阅读说明：本技术 选择性孕酮受体调节剂(sprm)方案 (Selective Progesterone Receptor Modulator (SPRM) regimens ) 是由 C·塞茨 R·克瑙斯 S·佐恩 于 2016-05-17 设计创作，主要内容包括：本发明针对用于治疗和/或预防子宫肌瘤(肌瘤,子宫平滑肌瘤)的含有孕酮受体调节剂——即(11β,17β)-17-羟基-11-[4-(甲基磺酰基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮——的药物组合物,其遵循一种特定方案给药至被诊断患有子宫肌瘤的患者。另外,本发明针对一种遵循一种特定方案来治疗子宫肌瘤(肌瘤,子宫平滑肌瘤)和/或减小子宫肌瘤(肌瘤,子宫平滑肌瘤)大小并减少与子宫肌瘤相关的症状的方法,以及针对一种治疗月经大出血(HMB)的方法。(The present invention is directed to pharmaceutical compositions containing a progesterone receptor modulator, namely (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one, for the treatment and/or prevention of uterine fibroids (myomas, uterine leiomyoma) which is administered to a patient diagnosed with uterine fibroids following a specific regimen. In addition, the present invention is directed to a method of treating and/or reducing the size and symptoms associated with uterine fibroids following a particular regimen, and to a method of treating Heavy Menstrual Bleeding (HMB).)

1. A pharmaceutical composition for the treatment and/or prevention of uterine fibroids comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (Compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered daily for a period of four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks.

2. The pharmaceutical composition according to claim 1, wherein the administration period of (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) is followed by a discontinuation period, wherein the administration of compound 1 is discontinued until one (1) or two (2) bleeding events occur, and the administration period and the discontinuation period are repeated at least one (1) time.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein compound 1 is administered during twelve (12) weeks, sixteen (16) weeks, twenty (20) weeks, or twenty-four (24) weeks.

4. A method of treating uterine fibroids by administering to a patient a pharmaceutical composition comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (Compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered daily for a period of four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks, followed by an interruption, wherein administration of compound 1 is interrupted until one (1) or two (2) bleeding events occur; optionally the administration and discontinuation are repeated at least one (1) time.

5. A method of reducing uterine fibroid size and/or reducing symptoms associated with uterine fibroids by administering to a patient a pharmaceutical composition comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (Compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered daily for a period of four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks, followed by an interruption, wherein administration of compound 1 is interrupted until one (1) or two (2) bleeding events occur; optionally the administration and discontinuation are repeated at least one (1) time.

6. A method of treating Heavy Menstrual Bleeding (HMB) by administering to a patient a pharmaceutical composition comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (Compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered daily for a period of four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks, followed by an interruption, wherein administration of compound 1 is interrupted until one (1) or two (2) bleeding events occur; optionally the administration and discontinuation are repeated at least one (1) time.

7. The method of claim 3,4, or 5, wherein compound 1 is administered during twelve (12) weeks, sixteen (16) weeks, twenty (20) weeks, or twenty-four (24) weeks.

8. Compound 1, defined as (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one of the formula

Or a salt, solvate or solvate of a salt, including all crystal modifications, wherein

a) Compound 1 is administered daily for a period of four (4) weeks to one (1) year, preferably ten (10) weeks up to twenty-six (26) weeks.

9. The compound of claim 8, wherein step a) is followed by

b) A break period wherein administration of Compound 1 is discontinued and one (1) or two (2) bleeding events are covered and

c) steps a) and/or b) are repeated at least one (1) time.

10. The compound of claim 8 or 9, wherein amenorrhea is achieved during step a).

11. A compound according to claim 8 or 9, wherein ovulation inhibition is achieved during step a).

Technical Field

The present invention is directed to pharmaceutical compositions containing a progesterone receptor modulator, namely (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one, for the treatment and/or prevention of uterine fibroids (myomas, uterine leiomyoma) which is administered daily to a patient diagnosed with uterine fibroids following a specific regimen.

In addition, the present invention is directed to a method of treating and/or reducing the size and symptoms associated with uterine fibroids (myomas, uterine leiomyoma) following a particular regimen, and to a method of treating Heavy Menstrual Bleeding (HMB).

Background

Uterine fibroids (also known as uterine leiomyoma or myoma) are common benign tumors of the myometrium, and uterine fibroids have been reported to occur in about 30-40% of women of all childbearing ages. They may remain asymptomatic or cause bleeding abnormalities and/or bulk-related symptoms (bulk-related syndromes) depending on the number, size and location. A wide variety of drug treatments are used for symptom-directed therapy of mild disease (e.g., combination oral contraceptives, progestins, iron supplements). Gonadotropin releasing hormone agonists represent the most effective pharmacological treatments for short-term treatment and/or as precursors to surgery. However, their use is limited to 6 months due to low estrogenic side effects. To treat symptomatic leiomyoma definitively, the current treatment option is primarily surgery.

Uterine fibroids are the major cause of hysterectomy. Hysterectomy is currently the only definitive treatment and eliminates the possibility of recurrence.

Various studies have shown steroid dependence of fibroid growth, with progesterone having a key role. This is supported by the fact that: progesterone Receptor (PR) antagonists, such as mifepristone (RU 486), have been shown to reduce the size of fibroids and associated symptoms. Therefore, PR antagonists may provide a promising therapeutic alternative that meets the need for long-term drug treatment of symptomatic fibroids, where orally available agents have no clinically relevant side effects. Mifepristone (RU 486) is disclosed in EP 057115.

Spitz et al, Current Opinion in Obstetrics and Gynecology, 2009, 21: 318-324 discloses compounds that are effective in the treatment of uterine fibroids, where this is associated with reduced pain and bleeding as well as improved quality of life and reduced fibroid size. Long term treatment is associated with thickening of the endometrium, as evidenced by ultrasound and histological changes in the endometrium. Changes in the endometrium such as thickening of the endometrium appear to be linked to distension of the saccular gland.

Progesterone receptor antagonists having a fluorinated 17 α -side chain are disclosed in WO 98/34947 and Fuhrmann et al, j.med.chem.43, 5010-.

In the PEARL I and PEARL II trials (N Engl J Med.2012; 366: 409-.

WO2009/134178 discloses a method of treating endometrial hyperplasia wherein a progesterone antagonist such as CDB-4124 is used in a 6 month treatment regimen. Unfortunately, administration of lower concentrations of CDB-4124 resulted in significant thickening of the endometrium during treatment.

WO2004/098517 discloses a regimen wherein a combination dosage form of estrogen and progestin is administered to a female for more than 50 consecutive days.

Disclosure of Invention

The present invention is directed to a pharmaceutical composition for the treatment and/or prevention of uterine fibroids (myomas, uterine leiomyoma) comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1),

or a salt, solvate, or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered for a period of up to twenty-four (24) weeks for twelve (12) weeks, followed by a off-period in which administration of compound 1 is discontinued until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

In addition, the present invention is directed to a method for treating uterine fibroids and reducing uterine fibroid size and symptoms associated with uterine fibroids and for treating Heavy Menstrual Bleeding (HMB) by administering to a patient a pharmaceutical composition containing compound 1.

Compound 1 is a potent Selective Progesterone Receptor Modulator (SPRM), more particularly a competitive Progesterone Receptor (PR) antagonist, which has led to an alternative for the treatment of uterine fibroids. Amenorrhea was observed in healthy subjects treated with compound 1, which was originally disclosed in WO2011/009531a 1. Amenorrhea meets the primary objective of treatment, namely to control excessive uterine bleeding. Unexpectedly, it has now been found that long-term treatment with compound 1 is safe for patients in need thereof. In fact, amenorrhea is observed at an early stage and has high strength. In addition, ovulation inhibition was observed, pelvic pain was found to be reduced, no endometrial growth (TEAE) was reported, and uterine fibroids were significantly reduced in size. Finally, there is no report of primary security discovery.

In addition, it has been found that a short off-period (with one or two bleeding events) has resolved PAEC after one bleeding.

Detailed Description

In a first aspect, the present invention is directed to a pharmaceutical composition for the treatment and/or prevention of uterine fibroids (myomas, uterine leiomyoma) comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered for a period of from four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of uterine fibroids wherein compound 1 is administered for a period of up to twenty-four (24) weeks for twelve (12) weeks, followed by a off-period in which administration of compound 1 is discontinued until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of such uterine fibroids, wherein amenorrhea is additionally achieved during the treatment. Preferably, amenorrhea is achieved at least 3 weeks after administration. Preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 or 12 weeks. More preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 weeks.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of such uterine fibroids, wherein additionally ovulation inhibition is achieved during step a). Preferably, ovulation inhibition is achieved at least 3 weeks after administration.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of such uterine fibroids, wherein compound 1 is administered daily.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of uterine fibroids wherein compound 1 is administered daily at a dose of 1mg to 5 mg.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of such uterine fibroids wherein the period of administration of compound 1 is repeated as needed.

Preferably, the administration period of compound 1 is repeated at least one (1) time but no more than five (5) times. More preferably, the administration period of compound 1 is repeated at least two (2) to three (3) times.

In one embodiment, the present invention is directed to a pharmaceutical composition for the treatment and/or prevention of uterine fibroids (myomas, uterine leiomyoma) comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) of the formula

Or a salt, solvate, or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered during twelve (12) weeks, sixteen (16) weeks, twenty (20) weeks, or twenty-four (24) weeks, followed by an interruption, wherein administration of compound 1 is interrupted until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

In one embodiment, the present invention is directed to a pharmaceutical composition for the treatment and/or prevention of uterine fibroids (myomas, uterine leiomyoma) comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) of the formula

Or a salt, solvate, or solvate of a salt, including all crystalline modifications thereof, wherein 2mg of compound 1 is administered daily for a period of twelve (12) weeks, sixteen (16) weeks, twenty (20) weeks, or twenty-four (24) weeks, followed by an interruption, wherein administration of compound 1 is interrupted until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

In a second aspect, the present invention is directed to a method of treating uterine fibroids (myomas, uterine leiomyoma) by administering to a patient a pharmaceutical composition comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered during a period of from four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks, followed by an interruption, wherein administration of compound 1 is interrupted until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

In one embodiment, the invention is directed to a method of treating uterine fibroids wherein compound 1 is administered over a period of four (4) weeks to one (1) year.

In one embodiment, the invention is directed to a method of treating uterine fibroids wherein compound 1 is administered for up to twenty-four (24) weeks over twelve (12) weeks.

In one embodiment, the pharmaceutical composition is directed to the treatment and/or prevention of such uterine fibroids, wherein additionally amenorrhea is achieved during the treatment, preferably at least 3 weeks after administration. Preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 or 12 weeks. More preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 weeks.

In one embodiment, the invention is directed to a method of treating uterine fibroids wherein ovulation inhibition is additionally achieved during the treatment period. Preferably, ovulation inhibition is achieved at least 3 weeks after administration.

In one embodiment, the invention is directed to a method of treating uterine fibroids wherein compound 1 is administered daily.

The embodiments and preferred features described above are included herein.

In a third aspect, the present invention is directed to a method of reducing the size of and/or symptoms associated with uterine fibroids by administering to a patient a pharmaceutical composition comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered between four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) cycles, followed by a discontinuation period in which administration of compound 1 is discontinued until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

Reduction in uterine fibroids (myomas, uterine leiomyoma) size and/or reduction in symptoms associated with uterine fibroids is partial or complete.

Symptoms associated with uterine fibroids are Heavy Menstrual Bleeding (HMB), pain or pressure such as pelvic, back or lower limb pain or pressure, prolonged menstrual periods, frequent urination or constipation.

In one embodiment, the present invention is directed to a method of reducing the size of and/or symptoms associated with uterine fibroids, wherein compound 1 is administered over a period of four (4) weeks to one (1) year.

In one embodiment, the present invention is directed to a method of reducing the size of and/or symptoms associated with uterine fibroids, wherein compound 1 is administered for up to twenty-four (24) weeks over twelve (12) weeks.

In one embodiment, the present invention is directed to methods of reducing uterine fibroids (myomas, uterine leiomyoma) size and/or reducing symptoms associated with uterine fibroids, wherein amenorrhea is additionally achieved during the treatment period. Preferably, amenorrhea is achieved at least 3 weeks after administration. Preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 or 12 weeks. More preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 weeks.

In one embodiment, the present invention is directed to methods of reducing uterine fibroids (myomas, uterine leiomyoma) size and/or reducing symptoms associated with uterine fibroids wherein ovulation inhibition is additionally achieved during treatment. Preferably, ovulation inhibition is achieved at least 3 weeks after administration.

In one embodiment, the invention is directed to a method of treating uterine fibroids wherein compound 1 is administered daily.

The embodiments and preferred features described above are included herein.

In a fourth aspect, the present invention is directed to a method of treating Heavy Menstrual Bleeding (HMB) by administering to a patient a pharmaceutical composition comprising (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one (compound 1) of the formula

Or a salt, solvate or solvate of a salt, including all crystalline modifications thereof, wherein compound 1 is administered for a period of from four (4) weeks to one (1) year, preferably twelve (12) weeks for up to twenty-four (24) weeks, followed by a discontinuation period in which administration of compound 1 is discontinued until one (1) or two (2) bleeding events occur; optionally, the administration phase and the off-phase are repeated at least one (1) time.

In one embodiment, the present invention is directed to a method of treating Heavy Menstrual Bleeding (HMB), wherein amenorrhea is achieved during treatment. Preferably, amenorrhea is achieved at least 3 weeks after administration of compound 1.

In one embodiment, the invention is directed to a method of treating Heavy Menstrual Bleeding (HMB) wherein compound 1 is administered over a period of four (4) weeks to one (1) year.

In one embodiment, the invention is directed to a method of treating Heavy Menstrual Bleeding (HMB) in which compound 1 is administered for a period of up to twenty-four (24) weeks over twelve (12) weeks.

In one embodiment, the present invention is directed to a method of treating Heavy Menstrual Bleeding (HMB), wherein amenorrhea is additionally achieved during the treatment period, preferably after at least 3 weeks of administration. Preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 or 12 weeks. More preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 weeks.

In one embodiment, the invention is directed to a method of treating Heavy Menstrual Bleeding (HMB) wherein ovulation inhibition is additionally achieved during the treatment period. Preferably, ovulation inhibition is achieved after at least 3 weeks of administration.

In one embodiment, the invention is directed to a method of treating Heavy Menstrual Bleeding (HMB) wherein compound 1 is administered daily.

In a fifth aspect, the present invention is directed to compound 1, defined as (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one of the formula

Or a salt, solvate or solvate of a salt, including all crystal modifications thereof, wherein

a) Compound 1 is administered daily for a period of four (4) weeks to one (1) year, preferably ten (10) weeks up to twenty-six (26) weeks.

In one embodiment, the present invention is directed to the use in a method for the treatment and/or prevention of uterine fibroids, wherein step a) is followed by

b) An off-period wherein administration of compound 1 is discontinued and comprises one (1) or two (2) bleeding episodes

c) Steps a) and/or b) are repeated at least one (1) time.

In one embodiment, the invention is directed to use in a method of treating and/or preventing uterine fibroids wherein compound 1 is administered daily for a period of twelve (12) weeks up to twenty-four (24) weeks.

Preferably, steps a) and/or b) are repeated at least one (1) time but no more than five (5) times. More preferably, steps a) and/or b) are repeated at least two (2) to three (3) times.

In one embodiment, the present invention is directed to the use in a method for the treatment and/or prevention of uterine fibroids, wherein amenorrhea is additionally achieved during the treatment, preferably at least 3 weeks after administration. Preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 or 12 weeks. More preferably, at least 90% of patients treated with compound 1 achieve amenorrhea after 3 weeks.

In one embodiment, the invention is directed to the use in a method of treating and/or preventing uterine fibroids wherein additionally ovulation inhibition is achieved during the treatment. Preferably, ovulation inhibition is achieved after at least 3 weeks of administration.

In one embodiment, the present invention is directed to the use in a method for the treatment and/or prevention of uterine fibroids, wherein compound 1 in step a) is administered daily at a dose of 1mg to 5 mg.

Embodiments and preferred features described above/below are included herein.

Preferred features applicable to the first to fifth aspects:

treatment of uterine fibroids according to the present invention means that after administration of a pharmaceutical composition containing compound 1, the size of uterine fibroids is partially or completely reduced or known symptoms associated with uterine fibroids such as Heavy Menstrual Bleeding (HMB) or pelvic pain are partially reduced or no longer reported/detectable.

The patient is a human female in need of treatment for a diagnosis of the presence of or suffering from a uterine fibroid-related condition, such as Heavy Menstrual Bleeding (HMB), pain or pressure, e.g., pelvic, back or lower limb pain or pressure, extended menstrual period, urinary frequency or constipation.

The most common symptoms associated with uterine fibroids are pelvic pain and heavy menstrual bleeding. Preferably, the symptom treated is Heavy Menstrual Bleeding (HMB).

The pharmaceutical compositions of the present invention include compound 1 or a salt thereof that is preferably administered to a patient daily at about 0.7 to 5mg, 0.7 to 4.5mg, 1 to 4mg, 1.5 to 3.5mg, or 1.5 to 3mg, independently of each other. More preferably, about 0.7 to 5mg, 1 to 4mg, or 1.5 to 3mg of compound 1 is administered to the patient. Even more preferably, about 1 to 5mg or 1 to 4mg of compound 1 is administered to the patient. Even more preferably, 2mg of compound 1 is administered.

Preferably, 0.5mg, 0.7mg, 1mg, 2mg, 3mg, 4mg or 5mg of compound 1 is administered to the patient. More preferably, 2mg, 3mg, or 4mg of compound 1 is administered to the patient. Even more preferably, 2mg of compound 1 is administered.

It is understood that a dose "about 2 mg" means any dose of compound 1 from 1.5 to 2.5 mg. Preferably, the dose is 2mg of compound 1.

Compound 1 is administered over a period of four (4) weeks to one (1) year, preferably eleven (11) weeks for up to twenty-five (25) weeks.

Preferably, compound 1 is administered for a period of up to thirteen (13) weeks for eleven (11) weeks, up to seventeen (17) weeks for fifteen (15) weeks, up to twenty-one (21) weeks for nineteen (19) weeks, or up to twenty-five (25) weeks for twenty-three (23) weeks.

Compound 1 was administered for a period of up to twenty-four (24) weeks over twelve (12) weeks.

Preferably, compound 1 is administered during twelve (12) weeks, sixteen (16) weeks, twenty (20) weeks, or twenty-four (24) weeks.

More preferably, compound 1 is administered during twelve (12) or twenty-four (24) weeks.

Even more preferably, compound 1 is administered over a twelve (12) week period.

Even more preferably, compound 1 is administered over a twenty-four (24) week period.

More preferably, compound 1 is administered over a sixteen (16) or twenty (20) week period.

Even more preferably, compound 1 is administered over a sixteen (16) week period.

Even more preferably, compound 1 is administered over a period of twenty (20) weeks.

Preferably, compound 1 is administered for a period of up to sixteen (16) weeks for twelve (12) weeks, up to twenty (20) weeks for sixteen (16) weeks, or up to twenty-four (24) weeks for twenty (20) weeks.

Preferably, compound 1 is administered daily.

Optionally, administration-discontinuation of one (1) to four (4) days occurs during twelve (12) weeks up to twenty-four (24) weeks of administration or any other administration period defined above.

The administration period as defined above is understood to include variability of + or-1 or 2 days.

Preferably, there is one (1) bleeding event during the off-period.

Preferably, there are two (2) bleeding events in the off-period.

Optionally, the administration period and the off-period after administration are repeated at least one (1) time but no more than two (2) to ten (10) times. Repeat dosing began within the first three days of the first bleeding event following the previous dose.

The first administration is initiated within the first ten (10) days of the female menstrual cycle.

The patient no longer experiences menstruation during the course of treatment.

In addition, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are defined as fillers (e.g., sugars such as lactose, sucrose, dextrose, and dextrates; sugar alcohols such as mannitol, sorbitol, and xylitol); carbonates and phosphates of alkaline earth metals, such as calcium carbonate and calcium phosphate; cellulose such as powdered cellulose and microcrystalline cellulose; colloidal silicon dioxide; titanium dioxide; kaolin; talc), or a lubricant (e.g., magnesium stearate).

The present invention includes all salts, solvates or solvates of salts, including all crystal modifications thereof, of (11 β,17 β) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one.

The pharmaceutical composition has a suitable form for intravenous (i.v.) administration, intramuscular (i.m.) administration or oral administration. Preferably, the oral form for administration is a dosage form such as a tablet, capsule or solution. However, it may optionally be necessary to deviate from the stated amounts, i.e. depending on the body weight, the route of administration, the individual's response to the active substance, the type of formulation and the point in time or interval at which the administration takes place. Thus, in some cases it may be sufficient to use a smaller amount than the aforementioned minimum amount, while in other cases the upper limit must be exceeded. In the case of larger amounts, it is appropriate to divide them into several individual doses throughout the day.

Preferably, the administration period of compound 1 is repeated at least one (1) time but no more than five (5) times. More preferably, the administration period of compound 1 is repeated at least two (2) to three (3) times.

Definition of

The pharmaceutical compositions may be in the form of oral dosage forms additionally containing pharmaceutically acceptable excipients and/or at least one or more other active substances, in particular active substances known for the treatment and/or prevention of the aforementioned diseases.

Preferably physiologically harmless salts of the compounds of the invention are within the scope of the inventionSalt (salt). However, isolated or purified salts of the compounds which are not suitable per se for pharmaceutical use but which can be used, for example, in the present invention are also encompassed.

Physiologically harmless salts of the compounds of the invention include-when they contain a basic function-salts with inorganic or organic acids, in particular mineral, carboxylic and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalene-disulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically harmless salts of the compounds of the invention include, when they contain an acid function, alkali metal, alkaline earth metal or ammonium salts, obtainable, for example, by reaction with corresponding inorganic or organic bases. We may mention, for example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines containing from 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, D-methylglucamine, ethylglucamine, 1, 6-hexamethylenediamine, glucosamine, N-methylglycine, 2-amino-1, 3-propanediol, trihydroxymethylaminomethane and 1-amino-2, 3, 4-butanetriol.

Those forms of addition with solvent molecules, in which the compounds of the invention are present in solid or liquid form, are defined as being within the scope of the inventionSolvates. The solvent may be present in stoichiometric or even non-stoichiometric proportions. In the case of stoichiometric solvates, they are also referred to as semi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates. Hydrates are a special form of solvates in which coordination occurs with water.

The bleeding event is menstrual bleeding on at least one day.

A complete reduction of the uterine fibroids means that uterine fibroids cannot be detected by usual methods (ultrasound).

The compounds of the present invention are administered to a patient suffering from uterine fibroids and symptoms associated with uterine fibroids (e.g., Heavy Menstrual Bleeding (HMB), pain or stress such as pelvic, back pain or pain and stress in the lower extremities, extended menstrual periods, urinary frequency or constipation) and in need of treatment. The patient in need thereof is a female mammal patient and more particularly a human female.

By off-period is meant a period of time: wherein administration of compound 1 to a subject (human female) is discontinued and wherein one (1) or two (2) bleeding events occur.

Long-term treatment corresponds to treatment for more than 3 months.

Short term treatment is equivalent to less than 3 months of treatment.

One year means 12 months.

The pharmaceutical efficacy of the compounds of the invention can be explained by their action as progesterone receptor antagonists and thus by their antagonistic effect on progesterone receptors.

Experimental part

The compound 1 of the present invention shows unexpectedly valuable pharmacological, pharmacokinetic and pharmacodynamic effects.

The following examples are intended to illustrate the invention but not to limit it in any way.

Example 1: synthetic route to Compound 1

(11 beta, 17 beta) -17-hydroxy-11- [4- (methylsulfonyl) phenyl ] -17- (pentafluoroethyl) estra-4, 9-dien-3-one

5g of the above compound are dissolved in a mixture of 140ml of THF and 140ml of methanol. At 0 deg.C, 20g of the solution was slowly added dropwiseSolution in 94ml of water. Then stirred at 0 ℃ for a further 3.5 hours. A mixture of water and dichloromethane was then added to the reaction mixture. The phases were separated and the aqueous phase was extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography. This gave 3.8g of the title compound.

1H-NMR(300MHz,CDCl3)：δ＝7.86d(2H)；7.40d(2H)；5.81sbr (1H)；4.50dbr(1H)；3.07s(3H)；0.51s(3H).

Example 2: therapeutic efficacy and safety of compound 1 for patients diagnosed with uterine fibroids:

the research scheme is as follows:

women, 18 to 50 years old, with hysteromyoma as indicated by the results of vaginal or abdominal ultrasound at screening, with at least one hysteromyoma with a maximum diameter ≧ 3.0cm and major menstrual bleeding (HMB) >80mL, participated in the study as subjects. The primary efficacy variable is amenorrhea (yes/no), defined as no scheduled bleeding/drip bleeding after the end of the initial bleeding event was monitored until the end of each treatment.

Treatment groups a1, B1: 30 subjects per group

Treatment groups a2, B2: 6 subjects per group

A1: compound 1: 2mg (12 weeks), compound 1: 2mg (12 weeks),

a2: placebo (12 weeks), compound 1: 2mg (12 weeks),

b1: compound 1: 2mg (12 weeks), 1 bleeding event, compound 1: 2mg (12 weeks),

b2: placebo (12 weeks), 1 bleeding event, compound 1: 2mg (12 weeks).

Purpose research: amenorrhea was present after 12 weeks of treatment and up to 24 weeks.

Amenorrhea was selected as the primary therapeutic endpoint for assessing uterine fibroid pathology.

Example 3: endometrial thickness and PAEC for 3 month treatment with compound 1

Subjects with uterine fibroids were subjected to randomized, parallel-group, double-blind, placebo-controlled, multi-center studies to evaluate the efficacy of different doses of compound 1, with the primary efficacy variable being endometrial thickness and the secondary efficacy variable being PAEC, over a 3 month treatment [1 × 12 weeks/84 days ].

Study protocol (N ° 15788):

test drugs: compound 1

Dosage: 0.5mg, 1mg, 2mg or 4mg once daily

The administration route is as follows: is administered orally

Duration of treatment: 1X 12 weeks (84 days)

Control drugs: placebo

Duration of treatment: 1X 12 weeks (84 days)

Incorporated diagnostic and primary criteria:

women, 18 to 50 years old, with uterine fibroids indicated by the results of vaginal or abdominal ultrasound at screening, with at least 1 uterine fibroid with a maximum diameter of 3cm and Heavy Menstrual Bleeding (HMB) of 80mL, were eligible to participate in the study.

Number of women: 279 subjects (see "n" in the table below)

And (3) screening period:

after screening visit 1 (visit 1), there was a screening period of up to 90 days to prepare for the complete results of all baseline assessments. During the screening period, subjects have demonstrated eligibility, including the presence of at least one uterine fibroid with a maximum diameter of 3cm and HMB diagnosis-defined as 80ml menstrual blood loss assessed by Menstrual Pictograms (MP) during bleeding events after screening visit 1 (visit 1). All efforts were made to minimize the duration of the screening period. Endometrial biopsies were performed at screening visit 2.

First biopsy:biopsy during screening period:

after screening visit 1, i.e., at screening visit 2, a first endometrial biopsy was performed on day 9+/-2 of the first or second menstrual cycle.

Second biopsy:biopsies were randomly determined. This means that subjects take a second biopsy at random time points and are informed of the group they are in directly after randomization and then stratified by dose group. Each subject was biopsied at one of the following 4 time points: between treatment weeks 8 and 12.

If this time point for the subject is randomized, a biopsy is scheduled on day 9+/-2 of the first menstrual cycle after treatment visit 2 (equivalent to visit 5), i.e., during the last four weeks of study drug treatment. If there was no menstrual bleeding between treatment visit 2 (visit 5) and end of treatment (EoT) visit (visit 6), a biopsy was taken at the end of treatment (EoT) visit (visit 6).

Follow-up of first menstrual blood after treatment:

if the time point for the subject is randomized, a biopsy is scheduled to be taken on day 9+/-2 of the first menstrual cycle after the end of treatment. If no menstrual bleeding appeared until 12 weeks after the end of treatment, i.e. until visit 2 (visit 8), a biopsy was taken at visit 2 (visit 8) and bleeding induction was taken into account.

Follow-up of second menstrual blood after treatment:

if the time point for the subject is randomized, a biopsy is scheduled to be taken on day 9+/-2 of the second menstrual cycle after the end of treatment. If no menstrual bleeding appeared until 12 weeks after the end of treatment, i.e. until visit 2 (visit 8), a biopsy was taken at visit 2 (visit 8) and bleeding induction was taken into account.

Follow-up of third menstrual blood after treatment:

if the time point for the subject is randomized, a biopsy is scheduled to be taken on day 9+/-2 of the third menstrual cycle after the end of treatment. If no menstrual bleeding appeared until 12 weeks after the end of treatment, i.e. until visit 2 (visit 8), a biopsy was taken at visit 2 (visit 8) and bleeding induction was taken into account.

Third biopsy:at the end of the follow-up visit, i.e. 21 to 24 weeks after the end of treatment.

A third endometrial biopsy was performed at visit 3 (visit 9), which scheduled day 9+/-2 of the menstrual cycle starting after week 20 after the end of treatment. Visit 9 was performed 24 weeks after the end of treatment if no bleeding event occurred, i.e. visit 9 was performed 21 to 24 weeks after the end of treatment for all subjects. If a second endometrial biopsy is taken less than 6 weeks before the scheduled date of the third endometrial biopsy and no pathology is found, then the third endometrial biopsy need not be taken.

In some cases, unscheduled endometrial biopsy should additionally be performed.

The treatment period is as follows:

eligible subjects were evenly randomized into one of the treatment groups (placebo, 0.5mg compound 1, 1mg compound 1, 2mg compound 1, or 4mg compound 1). Treatment was started during the first week of the menstrual cycle after randomization. The treatment period was 12 weeks (84 days) of daily tablet intake.

A follow-up period:

after treatment, subjects were followed for 21 to 24 weeks (follow-up period). If spontaneous menstrual bleeding does not appear until 12 weeks after the end of treatment, vaginal ultrasound (TVU) and endometrial biopsy are additionally performed, followed by the induction of bleeding if necessary. If further follow-up is found to be required, additional visits are scheduled according to normal standard practice.

FIG. 1: overview of research design

EoT: visit of treatment ending

FUP1, 2, 3: follow-up 1, 2,3

RND: random visit

SCR1, 2: screening visit 1, 2

T1, 2: treatment visit 1, 2

And (3) measuring the curative effect:

endometrial biopsy

Examination of uterine precoated disc

Vaginal ultrasound TVU (endometrial thickness, ovary)

Subjects who detected endometrial thickness (bilayer) >18mm (or suspected bleeding patterns, e.g. continuous spot bleeding, rare major bleedings) were immediately assessed by additional endometrial biopsy.

As a result:

under treatment, no significant tendency to increase endometrial thickness was observed. Endometrial thickness was measured after 3 months of treatment, see table 1. At the end of the follow-up visit, endometrial biopsies demonstrated benign histological changes of the endometrium (PAEC) and reported endometrial biopsies of all available samples. There were no cases of hyperplasia.

As a result, no treatment-induced risk endometrial lesions occurred.

In addition, PAECs (progesterone receptor modulators associated with endometrial changes) returned to background levels during follow-up, fig. 2. The data indicate that PAEC has been resolved after one bleeding.

Table 1: endometrial thickness after 3 months of treatment

EoT: end of treatment

Cp 01: compound 01

n: number of subjects

max: maximum of

SD: standard deviation of

Safety data set (n 300 ═ n)

FIG. 2: PAEC in biopsies after first/second/third bleeding event (menses). Has therapeutic effect on endometrium. Percentage of subjects with PAEC.

EoT: end of treatment

BL: base line

Example 4: amenorrhea for 3 months treatment using compound 1 and ulipristal acetate (UPA)

Subjects with uterine fibroids were subjected to randomized, parallel-group, double-blind, placebo-controlled, multi-center studies to assess the efficacy of different doses of compound 1, with the primary efficacy variable being amenorrhea, following 3 months of treatment [1 × 12 weeks/84 days ].

Study protocol (N ° 15788):

test drugs: compound 1

Dosage: 0.5mg, 1mg, 2mg or 4mg once a day

The administration route is as follows: is administered orally

Duration of treatment: 1X 12 weeks (84 days)

Control drugs: placebo

Duration of treatment: 1X 12 weeks (84 days)

Diagnosis and primary criteria of the included subjects:

women, 18 to 50 years old, with uterine fibroids indicated by the results of vaginal or abdominal ultrasound at screening, with at least 1 uterine fibroid with a maximum diameter of 3cm and Heavy Menstrual Bleeding (HMB)80mL, were eligible to participate in the study.

Number of women: 279 subjects

And (3) screening period:

after screening visit 1 (visit 1), there was a screening period of up to 90 days to prepare for the complete results of all baseline assessments. During the screening period, the subjects proved eligible, including the presence of at least one diagnosis of uterine fibroids with a maximum diameter of 3cm and HMB-defined as 80ml of menstrual blood loss assessed by Menstrual Pictograms (MP) during bleeding events after screening visit 1 (visit 1). All efforts were made to minimize the duration of the screening period.

The treatment period is as follows:

eligible subjects were evenly randomized into one of the treatment groups (placebo, 0.5mg compound 1, 1mg compound 1, 2mg compound 1, or 4mg compound 1). Treatment was started during the first week of the menstrual cycle after randomization. The treatment period was 12 weeks (84 days) of daily tablet intake.

And (3) measuring the curative effect:

daily documentation of bleeding intensity (electronic diary or electronic diary (eDiary))

Menstrual pictographs MP (electronic diary or electronic notebook)

-collecting the sanitary article for analysis of menstrual bleeding volume with Alkaline Hemoglobin (AH) method

Time to onset of amenorrhea:

the onset of amenorrhea is defined by the first day of less than 2ml of menstrual blood loss (assessed by MP) for all subsequent 28-day cycles up to the end of the treatment period.

The primary objective is to estimate the dose-response curve based on primary end-point female amenorrhea and dose.

As a result:

dose-dependent amenorrhea induction in subjects has been demonstrated for compound 1. Heavy menstrual bleeding is rapidly and continuously reduced. Most subjects have even achieved amenorrhea during treatment, see figure 3.

At the end of treatment (EoT ═ 3 months), 91.65% of subjects treated with 2mg of compound 1 showed amenorrhea (<2ml bleeding), see table 2.

Table 2: EoT amenorrhea (<2ml) induced by Compound 1 vs Ulipristal acetate (UPA)

Cp 01: compound 01

EoT: end of treatment

*: data from Jacques Donnez et al

Comparable studies and results are reported by Jacques Donnez et al in "The new England journal of mediacine". (Donnez, Jacques et al, "Ulipristal Acetate salts Leuprolide Acetate for Ulrine fibers". N.Engl.J.Med. (2012): 366; 5.)

Table 3: ulipristal acetate (UPA) induced amenorrhea at EoT (<2ml)

EoT: end of treatment

FIG. 3: therapeutic efficacy of Compound 1 on Heavy Menstrual Bleeding (HMB)

Cp 01: compound 01

Example 5: treatment of 3 months vs. 6 months amenorrhea with Compound 1

Randomized, parallel-group, double-blind, placebo-controlled, multi-center studies were performed on subjects with uterine fibroids over 3 months [1 × 12 weeks ] and 6 months [2 × 12 weeks, without treatment break ] to evaluate the efficacy of compound 1 at a dose of 2mg, with the primary efficacy variable being amenorrhea.

Study protocol (N ° 17541):

test drugs: compound 1 dose: 2mg once a day

The administration route is as follows: is administered orally

Duration of treatment: 2X 12 weeks without treatment interruption

Control drugs: placebo

Duration of treatment: 1X 12 weeks (84 days)

Incorporated diagnostic and primary criteria:

women, 18 to 50 years old, with uterine fibroids indicated by the results of vaginal or abdominal ultrasound at screening, with at least 1 uterine fibroid with a maximum diameter of 3cm and Heavy Menstrual Bleeding (HMB)80mL, were eligible to participate in the study.

Number of women: 174 subjects were tested

And (3) screening period:

after screening visit 1 (visit 1), there was a screening period of up to 60 days to prepare for the complete results of all baseline assessments. During the screening period, the subjects proved eligible, including the presence of at least one diagnosis of uterine fibroids with a maximum diameter of 3cm and HMB-defined as 80ml of menstrual blood loss assessed by Menstrual Pictograms (MP) during bleeding events after screening visit 1 (visit 1). All efforts were made to minimize the duration of the screening period. The screening period is up to 60 days. The eligible subjects were randomized.

The treatment period is as follows:

eligible subjects were equally randomized to one of the treatment groups (placebo, 2mg compound 1). Treatment was started during the first week of the menstrual cycle after randomization. The treatment period was 1 × 12 and 2 × 12 weeks (84 days) of daily tablet intake.

Treatment a 1: 2mg Compound 1(12 weeks), with no treatment interruption

Treatment a 2: placebo (12 weeks), 2mg compound 1(12 weeks).

And (3) measuring the curative effect:

daily documentation of bleeding intensity (electronic diary)

Menstrual pictograms MP (electronic diary or electronic diary).

Time to onset of amenorrhea:

the onset of amenorrhea is defined by the first day of less than 2ml of menstrual blood loss (assessed by MP) for all subsequent 28-day cycles up to the end of the treatment period.

The primary objective was to estimate the dose-response curve based on the primary endpoint of female amenorrhea and the dose and presence of amenorrhea after 1 x 12 weeks and after 2 x 12 weeks of treatment.

As a result:

primary endpoint amenorrhea (no/yes) was based on bleeding intensity recorded in an electronic diary/daily bleeding diary.

Based on initial data of the subject, it was found that compound 1 continued to show treatment with induction of dose-dependent amenorrhea in the subject up to 6 months, with the observed amenorrhea maintained after 1 x 12 weeks.

Patients treated with compound 1 for 6 months (2 × 12 weeks, without treatment break) showed no increase in the proportion of adverse events with respect to ovarian cysts or bleeding. Also, no increase in the proportion of subjects with endometrial thicknesses above 18mm was found.

Example 6: endometrial thickness for 3 month versus 6 month treatment with Compound 1

A randomized, parallel-group, double-blind, placebo-controlled, multi-center study was conducted on subjects with uterine fibroids with or without treatment interruption over 3 months versus 6 months to evaluate the efficacy of compound 1 at a dose of 2mg, with the primary efficacy variable being endometrial thickness.

Study protocol (N ° 17541):

test drugs: compound 1

Dosage: 2mg once a day

The administration route is as follows: is administered orally

Duration of treatment: 2X 12 weeks (A1) or 1X 12 weeks (A2) without treatment interruption

Placebo: no treatment

Incorporated diagnostic and primary criteria:

women, 18 to 50 years old, with uterine fibroids indicated by the results of vaginal or abdominal ultrasound at screening, with at least 1 uterine fibroid with a maximum diameter of 3cm and Heavy Menstrual Bleeding (HMB)80mL, were eligible to participate in the study.

Number of women: 13 subjects who had completed treatment at present.

And (3) screening period:

after screening visit 1 (visit 1), there was a screening period of up to 60 days to prepare for the complete results of all baseline assessments. During the screening period, the subjects proved eligible, including the presence of at least one diagnosis of uterine fibroids with a maximum diameter of 3cm and HMB-defined as 80ml of menstrual blood loss assessed by Menstrual Pictograms (MP) during bleeding events after screening visit 1 (visit 1). All efforts were made to minimize the duration of the screening period. The screening period is up to 60 days. The eligible subjects were randomized.

The treatment period is as follows:

eligible subjects were equally randomized to one of the treatment groups (placebo, 2mg compound 1). The treatment period was started during the first three days of bleeding after randomization or when randomization was performed. The treatment period was 3 months (12 weeks) or 6 months [2 × 12 weeks (84 days) ] daily tablet intake without treatment interruption.

Treatment a 1: 2mg of Compound 1(12 weeks), 2mg of Compound 1(12 weeks).

Treatment a 2: placebo (12 weeks), 2mg compound 1(12 weeks).

A follow-up period:

after the treatment period, subjects were followed for 12 weeks. At the end of the follow-up visit, an endometrial biopsy was performed (unless a hysterectomy had been performed). If spontaneous menstrual bleeding does not appear until 10 weeks after the end of treatment, additional vaginal ultrasound (TVU) and endometrial biopsies are performed, followed by the induction of bleeding if necessary. If further follow-up is found to be required, additional visits are scheduled according to normal standard practice. Any decisions regarding surgical treatment are made by the patient/subject and the investigator. Surgery is not considered part of the study procedure and is not considered an Adverse Event (AE).

And (3) measuring the curative effect:

-an endometrial biopsy,

-a check of the pre-uterine lining,

vaginal ultrasound (TUV) (endometrial thickness, ovary).

FIG. 4: overview of research design

EoT: end of treatment

FUP: follow-up 1

RND: random visit

SCR1, 2: screening visit 1, 2

T1, 2,3,4, 5 and 6: treatment visits 1, 2,3,4, 5, 6

B: intermittent, duration dependent on group assignment (for group A, no interruption)

TP1, 2: treatment periods 1, 2

As a result:

the results of the studies disclosed above are still blind. Thus, in view of the results, it was not possible to distinguish subjects treated with compound 1 for 6 months from subjects treated with compound 1 for 3 months and subsequently treated with placebo.

Based on the initial data, it was found that no treatment-induced dangerous endometrial lesions were present in 13 subjects, wherein the endometrial size did not increase above 18 mm. In fact, endometrial sizes above 18mm are considered by the Food and Drug Administration (FDA) as a threshold for risk of endometrial hyperplasia and may trigger additional diagnostic procedures.

Example 7: endometrial thickness for 2X 3 month treatment and discontinuation using Compound 1

Subjects with uterine fibroids were subjected to a randomized, parallel-group, double-blind, placebo-controlled, multi-center study over 2 x 3 months with a break period that allowed bleeding events to evaluate the efficacy of compound 1 at a dose of 2mg, with the primary efficacy variable being endometrial thickness.

Study protocol (N ° 17541):

test drugs: compound 1

Dosage: 2mg, once a day

The administration route is as follows: is administered orally

Duration of treatment: 2X 3 months [ 2X 12 weeks ] + one bleeding event (B1) and 1X 3 months [ 1X 12 weeks ] (B2) without treatment interruption

Placebo: is free of

Incorporated diagnostic and primary criteria:

women, 18 to 50 years old, with uterine fibroids indicated by the results of vaginal or abdominal ultrasound at screening, with at least 1 uterine fibroid with a maximum diameter of 3.0cm and Heavy Menstrual Bleeding (HMB)80mL, were eligible to participate in the study.

Number of women: 6 subjects who had completed treatment

And (3) screening period: as described in example 6

The treatment period is as follows:

eligible subjects were equally randomized to one of the treatment groups (placebo, 2mg compound 1). The treatment period was started during the first three days of bleeding after randomization or at the time of randomization. The treatment period is daily tablet intake without treatment interruption.

Treatment B1: 2mg Compound 1(12 weeks), 1 bleeding event, 2mg Compound 1(12 weeks).

Treatment B2: placebo (12 weeks), 1 bleeding event, 2mg compound 1(12 weeks).

A follow-up period: as described in example 6

And (3) measuring the curative effect:

-an endometrial biopsy,

-a check of the pre-uterine lining,

vaginal ultrasound (TUV) (endometrial thickness, ovary).

FIG. 5: overview of research design

EoT: visit of treatment ending

FUP: follow-up 1

RND: random visit

SCR1, 2: screening visit 1, 2

T1, 2,3,4, 5, 6: treatment visits 1, 2,3,4, 5, 6

B: off-period, duration depending on group distribution

TP1, 2: treatment periods 1, 2

As a result:

the results of the studies disclosed above are still blind. Thus, subjects treated with compound 1 for 2 x 3 months with subsequent treatment discontinuation cannot be distinguished from subjects treated with compound 1 during a single cycle of 3 months with subsequent treatment with placebo.

It was found that no treatment-induced risk endometrial lesions were present in 6 subjects, in which the endometrial size did not increase above 18 mm. Indeed, endometrial sizes above 18mm are considered by the Food and Drug Administration (FDA) as a threshold for risk of endometrial hyperplasia and lead to additional diagnostic procedures.

Example 8: treatment of changes in maximum fibroma volume for 3 months with Compound 1

Subjects (where treatment was 3 months [1 x 12 weeks/84 days ]) were subjected to randomized, parallel-group, double-blind, placebo-controlled, multi-center studies to assess the efficacy of different doses of compound 1, with the secondary efficacy variable being the change in volume of the largest fibroids.

Study protocol (N ° 15788):

test drugs: compound 1

Dosage: 0.5mg, 1mg, 2mg or 4mg once daily

The administration route is as follows: is administered orally

Duration of treatment: 1X 12 weeks (84 days)

Control drugs: placebo

Duration of treatment: 1X 12 weeks (84 days)

Incorporated diagnostic and primary criteria:

women, 18 to 50 years old, with uterine fibroids indicated by the results of vaginal or abdominal ultrasound at screening, with at least 1 uterine fibroid of maximum diameter 3cm and major menstrual bleeding (HMB)80mL, were eligible for study participation.

Number of women: 279 subjects

And (3) screening period: as described in example 4

The treatment period is as follows: as described in example 4

And (3) measuring the curative effect:

the secondary efficacy variable was the percentage change in volume of the largest fibroids compared to baseline (measured by MRI and TVU)

MRI: magnetic resonance imaging

TVU: vaginal/abdominal ultrasound

Vaginal/abdominal ultrasound:

an ultrasound examination was performed in accordance with the program schedule (table 1). For each subject, the most appropriate ultrasound method (vaginal or abdominal) was used depending on the location of the fibroid and was used consistently throughout the study. The same ultrasound machine (per site) should be used throughout the study.

The 3 largest fibroids were identified during the screening period. The maximum transverse, longitudinal and anteroposterior diameter diameters of these 3 fibroids were recorded at each ultrasound examination for volume calculation.

Uterine size was also recorded at the same time point. This is particularly important in subjects with multiple small fibroids.

Magnetic resonance imaging:

pelvic MRI was performed on all subjects at specific time points for volumetric measurements of uterus and fibroids (see table 1). Pelvic MRI without administration of contrast agent is preferably performed with good diagnostic quality of the Tesla scanner. The images were sent to a specialized image core laboratory for further evaluation. Volume measurements of the uterus and fibroids were performed centrally by a neutral radiologist.

Table 3: MRI and ultrasound study design overview:

EoT: end of treatment visit

FUP1, 2, 3: follow-up 1, 2,3

RND: random visit

SCR1, 2: screening visit 1, 2

T1, 2: treatment visit 1, 2

As a result:

compound 1 has shown a dose-dependent reduction in fibroma size during treatment. This effect was confirmed by two methods, namely MRI and TVU. The effect was partially maintained during the follow-up period, see fig. 6 and 7.

FIG. 6: percent change in maximum fibroma volume (MRI)

FIG. 7: percent volume change of maximum fibroma (TVU)