about four weeks to about six months (e.g., from about 28 days to about 180 days, about 30 days to about 175 days, about 35 days to about 170 days, about 40 days to about 165 days, about 45 days to about 160 days, about 50 days to about 155 days, about 55 days to about 150 days, about 60 days to about 145 days, about 65 days to about 140 days, about 70 days to about 135 days, about 75 days, to about 130 days, about 80 days to about 125 days, about 85 days, to about 120 days, or about 90 days to about 115 days). In some embodiments, the GnRH antagonist is periodically administered to the patient over the course of from about eight weeks to about sixteen weeks (e.g., from about 60 days to about 110 days, about 65 days to about 105 days, about 70 days to about 100 days, about 75 days to about 95 days, or about 80 days, to about 90 days). In some embodiments, the GnRH antagonist is periodically administered to the patient over a treatment period of about 12 weeks. In some embodiments, the GnRH antagonist is periodically administered to the patient over a treatment period of about 24 weeks.
[0484] Additional dosing schedules for the treatment of estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein, using other GnRH antagonists disclosed herein are described in detail above.
Pharmaceutical Compositions
[0485] GnRH antagonists suitable for use with the compositions and methods described herein can be formulated into a pharmaceutical composition for administration to a patient, such as a female human patient, in a biologically compatible form suitable for administration in vivo. A pharmaceutical composition containing a GnRH antagonist, such as a compound described herein (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, such as the choline salt thereof), may additionally contain a suitable diluent, carrier, or excipient. GnRH antagonists can be administered to a patient, for example, orally or by intravenous injection. Under ordinary conditions of storage and use, a pharmaceutical composition may contain a preservative, e.g., to prevent the growth of microorganisms.
[0486] Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22.sup.nd ed.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33).
[0487] Pharmaceutical compositions may include sterile aqueous solutions, dispersions, or powders, e.g., for the extemporaneous preparation of sterile solutions or dispersions. In all cases the form may be sterilized using techniques known in the art and may be fluidized to the extent that may be easily administered to a patient in need of treatment.
[0488] A pharmaceutical composition may be administered to a patient, e.g., a human patient, alone or in combination with one or more pharmaceutically acceptable carriers, e.g., as described herein, the proportion of which may be determined by the solubility and/or chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
EXAMPLES
[0489] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regards as their invention.
Example 1. Concurrent Onset of GnRH Antagonist Therapy and Add-Back Therapy Depletes Endogenous Estradiol and Reduces Uterine Blood Loss to a Greater Extent than GnRH Antagonist Pre-Treatment
[0490] This example describes a series of experiments conducted in order to investigate the estrogen-modulating properties of GnRH antagonists, such as those of formulas (I)-(VIa) described herein, as well as the effect of GnRH antagonists on menstrual blood loss. To conduct these experiments, a set of pre-menopausal female human subjects were periodically administered a GnRH antagonist represented by formula (VI). Particularly, subjects were treated with the choline salt of compound (VI) in combination with add-back therapy. Treatment with this compound, among other GnRH antagonists described herein, can alleviate endometriosis-associated pain as well as uterine fibroids-associated heavy menstrual bleeding. In pharmacodynamic studies, compounds of formulas (I)-(VIa), such as compounds of formula (VI) (e.g., the choline salt of compound (VI)) have been shown to effectuate dose-dependent reductions in β17-estradiol (E2) levels in female human subjects, which, in turn, reduced uterine bleeding and increased the incidence of amenorrhea.
[0491] Significant reductions in E2 are associated with treatment-limiting bone mineral density (BMD) loss and hot flushes. To prevent BMD reduction, a GnRH antagonist, such as a compound of formulas (I) -(VIa) described herein, among others, can be co-administered with hormonal add-back therapy to restore appropriate endogenous levels of E2.
[0492] However, previous studies have shown that the inclusion of add-back therapy results in fewer women exhibiting amenorrhea. It has been observed that four weeks of daily administration of a GnRH antagonist, such as a GnRH antagonist represented by formula (VI) (e.g., delivered in the form of the choline salt of compound (VI)), to pre-menopausal female human subjects results in endogenous E2 levels and an endometrium status that are comparable to those of postmenopausal women.
[0493] Postmenopausal women treated with hormonal add-back therapy have amenorrhea rates exceeding those of pre-menopausal women treated with a GnRH antagonist and add-back therapy. Therefore, the experiments described in this example were conducted to assess whether co-administration of add-back therapy and GnRH antagonist therapy following four weeks of pre-treatment with a GnRH antagonist alone would result in reduced E2 levels and improved uterine bleeding patterns compared to dosing regimens in which subjects receive a simultaneous onset of GnRH antagonist and add-back therapy administration.
Methods
[0494] The experiments described in this example were conducted as part of a single-center, open-label, randomized, parallel-group clinical trial in 32 pre-menopausal women. Following screening assessments, and during the second half of the menstrual cycle, women received norethindrone (5 mg, three-times daily for 10 days) to synchronize menstrual cycles. After menstrual cycle synchronization, subjects were randomized with a 1:1 ratio to one of two treatment arms: (i) a cohort receiving once-daily administration of compound (VI) (200 mg per day, administered in the form of a choline salt) with concurrent onset of add-back therapy administration for 10 weeks (“Concurrent-ABT”), or (ii) a cohort receiving pre-treatment with compound (VI) (200 mg per day, administered in the form of a choline salt) for 4 weeks followed by combined daily administration of compound (VI) and add-back therapy (“Delayed-ABT”). The add-back therapy used in these experiments contained 1.0 mg of E2 and 0.5 mg of norethindrone acetate, and was administered to subjects once daily.
[0495] The main treatment outcomes and endpoints measured during these experiments included (i) a qualitative assessment of uterine blood loss, which was recorded on a daily basis throughout the study by characterizing each subject's bleeding pattern using one of the following four categories: “no bleeding,” “spotting” (light staining, dark blood, no sanitary protection needed or only panty liner), “bleeding” (1-4 completely soiled maxi sanitary towels or 1-8 soiled tampons or equivalent combination of the two), or “heavy bleeding” (>4 completely soiled maxi sanitary towels or >8 soiled tampons or equivalent combination of the two); (ii) a bi-weekly assessment of each subject's circulating E2 concentration; (iii) a bi-weekly assessment of each subject's circulating progesterone concentration (measured using a validated commercial chemiluminescence immunoassay method (Elecsys Progesterone III, Roche, Burgess Hill, UK)); (iv) the pharmacokinetic profile of compound (VI) and the add-back therapy; and (v) adverse events.
Results
[0496] Compound (VI) alone promptly reduced uterine bleeding, leading to amenorrhea in all subjects by week 5 (
[0497] The occurrence of amenorrhea, which, in this study, was defined as either “no bleeding” or the combination of “no bleeding” and “spotting” during the last 4 weeks of treatment, was investigated over the duration of GnRH antagonist treatment. In the “Concurrent-ABT” group, close to 80% of women were in complete amenorrhea (“no bleeding”) during the last 4 weeks of treatment, approximately half of which (˜40%) had reached amenorrhea within 5 days of treatment. In the “Delayed-ABT” group, significantly less women (40%) were in amenorrhea (p=0.03) during the last 4 weeks of treatment, and only ˜20% of women were in amenorrhea within 5 days of treatment. The proportions of patients in each cohort falling into the “no bleeding” category over the duration of the GnRH antagonist are shown in
[0498] The uterine bleeding patterns observed in each of the “Concurrent-ABT” and “Delayed-ABT” cohorts are summarized in Table 7, below.
TABLE-US-00004 TABLE 7 Comparison of uterine bleeding patterns observed in the “Concurrent- ABT” and “Delayed-ABT” cohorts Treatment Arm Time of Study Uterine Bleeding Pattern “Concurrent-ABT” Weeks 2-4 Spotting: ≤8% Bleeding: ≤4% Spotting and bleeding generally decreased over time Weeks 7-10 Spotting: 1-5% Bleeding: ≤2% Amenorrhea: Up to 98% “Delayed-ABT” Weeks 2-4 Occasional spotting and bleeding, decreasing to almost 100% amenorrhea (achieved in week 5) Weeks 6-10 Spotting and bleeding began after 1 week of add- back therapy (i.e., week 6); Bleeding more frequent than during initial weeks of “Concurrent-ABT” treatment
[0499] In addition to characterizing the bleeding patterns of subjects in each of the “Delayed-ABT” and “Concurrent-ABT” cohorts described above, subjects were assessed to determine the extent to which each dosing regimen suppressed endogenous E2 levels and modulated serum progesterone levels. Both cohorts resulted in a sustained reduction in circulating progesterone (
[0500] The more marked reduction in E2 levels effectuated by simultaneous onset of GnRH antagonist therapy and add-back therapy was manifest not only as reduced uterine blood loss among subjects in the “Concurrent-ABT” cohort relative to the “Delayed-ABT” cohort, but also as a lower incidence of adverse events associated with excessive estrogen depletion. Compound (VI) was well-tolerated, with the most frequently reported adverse events being headache (38/166) and hot flushes (19/166). Notably, hot flushes exclusively occurred in the “Delayed-ABT” group.
[0501] A detailed summary of the E2 concentrations, uterine bleeding patterns, and incidences of hot flushes in patients within the “Concurrent-ABT” cohort (labelled as treatment group “A”) and “Delayed-ABT” (labelled as treatment group “B”) cohort over the duration of GnRH antagonist administration is shown in Table 8, below.
TABLE-US-00005 TABLE 8 Comparison of serum E2 levels, bleeding patterns, and incidences of hot flushes in “Concurrent- ABT” and “Delayed-ABT” cohorts over the duration of GnRH antagonist administration Plasma Estradiol Level (pg/mL) Time Point Subject Characteristic Treatment N <20 20-50 >50 Days 1-14 Hot Flush A 16 0 (0.0%) 0 (0.0%) 0 (0.0%) B 16 2 (12.5%) 0 (0.0%) 0 (0.0%) Overall 32 2 (6.3%) 0 (0.0%) 0 (0.0%) No Bleeding A 16 0 (0.0%) 0 (0.0%) 1 (6.3%) B 16 1 (6.3%) 0 (0.0%) 0 (0.0%) Overall 32 1 (3.1%) 0 (0.0%) 1 (3.1%) No Bleeding or Spotting A 16 0 (0.0%) 3 (18.8%) 1 (6.3%) B 16 5 (31.3%) 0 (0.0%) 0 (0.0%) Overall 32 5 (15.6%) 3 (9.4%) 1 (3.1%) Days 15-28 Hot Flush A 16 0 (0.0%) 0 (0.0%) 0 (0.0%) B 16 4 (25.0%) 0 (0.0%) 0 (0.0%) Overall 32 4 (12.5%) 0 (0.0%) 0 (0.0%) No Bleeding A 16 2 (12.5%) 6 (37.5%) 1 (6.3%) B 16 14 (87.5%) 1 (6.3%) 0 (0.0%) Overall 32 16 (50.0%) 7 (21.9%) 1 (3.1%) No Bleeding or Spotting A 16 2 (12.5%) 10 (62.5%) 1 (6.3%) B 16 15 (93.8%) 1 (6.3%) 0 (0.0%) Overall 32 17 (53.1%) 11 (34.4%) 1 (3.1%) Days 29-42 Hot Flush A 14 0 (0.0%) 0 (0.0%) 0 (0.0%) B 15 2 (13.3%) 3 (20.0%) 0 (0.0%) Overall 29 2 (6.9%) 3 (10.3%) 0 (0.0%) No Bleeding A 14 1 (7.1%) 7 (50.0%) 3 (21.4%) B 15 3 (20.0%) 5 (33.3%) 2 (13.3%) Overall 29 4 (13.8%) 12 (41.4%) 5 (17.2%) No Bleeding or Spotting A 14 1 (7.1%) 9 (64.3%) 3 (21.4%) B 15 3 (20.0%) 7 (46.7%) 3 (20.0%) Overall 29 4 (13.8%) 16 (55.2%) 6 (20.7%) Days 43-56 Hot Flush A 14 0 (0.0%) 0 (0.0%) 0 (0.0%) B 15 1 (6.7%) 0 (0.0%) 0 (0.0%) Overall 29 1 (3.4%) 0 (0.0%) 0 (0.0%) No Bleeding A 14 1 (7.1%) 7 (50.0%) 3 (21.4%) B 15 2 (13.3%) 4 (26.7%) 1 (6.7%) Overall 29 3 (10.3%) 11 (37.9%) 4 (13.8%) No Bleeding or Spotting A 14 1 (7.1%) 8 (57.1%) 3 (21.4%) B 15 7 (20.0%) 7 (46.7%) 2 (13.3%) Overall 29 4 (13.8%) 15 (51.7%) 5 (17.2%) Days 57-70 Hot Flush A 14 0 (0.0%) 0 (0.0%) 0 (0.0%) B 15 0 (0.0%) 0 (0.0%) 0 (0.0%) Overall 29 0 (0.0%) 0 (0.0%) 0 (0.0%) No Bleeding A 14 3 (21.4%) 6 (42.9%) 3 (21.4%) B 15 3 (20.0%) 6 (40.0%) 0 (0.0%) Overall 29 6 (20.7%) 12 (41.4%) 3 (10.3%) No Bleeding or Spotting A 14 3 (21.4%) 7 (50.0%) 3 (21.4%) B 15 3 (20.0%) 7 (46.7%) 1 (6.7%) Overall 29 6 (20.7%) 14 (48.3%) 4 (13.8%)
CONCLUSIONS
[0502] Taken together, the results of these experiments demonstrate that concurrent onset of GnRH antagonist therapy and add-back therapy results in a more efficacious and controlled reduction in endogenous E2 levels, and indicate that dosing regimens employing a simultaneous onset of administration of these agents provide the benefit of effectively treating estrogen-dependent diseases without reducing estrogen to levels so low as to trigger undesirable side effects. That a concurrent onset of administration of GnRH antagonist therapy and add-back therapy engenders superior E2 reduction and more markedly diminished uterine blood loss relative to instances in which a subject is pre-treated with a GnRH antagonist is particularly unexpected. Since post-menopausal subjects, which exhibit endogenous E2 levels similar to pre-menopausal subjects that are treated with GnRH antagonist therapy alone, maintain low uterine bleeding patterns upon administration of add-back therapy, one might have concluded that pre-treatment with a GnRH antagonist prior to commencement of add-back therapy would result in more substantial reductions in E2, and thus, higher rates of amenorrhea. The results of the experiments described herein demonstrate that, surprisingly, the reverse is true.
[0503] In view of these findings, the compositions and methods of the present disclosure may be used to treat a variety of estrogen-dependent disorders. Examples 2-4, below, describe how a GnRH antagonist, such as a GnRH antagonist disclosed herein, may be used in combination with add-back therapy for the treatment of a few of these diseases.
Example 2. Use of a GnRH Antagonist for the Treatment of a Patient Having Uterine Fibroids
[0504] Using the compositions and methods described herein, a patient may be administered a GnRH antagonist so as to treat, and/or ameliorate the symptoms of, uterine fibroids. The GnRH antagonist (e.g., a compound of formula (I), above, such as compound (VI) or the choline salt thereof) may be administered to the patient in an amount sufficient to reduce the serum concentration of LH, FSH, and/or E2 in circulation. The GnRH antagonist may be administered, for example, in an amount of from about 25 mg to about 500 mg per dose. Exemplary doses of the GnRH antagonist include, without limitation, an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose. For example, when the GnRH antagonist is compound (VI) or the choline salt thereof, the compound may be administered at a dose of 200 mg.
[0505] The GnRH antagonist may be administered to the patient periodically, for instance, over a treatment period of at least two weeks. The GnRH antagonist may be provided to the patient in combination with add-back therapy, such that administration of the GnRH antagonist therapy and the add-back therapy commence at substantially the same time (e.g., within from about 1 to about 48 hours of one another, such as on the same day). To determine the responsiveness of the patient to the GnRH antagonist, a physician may monitor the time required for the patient to achieve a reduction in uterine blood loss, such as the time required to achieve amenorrhea. For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in menstrual blood loss to less than 80 ml per menstrual cycle, such that the patient no longer exhibits heavy menstrual blood loss, the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient, and/or (ii) an improvement in the patient's overall well-being as determined by an improvement in the patient's Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.
Example 3. Use of a GnRH Antagonist for the Treatment of a Patient Having Endometriosis
[0506] Using the compositions and methods described herein, a patient may be administered a GnRH antagonist so as to treat, and/or ameliorate the symptoms of, endometriosis (e.g., rectovaginal endometriosis). The GnRH antagonist (e.g., a compound of formula (I), above, such as compound (VI) or the choline salt thereof) may be administered to the patient in an amount sufficient to reduce the serum concentration of LH, FHS, and/or E2 in circulation. The GnRH antagonist may be administered, for example, in an amount of from about 25 mg to about 500 mg per dose. Exemplary doses of the GnRH antagonist include, without limitation, an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose. For example, when the GnRH antagonist is compound (VI) or the choline salt thereof, the compound may be administered at a dose of 200 mg.
[0507] The GnRH antagonist may be administered to the patient periodically, for instance, over a treatment period of at least two weeks. The GnRH antagonist may be provided to the patient in combination with add-back therapy, such that administration of the GnRH antagonist therapy and the add-back therapy commence at substantially the same time (e.g., within from about 1 to about 48 hours of one another, such as on the same day). To determine the responsiveness of the patient to the GnRH antagonist, a physician may monitor the length of one or more endometriosis lesions (e.g., rectovaginal endometriosis lesions) in the patient, for example, by way of magnetic resonance imaging (MRI) and/or transvaginal ultrasound (TVUS). For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient, (ii) a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient, (iii) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (iv) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (v) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vi) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (vii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (viii) achievement of amenorrhea following administration of the GnRH antagonist to the patient; and (xi) an improvement in the patient's overall well-being as determined by an improvement in the patient's EHP-30 score following administration of the GnRH antagonist to the patient and/or by way of a positive PGIC score following administration of the GnRH antagonist to the patient.
Example 4. Use of a GnRH Antagonist for the Treatment of a Patient Having Adenomyosis
[0508] Using the compositions and methods described herein, a patient may be administered a GnRH antagonist so as to treat, and/or ameliorate the symptoms of, adenomyosis. The GnRH antagonist (e.g., a compound of formula (I), above, such as compound (VI) or the choline salt thereof) may be administered to the patient in an amount sufficient to reduce the serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FHS), and/or β17-estradiol (E2) in circulation. The GnRH antagonist may be administered, for example, in an amount of from about 25 mg to about 500 mg per dose. Exemplary doses of the GnRH antagonist include, without limitation, an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose. For example, when the GnRH antagonist is compound (VI) or the choline salt thereof, the compound may be administered at a dose of 200 mg.
[0509] The GnRH antagonist may be administered to the patient periodically, for instance, over a treatment period of at least two weeks. The GnRH antagonist may be provided to the patient in combination with add-back therapy, such that administration of the GnRH antagonist therapy and the add-back therapy commence at substantially the same time (e.g., within from about 1 to about 48 hours of one another, such as on the same day). To determine the responsiveness of the patient to the GnRH antagonist, a physician may monitor the patient's uterine volume, as well as the level of pain experienced by the patient. For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in uterine volume following administration of the GnRH antagonist to the patient, (ii) a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient, (iii) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (iv) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (v) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vi) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (vii) a reduction in uterine tenderness following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (ix) achievement of amenorrhea following administration of the GnRH antagonist to the patient; (x) a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient; and (xi) an improvement in the patient's overall well-being as determined by an improvement in the patient's EHP-30 score following administration of the GnRH antagonist to the patient and/or by way of a positive PGIC score following administration of the GnRH antagonist to the patient.
Other Embodiments
[0510] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.
[0511] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.
[0512] Other embodiments are within the claims.