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WO 2018/060501 A2 05 April 2018 (05.04.2018) W ! P O PCT

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WO 2018/060501 A2 05 April 2018 (05.04.2018) W ! P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/060501 A2 05 April 2018 (05.04.2018) W ! P O PCT (51) International Patent Classification: (71) Applicants: MYOVANT SCIENCES GMBH [CH/CH]; A61K 31/513 (2006.01) Viaduktstrasse 8, 405 1 Basel (CH). TAKEDA PHAR¬ MACEUTICAL COMPANY LIMITED [JP/JP]; 1-1, (21) International Application Number: Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, PCT/EP20 17/074907 541-0045 (JP). (22) International Filing Date: (72) Inventors: JOHNSON, Brendan Mark; 2017 Markham 29 September 2017 (29.09.2017) Drive, Chapel Hill, 275 14 (NC). SEELY, Lynn; 537 Occi (25) Filing Language: English dental Avenue, San Mateo, 94402 (US). MUDD, JR., Paul N.; 302 Beacon Falls Court, Cary, North Carolina 27519 (26) Publication Langi English (US). WOLLOWITZ, Susan; 32 Topper Court, Lafayette, (30) Priority Data: California 94549 (US). HIBBERD, Mark; The Old House, 62/402,034 30 September 2016 (30.09.2016) US Hawkley, Liss Hampshire GU33 6NQ (GB). TANIMO- 62/402,055 30 September 2016 (30.09.2016) US TO, Masataka; c/o Takeda Pharmaceutical Company Lim 62/402,150 30 September 2016 (30.09.2016) US ited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, O sa 62/492,839 0 1 May 2017 (01 .05.2017) US ka, 541-0045 (JP). RAJASEKHAR, Vijaykumar Reddy; 62/528,409 03 July 2017 (03.07.2017) US 20200 Quail Hollow Road, Apple Valley, California 92308 (54) Title: METHODS OF TREATING UTERINE FIBROIDS AND ENDOMETRIOSIS PBAC=0 Lumbar BMD CD n co CD P g CO O O CD Dose (mg) FIG. 174 (57) Abstract: Methods for treating uterine fibroids, endometriosis, adenomyosis, or heavy menstrual bleeding in a subject, which < include administering to the subject from 10 mg to 60 mg per day of N-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6- methoxy-3-pyridazmyl)-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyure and from 0.01 mg to 5 mg o per day of a hormone replacement medicament. The present disclosure has methods for reducing menstrual bleeding in a subject, reducing bone mineral density loss in a subject caused by administering a GnRH antagonist to the subject, suppressing sex hormones in a subject, reducing vasomotor symptoms or hot flashes in a subject, and reducing symptoms of decreased libido in a subject having © uterine fibroids, endometriosis, or adenomyosis. Further provided are methods of maintaining blood glucose profile, maintaining lipid 0 0 profile, and/or maintaining bone mineral density in a pre-menopausal woman being treated for one or more conditions or symptoms of ¾ endometriosis, adenomyosis, uterine fibroids, or heavy menstrual bleeding; and methods of contraception and treating infertility. [Continued on nextpage] WO 2018/060501 A2 llll II II 11III II I II II III I III il II I II (US). SHUKHATME, Mayukh Vasant; 7 Bruce Road, Mamaroneck, NY 10543 (US). (74) Agent: COOLEY (UK) LLP; Dashwood, 69 Old Broad Street, London Greater London EC2M 1QS (GB). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) METHODS OF TREATING UTERINE FIBROIDS AND ENDOMETRIOSIS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/402,034, filed September 30, 2016; U.S. Provisional Application No. 62/402,055, filed September 30, 2016; U.S. Provisional Application No. 62/402,150, filed September 30, 2016; U.S. Provisional Application No. 62/492,839, filed May 1, 2017; and U.S. Provisional Application No. 62/528,409, filed July 3, 2017; the disclosures of which are incorporated herein by reference in their entireties. FIELD [0002] The present disclosure generally relates to methods of treating estrogen- sensitive conditions, and more specifically relates to methods of treating uterine fibroids, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis in a subject in need thereof. The present disclosure also relates to methods of treating one or more side effects of gonadotropin-releasing hormone (GnRH) antagonist administration. BACKGROUND [0003] Hormone-sensitive diseases of the reproductive system, such as uterine fibroids, endometriosis, and adenomyosis, can have a significant effect on the quality of life for many women. In these conditions, hormones such as estrogens and progesterone can have an impact on the severity and/or frequency of symptoms. [0004] For example, uterine fibroids are benign, estrogen-sensitive tumors (myomas) that grow in the muscular wall of the uterus in approximately 25% of women of reproductive age. Most uterine fibroids are asymptomatic, but approximately 25% of women with uterine fibroids develop symptoms requiring treatment. In addition to an individual's genetic predisposition, estrogens, progesterone and human growth hormone may all play important roles in the regulation of fibroid growth. Although uterine fibroids are benign tumors that are often asymptomatic, they can cause debilitating symptoms such as abnormal uterine bleeding, heavy or painful periods, anemia, abdominal pain, backache, increased abdominal girth and bloating, urinary frequency or retention, constipation or painful defecation, pregnancy loss, painful intercourse and, in some cases, infertility. Endometriosis is a gynecological medical condition in which cells from the lining of the uterus grow outside the uterine cavity, most commonly on the ovaries. Endometriosis is a chronic and usually progressive disease that occurs almost exclusively in women of reproductive age and can cause nonmenstrual pelvic pain, dysmenorrhea, dyspareunia, and infertility. It has an estimated prevalence of 10% among fertile women and from 20% to 40% among infertile women. Endometriosis lesions outside the uterus exhibit a pattern of hormonal responsiveness similar to that of the lining of the uterus. During the menstrual cycle, the lesions grow, differentiate and shed into the abdomen, thereby inducing a cascade of inflammatory events that may lead to nonmenstrual pelvic pain, pain during menstruation, painful intercourse and, in some cases, infertility. Adenomyosis is a condition distinct from endometriosis where endometrial tissue is found within the myometrium (muscular layer of the uterus). Patients with adenomyosis may experience heavy menstrual bleeding (HMB) and chronic pain, among other symptoms. [0005] Non-surgical therapies for these conditions may include non-steroidal anti inflammatory drugs, oral contraceptives, and GnRH agonists. Surgical interventions may include hysterectomy and myomectomy and may be used when the non- surgical therapies are unsuccessful in treating symptoms or cease to be effective. [0006] As these conditions are hormone-sensitive, there is an interest in methods of treatment that include regulating one or more hormones, such as estrogen or progesterone, for example using a GnRH agonist (GnRH receptor agonist) or GnRH antagonist (GnRH receptor antagonist). Achieving a balance of estrogen and progesterone that alleviates one or more symptoms while also avoiding serious side effects of hormone suppression is challenging. For example, bone mineral density (BMD) loss may occur if estradiol levels drop below a certain threshold. Bone mineral density loss over time can lead to serious negative effects such as increased bone fracture or osteoporosis. Suppressing progesterone without concurrent estrogen suppression can lead to endometrial hyperplasia, which is a risk factor for endometrial cancer. Conversely, estrogen or progesterone sensitive symptoms and disorders may be aggravated if the estrogen or progesterone levels are above an upper therapeutic limit. The balancing of these hormone interactions is further complicated by the sensitivities of the conditions themselves, as hormone -responsive gynecological conditions are not all responsive to the same levels of estrogen or progesterone. For example, certain conditions exhibit a hierarchy of responsivity to estrogen - myomas (e.g., uterine fibroids) are generally more responsive to estrogen than endometriosis. (See R. L. Barbieri, Am. J. Obstet. Gynecol (1992), 166(2): 740-745). In addition, certain symptoms of one condition may be reduced more readily by suppressing progesterone, while other symptoms of the same condition may respond more readily to estrogen suppression. Thus, the development of a therapy that may be used to treat more than one condition, or more than one symptom, or combinations thereof, is challenging. [0007] GnRH peptide agonists, such as leuprolide acetate (sold by AbbVie Endocrine Inc. under the trademarks LUPRON and LUPANETA), are commonly used for the treatment of benign sex hormone-dependent gynecological diseases, such as endometriosis and uterine fibroids.
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