Compounds and their use in alleviating menopausal related symptoms

Abstract

The present invention relates to hormone replacement therapies, related compounds and related packaging units for alleviating menopausal-related symptoms based on the administration of an estetrol component, optionally in combination with a progestational hormone component, to a female mammal in a specific daily dose. The therapy of the present invention statistically exhibits significant efficacy and has advantageous properties in terms of side effects compared to currently useful methods for alleviating menopause-related symptoms.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: April 19, 2019; application number: 201980026758.3 (International application number: PCT / EP2019 / 060220). Field of the Invention

[0002] The present invention relates to hormone replacement therapy for alleviating menopausal-related symptoms, related compounds and related packaging units based on the administration of an estetrol component, optionally in combination with a progestogen component, to a female mammal at a specific daily dose.

[0003] As described in further detail herein, the therapy demonstrates statistically significant efficacy and has a favorable profile in terms of side effects compared to currently available methods for alleviating menopausal-related symptoms. Background Art

[0004] Hormone replacement therapy (HRT) is a term used to describe the unopposed use of estrogen (for women who have had a hysterectomy) or combined estrogen-progestin therapy (for women who still have a uterus). The goal of HRT is to relieve menopausal symptoms, most importantly vasomotor symptoms (VMS), such as hot flashes. Other diseases and symptoms associated with perimenopause and menopause that respond to estrogen therapy include osteoporosis, vaginal atrophy, and sleep disturbances (when associated with hot flashes).

[0005] VMS most often occurs in the late menopausal transition and early postmenopause. VMS is the most important menopausal complaint. Estimates suggest that about 75% of women over 50 are troubled by hot flashes (Utian et al., 2005, "Comparative controlled trial of a novel oral estrogen therapy, estriolacetate, for relief of menopause symptoms" Menopause 12(6): 708-715). Most people experience hot flashes for about two years, but about 10% suffer for more than 10 years (Rodstrom et al., 2002, "Alongitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century" Menopause 9(3): 156-161). VMS may lead to physical and psycho-social impairments that reduce quality of life and is one of the main reasons women may seek medical care for menopause (Santoro, 2008, "Symptoms of menopause: hot flushes" Clin Obstet Gynecol 51(3):539-548).

[0006] The epithelial lining of the vagina and urethra is very sensitive to estrogen, and estrogen deficiency causes thinning of the epithelial cells of both. This leads to vulvovaginal atrophy (VVA) and urinary tract disease, causing symptoms of vaginal dryness, itching, dyspareunia, dysuria, urinary frequency, and increased risk of recurrent urinary tract infections. In early 2014, the International Society for the Study of Women's Sexual Health (ISSWSH) and the North American Menopause Society (NAMS) approved the new term "genitourinary syndrome of menopause (GSM)" to replace the term VVA. The rationale for using this new terminology is that the term VVA is too restrictive, whereas GSM is a more comprehensive term that includes symptomatic VVA as well as lower urinary tract symptoms associated with low estrogen levels (Portman et al., 2014, "Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society" Menopause 21(10): 1063-1068). Please note that the GSM terminology has not yet been adopted in the industry guidance issued by the FDA and EMA, so the VVA terminology will be used in this article.

[0007] Estrogen therapy remains the gold standard for relieving menopausal symptoms, particularly VMS. All routes of administration appear to be equally effective for relieving symptoms, but they are metabolized differently. Estrogen should be given continuously; previous regimens that administered estrogen from days 1 to 25 of the calendar month are considered outdated. Women often get VMS during the off-dose period, and there is no known advantage to stopping for a few days each month.

[0008] With current HRT, all women with an intact uterus require a progestin in addition to estrogen to prevent endometrial hyperplasia—and subsequent carcinogenesis—which occurs after only 6 months of estrogen therapy. Progestin can be given continuously or sequentially (e.g., 10 to 14 days per month or 14 days every 3 months).

[0009] Estrogen therapy is the most durable and effective treatment for menopausal VMS in the United States and Europe. Following safety issues reported in the basic Women's Health Initiative publication (Anderson et al., 2004, "Effects of conjugatedequine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial" JAMA 291 (14): 1701-1712) and the requirement for continued subject treatment, the challenge facing clinicians is to determine the lowest effective dose of estrogen to relieve menopausal symptoms (Simon et al., 2007, "Menopausal hormone therapy for vasomotor symptoms: balancing the risks and benefits with ultra-low doses of estrogen" Expert Opin Investig Drugs 16 (12): 2005-2020). In addition, it is also a challenge to develop safer estrogens than currently used estrogens.

[0010] In a 2016 publication, Coelingh Bennink et al. (“Clinical effects of the fetalestrogen estetrol in a multiple-rising-dose study in postmenopausal women”, Maturitas, 2016 Sep;91:93-100) reported a partially randomized, open-label, multiple-rising-dose study of 49 postmenopausal women who received either 2 mg estetrol or 2 mg estradiol valerate daily for 28 days (randomized portion of the study) followed by a dose increase to 10, 20, and 40 mg estetrol daily (non-randomized portion of the study). The authors compared the effects of estradiol valerate (2 mg) and only two doses of estetrol (2 and 10 mg) on ​​the relief of hot flashes in subjects who were screened for >35 hot flashes per week (note Table 1). The authors report that at a daily dose of 2 mg estetrol, the mean number of hot flashes and sweating decreased, while endometrial thickness was found to be stable in the 2 mg estetrol group but increased in the 10 mg estetrol group (abstract).

[0011] From this study, since the authors did not measure VMS in the 20mg and 40mg estetrol groups, it is obvious to the technician that the authors believe that only lower doses (2mg and 10mg) are suitable for managing VMS. In addition, the technician understands that a daily dose of 2mg estetrol is as effective as a daily dose of 10mg estetrol in reducing the number of hot flashes per day (see, for example, Coelingh Bennink et al., Maturitas, Fig. 3 in 2016). In addition, the publication teaches the technician that a daily dose of 2mg does not change the endometrial thickness, while a daily dose of 10mg has an important effect on the endometrial thickness (see, for example, Coelingh Bennink et al., Fig. 2 in 2016). Therefore, the technician concludes that the minimum effective dose of estetrol for treating VMS is 2mg per day. SUMMARY OF THE INVENTION

[0013] Against this background, the present inventors have now surprisingly found that the minimum effective dose of estetrol for alleviating VMS in peri- and post-menopausal women is about 15 mg per day.

[0014] The determination of the minimum effective dose actually involves many parameters that take into account not only the average number of VMS per day (as done by Coelingh Bennink et al. in Maturitas, 2016), but also the severity of VMS, and also a weighted score per week, as further defined herein.

[0015] Therefore, in terms of efficacy, it was surprising to find that a daily dose of 15 mg was required to produce a clear effect on VMS.

[0016] In addition, the inventors observed that several side effects of the treatment, such as reflected in the number of treatment-emergent adverse events (TEAEs), or the number of patients who withdrew from the study in each group, or the number of biopsies that had to be performed in each group, tended to plateau at about 10 mg per day and did not worsen when the dose was further increased. Unexpectedly, some of these parameters actually regressed when going from 10 mg per day to 15 mg per day, thus suggesting that adverse events may be more tolerable when the dose exceeds 10 mg per day.

[0017] Based on this surprising finding, and based on the measured results when 20 mg and 30 mg were administered daily, the inventors therefore came to the unexpected conclusion that the optimal daily dose of estetrol for reducing VMS in postmenopausal women is 15 mg to 25 mg. As shown in the examples, this dose range does allow the observation of a statistically significant effect on VMS while keeping the side effects of treatment within an acceptable range.

[0018] In the following numbered paragraphs 1-14, embodiments of the present invention are described.

[0019] 1. A composition for alleviating menopausal-related symptoms, wherein the composition comprises estetrol as a component, and wherein the composition is administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0020] 2. A composition for relieving vasomotor symptoms selected from the group consisting of hot flashes, sweating episodes, night sweats, chills, increased sweating, palpitations, and combinations thereof, wherein the composition comprises estetrol as a component, and wherein the composition is administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0021] 3. A composition for alleviating mood aspects of the menopausal transition selected from depression, irritability, mood changes, insomnia, sleep disorders, anxiety, nervousness, and combinations thereof, wherein the composition comprises an estetrol component, and wherein the composition is administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0022] 4. A composition for alleviating a physiological aspect of the menopausal transition selected from the group consisting of joint pain, decreased bone density, urinary tract infection, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, dyspareunia, cardiovascular disease, diabetes, and combinations thereof, wherein the composition comprises an estetrol component, and wherein the composition is administered in an amount equivalent to about 15 mg to about 25 mg of estetrol per day.

[0023] 5. A composition for reducing VMS frequency, VMS severity, hot flash weekly weighted score, vaginal dryness, dyspareunia, and combinations thereof, or for improving quality of life according to MRS and / or MENQOL questionnaires, wherein the composition comprises estetrol as a component, and wherein the composition is administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0024] 6. A composition for use according to any of paragraphs 1 to 5 above, wherein the composition is administered daily for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 12 weeks.

[0025] 7. A composition for use according to any one of paragraphs 1 to 6, wherein a second composition comprising a progestogen component is additionally used.

[0026] 8. The composition for use according to paragraph 7, wherein the progestogen component is selected from drospirenone, progesterone and dydrogesterone.

[0027] 9. The composition for use according to paragraph 7, wherein the progesterone is administered in a daily dose of 50 mg to 200 mg.

[0028] 10. The composition for use according to any of paragraphs 1 to 6, wherein a second composition comprising bazedoxifene is additionally used.

[0029] 11. A composition for use according to any one of paragraphs 7 to 10, wherein said second composition comprising a progestogen component or bazedoxifene is the same as the composition comprising an estetrol component.

[0030] 12. A composition for use according to any one of paragraphs 1 to 11, wherein the estetrol component is estetrol, preferably estetrol monohydrate.

[0031] 13. A composition for use according to any of the preceding paragraphs, wherein the composition is formulated as an oral dosage unit.

[0032] 14. A composition for use according to paragraph 13, wherein the oral dosage unit is formulated to correspond to a daily dosage unit.

[0033] In the following numbered paragraphs 15-28, further embodiments of the invention are described.

[0034] 15. A method for alleviating symptoms associated with menopause, the method comprising administering a composition comprising estetrol as a component in a daily dosage equal to about 15 mg to about 25 mg of estetrol.

[0035] 16. A method for relieving vasomotor symptoms selected from the group consisting of hot flashes, sweating episodes, night sweats, chills, increased sweating, palpitations, and combinations thereof, the method comprising administering a composition comprising an estetrol component in a daily dose equal to about 15 mg to about 25 mg of estetrol.

[0036] 17. A method of alleviating emotional aspects of the menopausal transition selected from depression, irritability, mood changes, insomnia, sleep disturbances, anxiety, nervousness, and combinations thereof, the method comprising administering a composition comprising an estetrol component in a daily dose equal to about 15 mg to about 25 mg of estetrol.

[0037] 18. A method of alleviating a physiological aspect of the menopausal transition selected from the group consisting of joint pain, decreased bone density, urinary tract infection, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, dyspareunia, cardiovascular disease, diabetes, and combinations thereof, the method comprising administering a composition comprising an estetrol component in a daily dose equal to about 15 mg to about 25 mg of estetrol.

[0038] 19. A method of reducing VMS frequency, VMS severity, hot flash weekly weighted score, vaginal dryness, dyspareunia, and combinations thereof, or improving quality of life as measured by MRS and / or MENQOL questionnaires, the method comprising administering a composition comprising an estetrol component at a daily dose equal to about 15 mg to about 25 mg of estetrol.

[0039] 20. The method according to any of paragraphs 15-19 above, wherein the composition is administered daily for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 12 weeks.

[0040] 21. The method according to any of paragraphs 15 to 20, wherein a second composition comprising a progestogen component is additionally administered.

[0041] 22. The method according to paragraph 21, wherein the progestogen component is selected from drospirenone, progesterone and dydrogesterone.

[0042] 23. The method according to paragraph 22, wherein the progesterone is administered in a daily dose of 50 mg to 200 mg.

[0043] 24. The method according to any of paragraphs 15-20, wherein a second composition comprising bazedoxifene is additionally administered.

[0044] 25. The method according to any of paragraphs 21-24, wherein said second composition comprising a progestogen component or bazedoxifene is the same as the composition comprising an estetrol component.

[0045] 26. The method according to any of paragraphs 15 to 25, wherein the estetrol component is estetrol, preferably estetrol monohydrate.

[0046] 27. The method according to any of the preceding paragraphs, wherein the composition is formulated in an oral dosage unit.

[0047] 28. The method according to paragraph 27, wherein the oral dosage unit is formulated to correspond to a daily dosage unit.

[0048] In the following numbered paragraphs 29-42, further embodiments of the invention are described.

[0049] 29. Use of an effective amount of an estetrol component in the preparation of a composition for alleviating menopausal-related symptoms, wherein the estetrol component is used in an amount equivalent to about 15 mg to about 25 mg of estetrol per day.

[0050] 30. Use of an effective amount of an estetrol component in the preparation of a composition for relieving vasomotor symptoms selected from the group consisting of hot flashes, sweating attacks, night sweats, chills, increased sweating, palpitations, and combinations thereof, wherein the estetrol component is used in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0051] 31. Use of an effective amount of an estetrol component in the preparation of a composition for alleviating a mood aspect of the menopausal transition selected from depression, irritability, mood changes, insomnia, sleep disorders, anxiety, nervousness, and combinations thereof, wherein the estetrol component is used in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0052] 32. Use of an effective amount of an estetrol component in the preparation of a composition for alleviating a physiological aspect of the menopausal transition selected from the group consisting of joint pain, decreased bone density, urinary tract infection, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, dyspareunia, cardiovascular disease, diabetes, and combinations thereof, wherein the estetrol component is used in an amount equivalent to about 15 mg to about 25 mg of estetrol per day.

[0053] 33. Use of an effective amount of an estetrol component in the preparation of a composition for reducing VMS frequency, VMS severity, hot flash weekly weighted score, vaginal dryness, dyspareunia, and combinations thereof, or for improving quality of life according to MRS and / or MENQOL questionnaires, wherein the estetrol component is used in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0054] 34. The use according to any of paragraphs 29-33 above, wherein the composition is administered daily for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 12 weeks.

[0055] 35. The use according to any of paragraphs 29 to 34, wherein a second composition comprising a progestogen component is additionally administered.

[0056] 36. The use according to paragraph 35, wherein the progestogenic component is selected from drospirenone, progesterone and dydrogesterone.

[0057] 37. The use according to paragraph 35, wherein the progesterone is administered in a daily dose of 50 mg to 200 mg.

[0058] 38. The use according to any of paragraphs 29 to 34, wherein a second composition comprising bazedoxifene is additionally administered.

[0059] 39. The use according to any one of paragraphs 35 to 38, wherein the second composition comprising a progestogen component or bazedoxifene is the same as the composition comprising an estetrol component.

[0060] 40. The use according to any one of paragraphs 29 to 39, wherein the estetrol component is estetrol, preferably estetrol monohydrate.

[0061] 41. The use according to any of the preceding paragraphs, wherein the composition is formulated in an oral dosage unit.

[0062] 42. The use according to paragraph 41, wherein the oral dosage unit is formulated to correspond to a daily dosage unit.

[0063] In the following numbered paragraphs 43-50, further embodiments of the invention are described.

[0064] 43. A packaging unit comprising at least 14, preferably at least 21, even more preferably at least 28 containers for containing separately packaged and individually removable daily solid oral dosage forms, wherein each container comprises at least one daily solid oral dosage form containing about 15 mg to about 25 mg of estetrol.

[0065] 44. A packaging unit according to paragraph 43, wherein the packaging unit further comprises at least 10, preferably 12, more preferably 14 additional containers for containing separately packaged and individually removable, preferably solid, daily oral dosage forms, wherein each additional container comprises at least one, preferably solid, daily oral dosage form containing a progestogen component.

[0066] 45. A packaging unit according to paragraph 44, wherein each additional container for containing a dosage form comprising a progestogen component is visually independently placed next to the container containing a solid dosage form comprising estetrol when both solid dosage forms have to be administered on the same day.

[0067] 46. ​​A packaging unit according to paragraph 44 or 45, wherein the progestogenic component is selected from drospirenone, progesterone and dydrogesterone.

[0068] 47. The packaging unit according to paragraph 46, wherein the progestogenic component is progesterone, and wherein each of said additional containers comprises at least one daily oral dosage form comprising about 200 mg of progesterone.

[0069] 48. The packaging unit according to paragraph 43, wherein the packaging unit further comprises the same number of additional containers for containing separately packaged and individually removable, preferably solid, daily oral dosage forms, wherein each additional container comprises at least one, preferably solid, daily oral dosage form containing a progestogen component, wherein the progestogen component is preferably selected from drospirenone, progesterone and dydrogesterone, wherein the progestogen component is more preferably progesterone, and wherein the additional container comprises at least one daily oral dosage form containing about 100 mg of progesterone.

[0070] 49. The packaging unit according to paragraph 43, wherein at least 10, preferably 12, more preferably 14 of said daily solid oral dosage forms additionally comprise a progestogen component.

[0071] 50. The packaging unit according to paragraph 43, wherein each of said daily solid oral dosage forms further comprises a progestogen component.

[0072] The skilled artisan will appreciate that the embodiments numbered as described in paragraphs 44-50 may be equivalently represented as a kit-of-parts comprising a first packaging unit, such as a blister pack containing daily oral dosage units containing an estetrol component, and a different second packaging unit, such as a different second blister pack containing daily oral dosage units containing a progestogen component.

[0073] The skilled person will also appreciate that within the scope of the present invention each packaging unit, such as a blister pack, may be numbered or otherwise marked.

[0074] Within the scope of the present invention, each packaging unit may be a sealed blister pack having a cardboard, paperboard, aluminum foil plastic backing and enclosed in a suitable cover.

[0075] In a particular embodiment of the invention, the packaging unit comprises 28 containers or a multiple of 28 containers, such as 2-12 times 28 containers. DETAILED DESCRIPTION OF THE INVENTION

[0077] definition

[0078] The term "estetrol component" used throughout the document includes substances selected from the following: estetrol; esters of estetrol, wherein the hydrogen atom of at least one hydroxyl group is substituted by an acyl group of a hydrocarbon carboxylic acid, sulfonic acid or aminosulfonic acid having 1 to 25 carbon atoms; and combinations thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrate). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

[0079] As used herein, the term "estetrol" refers to 1,3,5(10)-estratriene-3,15α, 16α, 17β-tetrol, or 15α-hydroxyestriol, and hydrates of estetrol, for example, estetrol monohydrate.

[0080] The term "progestogenic component" is defined as a substance capable of inducing a progestogenic response in vivo or a precursor capable of releasing such a substance in vivo. Typically, the progestogenic component is capable of binding to the progestogen receptor.

[0081] In the context of the present invention, other compounds can be used in conjunction with the estratetrol composition to be administered to women with a uterus. Selective estrogen receptor modulators (SERMs) define the type of this class of compounds, and in the method of the present invention, they are considered to be useful supplements of the estratetrol composition. Preferred SERMs for the present invention are bazedoxifene.

[0082] In the methods and compositions further described herein, it must be understood that when reference is made to a "progestogenic component," such reference includes SERMs, particularly bazedoxifene.

[0083] As used herein, "about" refers to a measurable value such as a parameter, amount, time duration, etc., and is intended to cover variations of + / -10% or less, more preferably + / -5% or less, even more preferably + / -1% or less of the specified value, so far as such variations are suitable for implementation in the disclosed invention. However, it is to be understood that the value to which the modifier "about" refers is itself also specifically disclosed.

[0084] The term "effective amount" refers to the amount required to achieve a physiological effect. The physiological effect can be achieved by one dose or by repeated doses.

[0085] As used herein, the term "perimenopause" (also in the context of "perimenopause women" and "perimenopause subjects", etc.) refers to a life stage that begins about three to four years before menopause and ends one year after the last menstrual period. Perimenopause is characterized by the appearance of continuous irregular menstrual cycles, drastic fluctuations in hormone levels, frequent anovulation, and VMS (reference: Harlow et al., Menopause, Vol. 19, No. 4, 2012, "Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of stagingreproductive aging" - see Figure 2 therein in particular). During this transition period, the focus of clinical care has changed. Although women still need effective contraceptive measures during perimenopause, problems that need to be addressed include decreased bone mineral density, changes in the menstrual cycle, and vasomotor instability. A large number of women also experience depressive symptoms such as mood swings, irritability, and difficulty concentrating (Bosworth et al., Psychosom Med., 2001, Jul-Aug; 63(4): 603-8, “Depressive symptoms, menopausal status, and climacteric symptoms in women at midlife”).

[0086] The term "postmenopause" as used herein (also in the context of "postmenopausal women" and "postmenopausal subjects", etc.) first covers spontaneous postmenopausal women, i.e. women who have experienced natural menopause (natural menopause is defined as the permanent cessation of menstrual periods, which is retrospectively determined after women have experienced twelve months of amenorrhea without other obvious pathological or physiological reasons). It occurs in normal women with a median age of 51.4 years old, and it reflects complete or near-complete ovarian follicle depletion, resulting in hypoestrogenemia (estradiol levels are usually less than 20pg / mL) and high follicle-stimulating hormone (FSH levels>40IU / L) concentrations. The term "postmenopause" also includes menopause caused by premature ovarian failure, surgery (e.g., oophorectomy), chemotherapy or radiotherapy for cancer, and certain diseases (e.g., infection or hypothyroidism).

[0087] As used herein, the term "VMS" (or in its non-abbreviated form, "vasomotor symptoms") corresponds to the temperature regulation disorders characteristic of menopause. VMS includes hot flashes (sometimes spelled "hotflushes"), sweating episodes such as night sweats, chills and increased sweating, and palpitations. VMS is an episode of massive fever accompanied by sweating and flushing, primarily around the head, neck, chest, and upper back. As further defined below, VMS is divided into mild, moderate, and severe categories.

[0088] As used herein, the term "menopausal-related symptoms" is used to describe VMS as defined above, but also includes the emotional aspects of the menopausal transition (including but not limited to depression, irritability, mood changes, insomnia, sleep disorders, anxiety, and nervousness) and the physical aspects of the menopausal transition (including but not limited to joint pain, decreased bone density, urinary tract infections, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, and dyspareunia, as well as cardiovascular disease and diabetes).

[0089] The term "quality of life" (and the abbreviation "QoL") as used herein refers to a parameter that can be assessed, for example, by using a questionnaire such as, but not limited to, the "Menopause Rating Scale" questionnaire (Heinemann et al., 2003, "International versions of the Menopause Rating Scale (MRS)" Health Qual Life Outcomes 1:28; Heinemann et al., 2004, "The Menopause Rating Scale (MRS) scale: A methodological review". Health Qual Life Outcomes 2:45; Heinemann et al., 2004, "The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study". Health Qual Life Outcomes 2:67; as further described in Part C of Example 1 below) or the MENQOL questionnaire (The Menopause-specific Quality of Life (MENQOL) questionnaire, Hilditch et al.; Maturitas 1996; A menopause-specific quality of life questionnaire: development and quality of life questionnaire). psychometric properties; 24(3); pp. 161-175).

[0090] As used herein, "BMI" (or "body mass index" in its non-abbreviated form) refers to an index related to a subject's weight and height, calculated by dividing the subject's weight in kilograms by the square of the subject's height in meters. Female subjects with a BMI of 27.3 or more are classified as "overweight," while female subjects with a BMI of 30 or more are classified as "obese."

[0091] Determination of the minimum effective dose

[0092] To determine the minimum effective dose (MED), first, the selection criteria required that patients had at least 7 moderate to severe VMS per day or at least 50 moderate to severe VMS per week in the week before randomization. Secondly, a placebo group was included in a double-blind manner. Third, the total number of patients made it possible to obtain statistical significance between the various groups of the study. Fourth, the absolute change in the weekly frequency of moderate to severe VMS relative to baseline was considered. An analysis of covariance (ANCOVA) was performed based on the untransformed change in the weekly frequency of moderate to severe VMS relative to baseline. Finally, the change in severity relative to baseline was assessed. To this end, the severity scoring system for VMS recorded by the subjects is as follows:

[0093] Mild score (1), feeling hot but without sweating;

[0094] Moderate score (2), a sensation of heat with sweating / subject able to continue activity; and

[0095] Severe score (3), a sensation of heat accompanied by sweating / which leads to cessation of activity.

[0096] Additionally, a severity score of zero was attributed to patients who experienced 100% VMS relief in a given week.

[0097] From these score records, severity at baseline was calculated by considering only moderate and severe VMS, so that the total number of moderate VMS during the 7-day period of the baseline week was multiplied by 2 and added to the total number of severe VMS during the 7-day period of the baseline week multiplied by 3. This total was then divided by the total number of moderate and severe VMS during the baseline period.

[0098] For each of these weeks, the severity at week 4 and week 12 was calculated using the following formula:

[0099] The number of mild VMS in a 7-day period is multiplied by 1;

[0100] The number of moderate VMS in a 7-day period multiplied by 2;

[0101] · The number of severe VMS in a 7-day period is multiplied by 3.

[0102] Add the 3 resulting numbers together and then divide that total by the total number of mild, moderate, and severe VMS during the 7-day week.

[0103] This method was used to generate the data contained in Part A b) "VMS Severity" of Example 1 below.

[0104] In an alternative embodiment, VMS severity is assessed as follows: Severity at baseline is also calculated by considering only moderate and severe VMS, such that the total number of moderate VMS during the 7 days of the baseline week is multiplied by 2 and added to the total number of severe VMS during the 7 days of the baseline week multiplied by 3. This total is then divided by the total number of moderate and severe VMS during the baseline week.

[0105] However, for each of these weeks, the severity at week 4 and week 12 was calculated using the following formula:

[0106] The number of moderate VMS in a 7-day period multiplied by 2;

[0107] · The number of severe VMS in a 7-day period is multiplied by 3.

[0108] Add these 2 resulting numbers together and then divide this total by the total number of moderate and severe VMS during the 7-day period of the week.

[0109] In another embodiment, the severity score can be calculated according to the method described in Archer et al., 2014 (A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17A-estradiol for moderate to severe vasomotor symptoms in postmenopausal women; Menopause, 2014; 21(3); pp. 227-235). According to this method, the daily severity score is calculated using the following formula every day during a 7-day period:

[0110] The number of moderate VMS in a day multiplied by 2;

[0111] The number of severe VMS in a day multiplied by 3;

[0112] Add the two numbers together;

[0113] • This summed result is then divided by the total number of VMS (moderate and severe) during the same day.

[0114] Apply the same formula for 7 consecutive days, add the 7 resulting numbers together and divide by 7 to calculate the "weekly average daily severity" score for moderate to severe VMS.

[0115] Furthermore, the term "hot flash weekly weighted score" as used herein corresponds to a score taking into account frequency and severity, which is calculated by using the severity score (calculated as above): [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)] during a 7-day period.

[0116] Such a weighted score is used, for example, by Notelovitz et al. (“Initial 17β-Estradiol Dose for Treating Vasomotor Symptoms”; Obstetrics and Gynaecology, Vol. 95(5), May 2000, pp. 726-731).

[0117] This score was used to generate the data contained in Example 1, Part A c) "Hot Flash Weekly Weighted Score" below.

[0118] In alternative embodiments, any combination of the above methods may be used to assess the weekly severity and / or frequency of VMS.

[0119] Hormone replacement therapy

[0120] Therapies of the present invention typically involve continuous administration of the estetrol component for a period of at least 10 days, preferably at least 20 days.

[0121] The estetrol component is administered in a daily dosage of about 15 mg to about 25 mg.

[0122] In a specific embodiment, the estetrol component is administered in a daily dosage of about 15 mg to less than 20 mg.

[0123] In another specific embodiment, the estetrol component is administered in a daily dose of greater than 20 mg to about 25 mg.

[0124] In one embodiment, the therapy of the present invention is administered to a non-hysterectomized patient. In a specific embodiment, the therapy of the present invention involves administering about 20 mg of the estetrol component per day, preferably to a non-hysterectomized patient.

[0125] In cases where the therapy of the present invention is administered to hysterectomized patients, the estetrol component is preferably administered as the sole active ingredient.

[0126] When the therapy of the present invention is applied to non-hysterectomized patients, the estratetrol component can be administered as the sole active ingredient, or can be administered together with an optional progestogen component. The optional progestogen component can be administered continuously (i.e., administered daily in addition to the estratetrol component) or sequentially (wherein sequentially means that the progestogen component is administered during, for example, 10 to 14 days per month or 14 days every 3 months).

[0127] The term "continuous" / "continuously" as used herein means that the ingredients are administered at relatively regular intervals without (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the method, and indeed these deviations are included in the present invention. In a preferred embodiment, more precisely, a dosing regimen is considered continuous if the longest interval between two consecutive administrations is no more than 3.5 times the average interval. Even more preferably, the longest interval is no more than 2.5 times the average interval, and most preferably no more than 1.5 times the average interval.

[0128] In one embodiment, the optional progestin component is administered via a non-oral route, such as using an intrauterine contraceptive device (IUD). In one embodiment, the IUD delivers the progestin component levonorgestrel. In one such embodiment, the IUD is IUD or IUD.

[0129] In one embodiment, the therapy of the present invention adopts oral, sublingual, buccal or sublabial administration of the estetrol component. The advantage of the latter three modes of administration is that the estetrol component does not have to pass through the digestive system and avoids first-pass liver exposure. In addition, these modes of administration provide a rapid onset of action.

[0130] The term "sublingual" as used herein refers to a pharmacological route of administration by which the estetrol component diffuses into the blood through the tissues under the tongue.

[0131] As used herein, the term "buccal" refers to the pharmacological route of administration by which the estetrol component diffuses into the bloodstream through the buccal vestibular tissues, the area within the mouth between the buccal lining (buccal mucosa) and the teeth / gingiva.

[0132] As used herein, the term "sublabial" refers to the pharmacological route of administration by which the estetrol component is placed between the lips and the gums.

[0133] In the method of the present invention, the estetrol and progestogen components may be administered in separate dosage units. However, it is also possible and indeed very convenient to combine the two components into a single dosage unit.

[0134] In the method according to the invention the combination of progestogen and estetrol components is suitably administered continuously over a period of at least 10 days.

[0135] The present invention can be appropriately simplified to be implemented in the form of various administration methods known to those skilled in the art. Among these methods, there is a method of using a single-phase preparation comprising a dosage unit having a constant amount of estetrol component and an optional progestogen component.

[0136] In embodiments of the invention where sequential administration of the progestogen components is chosen, it is also possible and convenient to combine the components into a single dosage unit on the days when both components are administered.

[0137] In one embodiment of the invention, hormone replacement therapy is administered to a perimenopausal subject. In this embodiment, the subject benefits from relief of VMS by administering the composition of the invention, while benefiting from contraceptive effects. In a particular perimenopausal population, contraception is often indeed required, and since VMS occurs during this period of life, the treatment of the present invention uniquely addresses these two needs in a single and simple treatment.

[0138] In another embodiment of the invention, hormone replacement therapy is administered to a postmenopausal subject.

[0139] In a specific embodiment of the invention, the hormone replacement therapy is advantageously administered to take advantage of the fact that the subject's smoking status does not affect the treatment of the invention. It is indeed known that smoking significantly reduces serum estrogen concentrations, for example, in a clinical study analysis by Bjarnason et al. (Bjarnason et al.; Climacteric 2012; Acute and long-termestradiol kinetics in smoking postmenopausal women; 15: 5; pp. 449-454), it was reported that in the estrogen group, smoking resulted in a significant reduction in serum estrone and serum estradiol levels at all randomized time points, while there was no difference between smokers and non-smokers in the placebo group. Bjarnason et al. concluded that: in the case of postmenopausal women receiving estrogen therapy, smoking reduces serum estrogen at trough and 2 hours later, the effect of smoking on estrogen concentrations is fully manifested in women who smoke ten or fewer cigarettes per day, and the effect of smoking on the metabolism of estrogen therapy is constant and has no dose response to standard smoking intensity.

[0140] In this specific embodiment, based on the surprising discovery that the therapy of the present invention is not affected by the smoking status of the subject, it is preferred to administer the hormone replacement therapy to a patient population that smokes 5 or more cigarettes per day, to a patient population that smokes 10 or more cigarettes per day, or to a patient population that smokes 15 or more cigarettes per day.

[0141] In another specific embodiment of the present invention, hormone replacement therapy is used beneficially to take advantage of the fact that the BMI of the experimenter is ineffective for the therapy of the present invention. It is indeed surprisingly found that, contrary to the hormone replacement therapy of the prior art, the effect of the therapy of the present invention is not affected by the BMI value of the experimenter. In this specific embodiment, the hormone therapy of the present invention is preferably applied to an experimenter whose BMI is 25 or more, 28 or more, 30 or more, 33 or more, 35 or more, 37 or more, or 40 or more. In this specific embodiment, the hormone therapy of the present invention is preferably applied to an overweight subject or an obese subject.

[0142] Hormone replacement therapy of the present invention is found to be particularly beneficial for alleviating menopausal-related symptoms, while having extremely limited effects on most of the liver, hemostasis, endocrine and metabolic parameters. In fact, the HRT treatment of the prior art has a negative impact on these parameters. Surprisingly and very beneficially, in contrast, it was found that the treatment of the present invention did not change or only minimally changed most of the parameters.

[0143] Composition

[0144] The estetrol component of the present invention includes substances selected from the following: estetrol; esters of estetrol, wherein the hydrogen atom of at least one hydroxyl group has been replaced by an acyl group of a hydrocarbon carboxylic acid, sulfonic acid or aminosulfonic acid having 1 to 25 carbon atoms; and combinations thereof. More preferably, the estetrol component is estetrol (including estetrol hydrate). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

[0145] The estratetol component of the present invention is used in a daily dose equivalent to about 15 mg to about 25 mg of estratetol monohydrate. In other words, when the estratetol component is not estratetol monohydrate itself, the daily dose of the estratetol component is adjusted to produce a therapeutic effect equivalent to a daily dose of about 15 mg to about 25 mg of estratetol monohydrate.

[0146] In a particularly preferred embodiment of the present invention, the pharmaceutical composition according to the invention is designed for daily administration, ie it represents a daily dosage unit.

[0147] In the case of oral administration, the oral dosage unit according to the present invention is preferably a solid or semisolid dosage form, such as tablets, capsules, cachets, pellets, pills, powders and granules. The term "solid or semisolid dosage form" also includes capsules containing a liquid (e.g., oil) in which the estratetol component of the present invention and / or the optional progestogen component are dissolved or dispersed. Tablets and equivalent solid and semisolid dosage forms may suitably contain the following materials: for example, binders (e.g., hydroxypropyl methylcellulose, polyvinyl pyrrolidone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrants (e.g., starch polymers and cellulosic materials) and lubricants (e.g., stearates and talc). These tablets and equivalent solid dosage forms can be prepared by wet granulation, for example, using an aqueous solution or an organic solution, or by direct compression.

[0148] In the case of sublingual, buccal or sublabial administration, the pharmaceutical composition according to the invention is preferably in the form of an orodispersible dosage unit.

[0149] As used herein, the term "orodispersible dosage unit" refers to a dosage unit designed to rapidly disintegrate in the oral cavity when it comes into contact with saliva and disperses the estetrol component into the saliva so that it can be absorbed through the mucosal lining of the oral cavity.

[0150] When the dosage unit is an orodispersible dosage unit, the method according to Ph. Eur. 2.9.1 ("Disintegration of tablets and capsules") and USP <701> The rate of release of the estetrol component from the dosage unit can be appropriately determined by a disintegration test ("disintegration"), for example, using water as the disintegration medium. When subjected to the above disintegration test, the orally dispersible solid dosage unit of the present invention typically disintegrates in less than 5 minutes, more preferably in less than 2 minutes, even more preferably in less than 1.5 minutes, even more preferably in less than 1 minute, even more preferably in less than 45 seconds, and most preferably in less than 30 seconds.

[0151] When the patient still has a uterus, an optional progestogen component may be administered in addition to the estetrol component.

[0152] Examples of progestogen components that can be suitably used according to the present invention include levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-β-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylnorgestimate, 19-desmethylprogesterone, acetoxypregnenolone, allylestradiol, amgestone, chlormadinolone, cyproterone acetate, demegestrol, desogestrel, dienogest, dihydroprogesterone, demegestrol, ethinylestradiol, , norethindrone acetate, fluprogesterone acetate, gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, linegestrol, mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone, norgestrel, norgestrel (including d-norgestrel and dl-norgestrel), norgestrel, norgestrel , progesterone, quinoline, (17α)-17-hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3-one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone ester, 19-nor-17-hydroxyprogesterone, 17-α-ethynyltestosterone , 17-α-ethynyl-19-nortestosterone, d-17β-acetoxy-13β-ethyl-17α-ethynyl-4-en-3-one oxime, 6β,7β;15β,16β-dimethylene-3-oxo-17-pregn-4,9(11)-diene-21,17β-lactone or tanaproget, and precursors of these compounds that are capable of releasing these progestogens in vivo when used in the methods of the present invention.

[0153] Preferably, the progestogen component used in the method of the present invention is selected from the group consisting of progesterone, drospirenone, dydrogesterone, precursors of these progestogens and mixtures thereof.

[0154] In one embodiment, the present invention provides a combination composition comprising an estetrol component and a progesterone.

[0155] In one embodiment, the present invention provides a combination composition comprising an estetrol component and drospirenone.

[0156] In one embodiment, the present invention provides a combination composition comprising an estetrol component and dydrogesterone.

[0157] When the progestogen component of the present invention is drospirenone, it is preferably used in a daily dose of 0.5 mg to 10 mg, even more preferably 1 mg to 4 mg.

[0158] When the progestogen component of the present invention is dydrogesterone, it is preferably used in a daily dose of about 5 mg to about 10 mg, more preferably in a daily dose of about 5 mg.

[0159] When the progestogen component of the present invention is progesterone, it is preferably used in a daily dose of 50 mg to 200 mg. In one embodiment, when progesterone is used continuously, it is used in a daily dose of 50 mg to 100 mg. In another embodiment, when used sequentially, for example when progesterone is administered during a period of about 14 days per month, it is used in a daily dose of 100 mg to 200 mg.

[0160] When a different progestogen component is used, the daily dose is adjusted to produce the same pharmacological effect as a dose of 50 mg to 200 mg of progesterone.

[0161] In a preferred embodiment of the invention, the composition combines an estetrol component and an optional progestogen component into a single dosage unit, preferably a daily dosage unit. In a more preferred embodiment of the invention, the combined daily dosage unit is an oral combined daily dosage unit.

[0162] In one embodiment, the present invention provides an oral combination daily dosage unit comprising an estetrol component and a progestin.

[0163] In one embodiment, the present invention provides an oral combination daily dosage unit comprising an estetrol component and drospirenone.

[0164] In one embodiment, the present invention provides an oral combination daily dosage unit comprising an estetrol component and dydrogesterone.

[0165] In a preferred embodiment of the invention, an oral combination daily dosage unit is provided which combines a daily dosage of about 20 mg of estetrol with a daily dosage of about 100 mg of progesterone.

[0166] In another embodiment of the invention, the estratetol component is administered in combination with a selective estrogen receptor modulator (SERM), particularly in combination with bazedoxifene, to a patient still having a uterus. Preferably, bazedoxifene is administered in a daily dose of about 10 mg to 50 mg. More preferably, bazedoxifene is administered in a daily dose of about 20 mg.

[0167] In one embodiment, the present invention provides a combination therapy comprising an estetrol component and bazedoxifene.

[0168] In one embodiment, the present invention provides an oral combination daily dosage unit comprising an estetrol component and bazedoxifene.

[0169] The invention has been described above with reference to a number of exemplary embodiments. Modifications and substitutions of some components or elements may be made and are included within the scope of protection defined in the appended claims. Example

[0170] Example 1 - Dose-finding study to select a daily oral dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women

[0171] Study Enrollment and Duration:

[0172] Enrollment was approximately 18 months. Individual subjects participated for up to 27 weeks: up to 6 weeks of prescreening and washout; up to 4 weeks of screening and run-in period, up to 91 days (13 weeks) of E4 / placebo treatment followed by 2 weeks (14 days) of progestin treatment, and a 1-week follow-up after progestin treatment in non-hysterectomized subjects only.

[0173] Main efficacy goals:

[0174] The minimum effective dose (MED) of oral E4 was defined by evaluating changes in the frequency and severity of moderate to severe vasomotor symptoms (VMS).

[0175] Methodology:

[0176] This was a prospective, multicenter, randomized, placebo-controlled, double-blind, dose-finding study.

[0177] Subject population:

[0178] Eligible subjects were hysterectomized and non-hysterectomized postmenopausal women aged 40 to 65 years (inclusive) who experienced at least 7 moderate to severe hot flashes per day or at least 50 moderate to severe hot flashes per week.

[0179] Diagnosis and inclusion criteria:

[0180] Subjects met all of the following inclusion criteria at the randomization visit. These criteria were assessed during the screening period:

[0181] 1. Women aged 40 to 65 years (inclusive) who experienced at least 7 moderate to severe hot flashes per day in the week before randomization, or at least 50 moderate to severe hot flashes per week.

[0182] 2. Body mass index (BMI) between 18.0 and 35.0 kg / m2 (inclusive).

[0183] 3. Postmenopausal status is defined as follicle-stimulating hormone (FSH) level >40 IU / L and:

[0184] - Amenorrhea for at least 12 consecutive months, or

[0185] - Amenorrhea for at least 6 months, estradiol (E2) <20 pg / mL, or

[0186] - Regardless of whether a hysterectomy was performed, a copy of the pathology report or a statement on letterhead from the subject's physician documenting that both ovaries were removed was required at least 6 weeks after bilateral oophorectomy.

[0187] 4. For non-hysterectomized women: intact uterus with bilayer endometrial thickness ≤5 mm on TVUS.

[0188] 5. Negative pregnancy test.

[0189] 6. Be in good physical and mental health, as judged by the Principal Investigator (PI), based on medical, surgical and gynecological history; physical examination; gynecological examination; clinical tests and vital signs.

[0190] 7. Before entering the study, the subjects provided signed and dated written informed consent.

[0191] 8. The subject is able to understand and comply with the protocol requirements, instructions, and limitations specified in the protocol.

[0192] Exclusion criteria:

[0193] Potential study subjects were excluded if one of the following exclusion criteria was present at the randomization visit. These criteria were assessed during Screening:

[0194] 1. For non-hysterectomized women: Uterine diseases or medical conditions, including:

[0195] a. Double endometrial thickness >5 mm as determined by TVUS;

[0196] b. The presence of fibroids precludes TVUS assessment of the endometrium;

[0197] c. History or presence of uterine cancer;

[0198] d. Presence of endometrial hyperplasia;

[0199] e. Presence of endometrial polyps with associated hyperplastic or malignant epithelium.

[0200] 2. Undiagnosed vaginal bleeding in the past 12 months.

[0201] 3. Any history of malignancy, except basal cell carcinoma (excluded if within the previous 2 years) or squamous cell carcinoma (excluded if within the previous year) of the skin. Any clinically significant findings suspicious for breast malignancy on breast examination and / or mammography require additional clinical testing to exclude breast cancer (however, simple cysts confirmed by ultrasound are permitted). Note: Screening mammogram is required unless the subject has written documentation of a mammogram performed within the past 9 months.

[0202] 4. Evidence of cervical dysplasia greater than low-grade squamous intraepithelial lesion (LSIL) on abnormal Pap smear in non-hysterectomized subjects (written documentation of prior testing within 18 months or testing at screening examination). Women diagnosed with atypical squamous cells of uncertain significance (ASCUS) were enrolled in the study.

[0203] 5. Systolic blood pressure (BP) outside the range of 90 to 140 mmHg, diastolic BP outside the range of 60 to 90 mmHg, and / or heart rate outside the range of 40 to 100 bpm. Subjects with mild to moderate hypertension controlled by a stable antihypertensive regimen were enrolled in the study if they met the inclusion / exclusion criteria.

[0204] 6. Any clinically significant abnormalities detected on the 12-lead ECG screening.

[0205] 7. History of venous or arterial thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), known history of coagulation disorder or coagulation factor abnormalities.

[0206] 8. Diabetes mellitus with poor glycemic control in the past 6 months as assessed by laboratory values ​​of glucose outside the normal range and glycated hemoglobin exceeding 7%.

[0207] 9. Dyslipoproteinaemia predisposes subjects to atherosclerotic cardiovascular disease (ASCVD). If a subject has a 10-year ASCVD score ≥ 5% calculated using the ASCVD risk assessment (ACC / AHA Cardiovascular risk assessment guideline, 2013), she cannot be included in this trial. In all cases, LDL cholesterol levels ≥ 190 mg / dL or triglyceride plasma levels > 400 mg / dL are excluded.

[0208] If the subject was receiving lipid-lowering therapy, her treatment had to be stable at a dose for at least 1 month before screening, and the same eligibility criteria had to apply.

[0209] 10. Smoking > 10 cigarettes / day, or using nicotine-containing liquid for electronic cigarettes > 1 mL / day.

[0210] 11. The presence or history of gallbladder disease unless a cholecystectomy has been performed.

[0211] 12. Systemic lupus erythematosus.

[0212] 13. Multiple sclerosis.

[0213] 14. Acute or chronic liver disease.

[0214] 15. Acute or chronic renal insufficiency, including severe renal insufficiency.

[0215] 16. Uncontrolled thyroid disease.

[0216] 17. Subjects with a history of major depression or post-traumatic stress disorder (PTSD) within 2 years, or a history of other serious mental illness (e.g., schizophrenia, bipolar disorder, etc.) at any time.

[0217] 18. Use of medications containing estrogen or progestin. A washout period is required before the introduction period if the following substances are used:

[0218] a. Vaginal hormone products (rings, creams, gels): wash out for at least 4 weeks;

[0219] b. Transdermal estrogen or estrogen / progestin: washout for at least 4 weeks;

[0220] c. Oral estrogen and / or progestin: washout for at least 4 weeks;

[0221] d. Intrauterine progestin therapy: washout for at least 4 weeks;

[0222] Current users of progestin implants or estrogen-alone injections were not allowed to participate unless treatment was stopped more than 3 months ago. Current users of estrogen pills or progestin injections were not allowed to participate unless treatment was stopped more than 6 months ago.

[0223] 19. Use of non-hormonal treatments to reduce hot flashes. In the case of non-hormonal prescription and over-the-counter (OTC) treatments for hot flashes (e.g., antidepressants paroxetine, escitalopram, venlafaxine, desvenlafaxine, and clonidine; or phytoestrogens, black cohosh, etc.), a 1-week washout period is required prior to the run-in period. If one of these treatments is taken concurrently with an estrogen- or progestin-containing medication, the washout periods can be combined and do not have to be sequential.

[0224] 20. Use of drugs that may affect VMS endpoint results within 28 days before the run-in period, including (but not limited to): SSRI [selective serotonin reuptake inhibitor], SNRI [serotonin and norepinephrine reuptake inhibitor], dopaminergic or antidopaminergic drugs, or gabapentin.

[0225] 21. Have a history of allergy or allergy to the investigational product or such drugs, or have a history of drugs or other allergies that the investigator believes prohibits the subject from participating.

[0226] 22. History of or existing allergy or intolerance to any ingredient of the study product.

[0227] 23. History of alcohol or drug abuse or dependence within 12 months as determined by the investigator, i.e., the subject has consumed alcohol excessively, abused drugs, or the investigator believes that the subject's condition may impair the subject's ability to comply with the study requirements.

[0228] 24. Employees of the sponsor or contract research organization (CRO), or personnel in the investigator’s department and relatives related to this study.

[0229] 25. Subjects with porphyria and subjects with a known or suspected history of clinically significant systemic illness, unstable medical illness, life-threatening illness, or current malignancy who, in the opinion of the investigator, will pose a risk to the subjects.

[0230] 26. Participated in another clinical study of investigational drugs within 1 month (30 days) or received investigational drugs within the last 3 months (90 days).

[0231] 27. Deemed unsuitable by the investigator for any reason.

[0232] Number of subjects:

[0233] Intention-to-treat principle

[0234] This principle states that the effects of a treatment policy can best be assessed by evaluating it based on intention to treat (i.e., the planned treatment regimen) rather than the actual treatment given. As a result, subjects assigned to a treatment group should be followed, assessed, and analyzed as members of that group regardless of whether they adhere to the planned treatment regimen.

[0235] Furthermore, the intention-to-treat principle implies that the primary analysis should include all randomized subjects.

[0236] Preserving the initial randomization in the analysis is important to prevent bias and provide a reliable basis for statistical tests. In many clinical trials, the use of the full analysis set provides a conservative strategy. In many cases, it can also provide estimates of treatment effects that are more likely to reflect the effects observed in subsequent administrations.

[0237] In this study, the intention-to-treat group included a total of 257 patients.

[0238] Subjects were randomly assigned to one of five treatment groups in a 1:1:1:1:1 ratio. Randomization was stratified by center.

[0239] Research visits:

[0240]

[0241] Test product and reference therapy, dosage and route of administration

[0242] All treatments (estetrol, hereinafter referred to as E4, [2.5 mg, 5 mg, 10 mg, 15 mg] capsules) were orally administered once daily (QD) for at least 12 consecutive weeks until the final biological assessment was performed (maximum day 91).

[0243] Placebo, 1 capsule orally once daily for at least 12 consecutive weeks until the last biological assessment is performed (maximum day 90).

[0244] If during the trial, a bilayered endometrium with a thickness of ≥15 mm, and / or abnormal uterine bleeding (based on estrogen therapy as judged by the gynecologist) was detected on TVUS as reported by a non-hysterectomized woman, she underwent an endometrial biopsy and sequential treatment with a progestin (10 mg dydrogesterone) once daily in addition to E4 / placebo treatment (i.e., a 14-day progestin treatment period followed by a 14-day progestin treatment break) until the end of Week 11. If the endometrial biopsy showed endometrial hyperplasia, the subject's participation was immediately discontinued and proliferative treatment was initiated according to local guidelines. If abnormal uterine bleeding recurred after a first normal endometrial biopsy, a thorough gynecologic examination and TVUS were performed. A second endometrial biopsy was performed if necessary in the judgment of the gynecologist.

[0245] Following the E4 / placebo treatment period, all non-hysterectomized subjects (including those who had previously received a progestin) received progestin treatment with 10 mg dydrogesterone once daily for 14 days.

[0246] result

[0247] A. Vascular motion parameters in each of the five treatment groups

[0248] a. VMS frequency

[0249] i. Absolute change in weekly frequency of moderate to severe VMS (mean change from baseline)

[0250] a) Each group, week by week

[0251]

[0252] To analyze the data recorded in this study, ANCOVA (analysis of covariance) was used to compare the treatment groups, targeting the change from baseline in the weekly frequency of moderate to severe VMS at Weeks 4 and 12. The ANCOVA model included treatment ("trt1") and study center ("SITEPOOL") as fixed effects, and baseline ("base") as a covariate.

[0253] b) Covariate significance

[0254] The table below shows the comparison of all treatment groups.

[0255]

[0256] After review, the effect of study center was considered not to be significant, and a second ANCOVA was conducted without considering study center.

[0257] No position effect

[0258]

[0259] c) The following table shows the mean change from baseline on treatment by week:

[0260]

[0261] No position effect

[0262]

[0263]

[0264] All statistical tests were supported by providing least squares-adjusted means (LS-adjusted means: group means after controlling for covariates; also called marginal means or estimated marginal means) and corresponding 95% confidence intervals for treatment effects. These LS-adjusted means and confidence intervals were based on the statistical model used for the analysis.

[0265] A confidence interval states that if you sample the same population on many occasions and make the interval estimate in each case, then approximately 95% of the time the resulting interval will contain the true population parameter.

[0266] d) The following table shows the difference between treatment and placebo by week

[0267]

[0268] No position effect

[0269]

[0270] As can be seen from these tables, the 15 mg daily dose produced near statistically significant differences from placebo at 4 weeks (p value was 0.10653 in the first statistical analysis and p value was 0.06834 in the analysis without pooling sites) and 12 weeks (p value was 0.10838 in the first statistical analysis and p value was 0.07057 in the analysis without pooling sites).

[0271] ii. Relative change in weekly frequency of moderate to severe VMS (% relative to baseline)

[0272] a) Each group, week by week

[0273]

[0274] As can be seen from the table, a 15 mg daily dose reduced the frequency of moderate to severe VMS by more than 80% compared to baseline.

[0275] b) Covariate significance

[0276] The table below shows the comparison of all treatment groups.

[0277]

[0278]

[0279] No position effect

[0280]

[0281] c) The following table shows the mean relative change (%) from baseline in treatment by week:

[0282]

[0283] No position effect

[0284]

[0285] d) The following table shows the difference between treatment and placebo by week

[0286]

[0287] As can be seen from the table, the 15 mg daily dose produced a statistically significant difference compared to placebo at 12 weeks (p value of 0.03771), and a nearly statistically significant difference compared to placebo at 4 weeks (p value of 0.05622).

[0288] It was particularly surprising to observe that the 15 mg dose achieved a low p-value compared to the elevated p-value achieved with the 10 mg dose.

[0289] No position effect

[0290]

[0291] As can be seen from the table, in the statistical analysis without considering the position effect, the 15 mg daily dose produced statistically significant differences from placebo at 4 weeks (p=0.03206) and 12 weeks (p=0.02210).

[0292] It was particularly surprising to observe that the 15 mg dose achieved a low p-value compared to the elevated p-value achieved with the 10 mg dose.

[0293] iii. Change in the frequency of moderate to severe VMS per week in the responder group

[0294] The frequency of VMS was also studied by grouping the patients according to their degree of response.

[0295] The first group of patients showing a response (relative change from baseline) of 50% or greater was prepared. According to this analysis, at week 12, the 15 mg daily dose group contained 91.8% responders, while the placebo group contained 65.5% responders. The p-value difference between these two groups was less than 0.01, while the difference between the 10 mg daily dose group and the placebo group was not statistically significant (p-value>0.1).

[0296] A second group of patients showing a response of 75% or greater was prepared. According to this analysis, at week 12, the 15 mg daily dose group contained 77.6% responders, while the placebo group contained 43.6% responders. The p-value difference between these two groups was less than 0.001, while the difference between the 10 mg daily dose group and the placebo group was not statistically significant (p-value>0.05).

[0297] b. VMS severity

[0298] i. Absolute change in weekly severity of moderate to severe VMS (mean change from baseline)

[0299] a) Each group, week by week

[0300]

[0301] To better analyze the data recorded in this study, for each active therapy versus the placebo group, the treatment groups have been compared using ANCOVA (analysis of covariance) for the change from baseline to mild, moderate, and severe VMS severity at Week 4 and Week 12 for moderate to severe VMS. Women who experienced 100% VMS relief at Week 4 and / or Week 12 were assigned a value of zero. The ANCOVA model included treatment ("trt1") as a fixed effect and baseline ("base") as a covariate.

[0302] b) Covariate significance

[0303] The table below shows the comparison of all treatment groups.

[0304]

[0305] c) The following table shows the mean change from baseline on treatment by week

[0306]

[0307] d) The following table shows the difference between treatment and placebo by week

[0308]

[0309] As can be seen from the table, the 15 mg daily dose produced a statistically significant difference compared with placebo at week 4 (p value of 0.0486) and a statistically significant difference compared with placebo at week 12 (p value of 0.0489). Therefore, the 15 mg dose significantly improved the severity of VMS at week 4 and week 12 compared with placebo.

[0310] For the severity parameters, the differences between the 10 mg and 15 mg doses were also impressive: this is first reflected in the mean changes from baseline in the table in section c) above, e.g. at week 12, the LS corrected mean for 10 mg was -0.69 (compared to -0.66 for placebo) and the LS corrected mean for the 15 mg daily dose group was -1.04. This is reflected in the clear differences, with a nearly 8-fold improvement in the p-value at week 4 when switching from 10 mg per day to 15 mg per day, and a more than 20-fold improvement in the p-value at week 12 when switching from 10 mg per day to 15 mg per day.

[0311] ii. Relative change in weekly severity of moderate to severe VMS (% relative to baseline)

[0312] a) Each group, week by week

[0313]

[0314] As can be seen in this table, the 15 mg daily dose reduced the severity of moderate to severe VMS by more than 40% when compared to baseline.

[0315] b) Covariate significance

[0316] The table below shows the comparison of all treatment groups.

[0317]

[0318] c) The following table shows the mean relative change from baseline for treatment by week

[0319]

[0320] d) The following table shows the difference between treatment and placebo by week

[0321]

[0322] As can be seen from the table, the 15 mg daily dose produced a statistically significant difference from placebo at week 12 (p value of 0.0568). Compared with placebo, the 15 mg daily dose improved the severity of VMS at weeks 4 and 12, while the 10 mg daily dose was difficult to distinguish from placebo, especially at week 12.

[0323] c. Hot Flash Weekly Weighted Score

[0324] i. Absolute change in weekly weighted scores (mean change from baseline)

[0325] a) Each group, week by week

[0326]

[0327] b) Covariate significance

[0328] The table below shows the comparison of all treatment groups.

[0329]

[0330] c) The following table shows the mean change from baseline on treatment by week:

[0331]

[0332]

[0333] d) The following table shows the difference between treatment and placebo by week

[0334]

[0335] ii. Relative change in weekly weighted scores (% relative to baseline)

[0336] a) Each group, week by week

[0337]

[0338] b) Covariate significance

[0339] The table below shows the comparison of all treatment groups.

[0340]

[0341] c) The following table shows the mean relative change from baseline for treatment by week

[0342]

[0343]

[0344] d) The following table shows the difference between treatment and placebo by week

[0345]

[0346] As can be seen from the table, the 15 mg daily dose produced a statistically significant difference from the placebo at 4 weeks (p value is 0.0267) and produced a statistically significant difference from the placebo at 12 weeks (p value is 0.0276).

[0347] It was particularly surprising to observe that the 15 mg dose achieved a low p-value compared to the elevated p-value achieved with the 10 mg dose.

[0348] B. Compared with placebo and ineffective doses (2.5 mg and 5 mg) grouped together, vasodilator activity in the 10 mg and 15 mg groups was significantly higher than that in the placebo and ineffective doses grouped together (2.5 mg and 5 mg). Shortcut function parameters

[0349] Based on the results observed in Section A above, it is apparent that the two lowest doses tested (2.5 mg per day and 5 mg per day) did not show efficacy. Thus, a further analysis of the results was prepared in which data from these two doses were grouped with the placebo dose and compared with the 10 mg and 15 mg doses.

[0350] 1. Relative change in the weekly frequency of moderate to severe VMS (% relative to baseline)

[0351] a) Each group, week by week

[0352]

[0353] b) Covariate significance

[0354]

[0355] c) Paired comparisons with placebo (including ineffective doses of 2.5 mg and 5 mg)

[0356]

[0357]

[0358] d) Differences from placebo (including ineffective doses of 2.5 mg and 5 mg)

[0359]

[0360] As already mentioned above in section A), the low p-values ​​observed for the 15 mg daily dose are particularly striking by comparison with the elevated p-values ​​obtained for the 10 mg daily dose, demonstrating that the 15 mg daily dose can achieve unique relief.

[0361] 2. Relative change in hot flash weekly weighted score (% relative to baseline):

[0362] a) Each group, week by week

[0363]

[0364]

[0365] b) Covariate significance

[0366]

[0367] c) Paired comparisons with placebo (including ineffective doses of 2.5 mg and 5 mg)

[0368]

[0369] d) Differences from placebo (including ineffective doses of 2.5 mg and 5 mg)

[0370]

[0371] As already mentioned above in section A), it can be seen that the 15 mg daily dose produced a statistically significant difference compared to placebo at 4 weeks (p value 0.00178) and at 12 weeks (p value 0.00097).

[0372] Likewise, it was particularly surprising to observe that the 15 mg dose achieved a low p-value compared to the elevated p-value achieved with the 10 mg dose.

[0373] C. Menopause Rating Scale

[0374] The Menopause Rating Scale (MRS) is a health-related quality of life scale that allows measuring the severity of age / menopause-related discomfort by scoring symptoms (Heinemann et al., 2003, "International versions of the Menopause Rating Scale (MRS)" Health Qual Life Outcomes 1: 28; Heinemann et al., 2004, "The Menopause Rating Scale (MRS) scale: A methodological review". Health Qual Life Outcomes 2: 45; Heinemann et al., 2004, "The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study". Health Qual Life Outcomes 2: 67).

[0375] In each of the 11 items, the score increases as the subjectively perceived severity of the complaint increases (severity is expressed as 0 to 4 points in each item). Respondents can provide their own personal views by checking the boxes for the five possible "severity" for each item in the questionnaire. The total MRS score ranges from 0 (no symptoms) to 44 (highest level of complaints). Depending on the number of complaints assigned to each symptom dimension, the minimum / maximum score varies between the three dimensions (Heinemann et al., 2003, Health Qual Life Outcomes 1: 28):

[0376] 1. Psychological symptoms: 0 to 16 points (4 symptoms: depression, irritability, anxiety, exhaustion);

[0377] 2. Physical nutritional function symptoms: 0 to 16 points (4 symptoms: sweating / flush, heart discomfort, sleep disorders, joint and muscle discomfort);

[0378] 3. Urinary and reproductive system symptoms: 0 to 12 points (3 symptoms: sexual problems, urinary system discomfort, vaginal dryness).

[0379] Total MRS score

[0380]

[0381] The Menopausal Rating Scale (MRS) indicated an overall improvement in quality of life, with the strongest effect for the 15 mg dose. At this dose, a statistically significant effect was observed at week 4 with a p-value of 0.0113 and a near statistically significant effect was observed at week 12 with a p-value of 0.0694 compared to placebo.

[0382] D. Genitourinary symptoms (GSM)

[0383] Changes from baseline to week 12 in the following GSM symptoms (self-assessed by VVA subjects) were recorded:

[0384] a) Vaginal dryness (vaginal dryness or burning; none = 0, mild = 1, moderate = 2, or severe = 3):

[0385]

[0386] *p<0.05 compared with placebo at week 12.

[0387] b) Vaginal and / or vulvar irritation / itching (sensation of unusual vaginal irritation or sensitivity; none = 0, mild = 1, moderate = 2, or severe = 3):

[0388]

[0389] c) Dysuria (pain or difficulty urinating; none = 0, mild = 1, moderate = 2, or severe = 3):

[0391]

[0392] d) Vaginal pain related to sexual activity (pain during intercourse; none = 0, mild = 1, moderate = 2)

[0393] =2 or severe =3):

[0394]

[0395] *P<0.05 compared with placebo at week 12; **P<0.05 compared with placebo at week 12

[0396] p<0.001.

[0397] e) Vaginal bleeding related to sexual activity (blood loss during intercourse; present = 1, absent = 0):

[0398]

[0399] #Some patients have no sexual activity

[0400] The evolution of VVA symptoms showed an overall improvement, with the strongest effect for the 15 mg daily dose. For vaginal pain associated with sexual activity, the 5, 10, and 15 mg daily doses were significantly different from placebo, with p values ​​of 0.0246, 0.0004, and 0.0006, respectively. However, vaginal dryness, which is often considered the most bothersome symptom, was significantly improved only at the 15 mg daily dose, with a p value of 0.0291.

[0401] E. Measures related to treatment side effects

[0402] 1. Number of patients undergoing biopsy

[0403] Treatment Group Placebo 2.5 mg 5 mg 10 mg 15 mg Number of patients undergoing biopsy 4 4 5 11 9

[0404] 2. Adverse events (AEs)

[0405]

[0406] As you can see from the table above, patients in the 15 mg group experienced fewer TEAEs than those in the 10 mg group. In the 10 mg group of patients with AEs, there were an average of 3.2 AEs per patient. In contrast, in the 15 mg group, patients with AEs had an average of 2.6 AEs. Globally, those data suggest that the 15 mg daily dose can significantly relieve VMS without generating additional AEs for patients. In addition, the biopsy requirements were less in the 15 mg daily group than in the 10 mg daily group.

[0407] This was confirmed by the following statistical analysis. Using a Poisson regression model with random effects for patients and treatment groups as covariates to simulate the counts of TEAEs in different treatment groups, it was possible to demonstrate that there were no statistical differences between treatment groups (p-value 0.099). Second, the chi-square test was used to assess whether the prevalence of patients reporting TEAEs was similar in each treatment group. No statistical differences were found between treatment groups (p-value 0.575).

[0408] 3. Patients who withdrew from the study

[0409]

[0410] F. Measurements at 15 mg and 20 mg daily doses

[0411] In order to better assess the potential for increasing the daily dose beyond the minimum effective dose of 15 mg per day, a number of parameters were followed in studies in which estetrol was administered at increasing doses of 20 mg per day.

[0412] 1. Triglyceride level (mmol / L)

[0413]

[0414]

[0415] *For the 20 mg dose, treatment ends after 28 days; for the 15 mg dose, treatment ends after 12 weeks.

[0416] 2. Glucose level (mmol / L)

[0417]

[0418] *For the 20 mg dose, treatment ends after 28 days; for the 15 mg dose, treatment ends after 12 weeks.

[0419] 3. Cholesterol level (mmol / L)

[0420]

[0421] *For the 20 mg dose, treatment ends after 28 days; for the 15 mg dose, treatment ends after 12 weeks.

[0422] 4. HDL-cholesterol level (mmol / L)

[0423]

[0424]

[0425] *For the 20 mg dose, treatment ends after 28 days; for the 15 mg dose, treatment ends after 12 weeks.

[0426] 5. LDL-cholesterol level (mmol / L)

[0427]

[0428] *For the 20 mg dose, treatment ends after 28 days; for the 15 mg dose, treatment ends after 12 weeks.

[0429] As can be seen from the above 5 tables, these lipid parameters and glucose levels were not significantly different when the 20 mg daily dose was used instead of the 15 mg daily dose.

[0430] 6. C-terminal peptide (CTX-1) (ng / L)

[0431]

[0432] *For the 20 mg dose, treatment ends after 28 days; for the 15 mg dose, treatment ends after 12 weeks.

[0433] CTX-1 is a specific marker of bone resorption.

[0434] As can be seen in the table above, a daily dose of 15 mg resulted in a small decrease in bone resorption, and this effect was more pronounced after 28 days of treatment with a daily dose of 20 mg.

[0435] G. Measurements at 15 mg and 30 mg daily doses

[0436] The following treatments were administered to healthy women (between 15 and 50 years old, inclusive) according to the randomization code.

[0437] Placebo (n=16);

[0438] 15 mg group: after 14 days of washout, a single oral dose of 15 mg estetrol / 3 mg drospirenone (n=10), followed by multiple oral doses of 15 mg estetrol / 3 mg drospirenone (n=10), once daily for 14 days;

[0439] 30 mg group: after 14 days of washout, a single oral dose of 30 mg estetrol / 6 mg drospirenone (n=10) followed by multiple oral doses of 30 mg estetrol / 6 mg drospirenone (n=10) once daily for 14 days.

[0440] Adverse events were recorded from the first admission to the hospital until the end of follow-up (between 37 and 42 days after the first day of treatment).

[0441]

[0442] % = the percentage of subjects reporting one or more AEs in the corresponding treatment group compared to the total number of subjects

[0443] Overall, in this study, single-dose and once-daily 14-day oral doses of estetrol / drospirenone were demonstrated to be safe and well tolerated in healthy female subjects: 15 mg estetrol / 3 mg drospirenone to 30 mg estetrol / 6 mg drospirenone. No increase in the percentage of subjects reporting TEAEs or the number of TEAEs was observed with increasing single and multiple doses of estetrol / drospirenone (doubling of the dose).

[0444] Therefore, it is reasonable to believe that the use of the following hormone replacement therapy to relieve menopausal symptoms obtains a better benefit-risk ratio distribution, which uses 15 mg (minimum effective dose) to 20 mg, or even to 25 mg daily doses of estetrol. Increasing the dose of estetrol above the minimum effective dose of 15 mg per day does provide better efficacy in relieving VMS and in parameters such as bone resorption, while maintaining excellent safety (including but not limited to the adverse events described in the above E) 2) and G) sections, especially the lipid parameters and glucose levels described in the above F) 1) to 5) sections. When patients start hormone replacement therapy, increasing the dose of estetrol above the minimum effective dose of 15 mg per day can also enable the relief effect to start faster.

Claims

1. A composition for alleviating menopausal-related symptoms, wherein the composition comprises estetrol as a component, and wherein the composition is administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

2. The composition for use according to claim 1, wherein a second composition comprising a progestogen component is additionally used.

3. The composition for use according to claim 2, wherein the progestogen component is selected from the group consisting of drospirenone, progesterone and dydrogesterone.

4. The composition for use according to claim 2, wherein the progesterone is administered in a daily dose of 50 mg to 200 mg.

5. The composition for use according to claim 1, wherein a second composition comprising bazedoxifene is additionally used.

6. A composition for use according to any one of claims 2 to 5, wherein said second composition comprising a progestogen component or bazedoxifene is the same as the composition comprising an estetrol component.

7. A composition for use according to any one of claims 1 to 6, wherein the estetrol component is estetrol, preferably estetrol monohydrate.

8. A composition for use according to any one of the preceding claims, wherein the composition is formulated in an oral dosage unit form.

9. A composition for use according to claim 8, wherein the oral dosage unit is formulated to correspond to a daily dosage unit.

10. A packaging unit comprising at least 21, preferably at least 28 containers for containing separately packaged and individually removable daily solid oral dosage forms, wherein each container comprises at least one daily solid oral dosage form containing about 15 mg to about 25 mg of estetrol.

11. The packaging unit according to claim 10, wherein the packaging unit further comprises at least 10, preferably 12, more preferably 14 additional containers for containing separately packaged and individually removable, preferably solid, daily oral dosage forms, wherein each additional container comprises at least one, preferably solid, daily oral dosage form containing a progestogen component.

12. The packaging unit according to claim 11, wherein the progestogenic component is selected from the group consisting of drospirenone, progesterone and dydrogesterone.

13. The packaging unit according to claim 12, wherein said progestogenic component is progesterone, and wherein each of said additional containers comprises at least one daily oral dosage form containing about 200 mg of progesterone.

14. The packaging unit according to claim 10, wherein the packaging unit further comprises the same number of additional containers for containing separately packaged and individually removable, preferably solid, daily oral dosage forms, wherein each additional container comprises at least one, preferably solid, daily oral dosage form containing a progestogen component, wherein the progestogen component is preferably selected from drospirenone, progesterone and dydrogesterone, wherein the progestogen component is more preferably progesterone, and wherein the additional container comprises at least one daily oral dosage form containing about 100 mg of progesterone.

15. The packaging unit according to claim 10, wherein each of said daily solid oral dosage forms further comprises a progestogen component.

Images