Use of estetrol in patients with impaired hepatic function

Abstract

The present invention relates to a composition comprising an estetrol component for use in alleviating estrogen deficiency symptoms, including menopause-related symptoms, in subjects characterized by a certain degree of liver dysfunction.Compared with existing estrogen-based compositions intended to alleviate estrogen deficiency symptoms, the composition described herein exhibits favorable pharmacokinetic properties.Also described herein are the uses for the above and corresponding treatment methods.

Description

[Technical Field]

[0001] The present invention relates generally to the field of medicine, and more particularly to hormone treatment for menopausal female subjects characterized by liver dysfunction. Specifically, the present invention relates to a composition comprising an estetrol component for use in safely treating subjects with liver dysfunction, which composition is effective in treating symptoms of estrogen deficiency in the subject. [Background technology]

[0002] The liver is the primary organ for phase I and phase II drug metabolism and is involved in the clearance of many drugs via various oxidative and conjugative metabolic pathways and / or via biliary excretion of the unchanged drug or its metabolites (Non-Patent Document 1).

[0003] Numerous reports in the biomedical literature demonstrate that liver disease can alter the absorption and pharmacokinetics (PK) of drugs, as well as their efficacy and safety (PD) due to alterations in their excretion and metabolic activity. Such liver dysfunction can lead to the accumulation of drugs and their metabolites and / or impaired formation of active metabolites, subsequently resulting in differential susceptibility to both desirable and adverse pharmacological effects of administered drugs (Non-Patent Documents 2 and 3). These reports are based on clinical trials in patients with common liver diseases, such as alcoholic liver disease and chronic infection with hepatitis B and C viruses, as well as less common diseases, such as acute hepatitis D or E, primary biliary cirrhosis, primary sclerosing cholangitis, and α1-antitrypsin deficiency. The specific effects of disease on liver function are often poorly described and are highly variable, especially with regard to their effects on drug PK and PD.

[0004] In the average elderly population, the use of medications aimed at alleviating one or more symptoms of estrogen deficiency (such as menopausal-related symptoms) is widespread. Menopause has been well described and can be thought of as a gradual process typically involving different hormonal changes over several years, resulting in the permanent cessation of follicular activity and menstrual cycles. Briefly, the early stages of menopause include an increase in follicle-stimulating hormone levels and a decrease in inhibin B expression, while estrogen levels are largely preserved compared to those typically observed in premenopausal women. Over time, estrogen levels eventually decline as menstruation permanently ceases (Non-Patent Document 4). The menopausal process can have many undesirable effects on menopausal (perimenopausal) women, including, but not limited to, vasomotor symptoms (VMS) (e.g., night sweats, hot flashes, and flushing) (Non-Patent Document 5) and thinning of the epithelial lining of the vagina and urethra, resulting in the genitourinary syndrome of menopause (GSM), which encompasses a wide range of symptoms, such as vulvovaginal atrophy (VVA), urinary symptoms, vaginal dryness, itching, dyspareunia, difficulty urinating, frequent urination, and an increased risk of recurrent urinary tract infections (Non-Patent Document 6). Furthermore, menopause can have a profound impact on a subject's psychological state, leading to, for example, depression, irritability, mood changes, insomnia, sleep disorders, anxiety, and nervous tension. These psychological aspects of menopause may occur independently of, or may be the result of, physiological symptoms. Therefore, although there is considerable individual variation, the potential impact of menopause on one's overall well-being should not be underestimated or discounted.

[0005] To date, estrogen therapy (i.e., hormone replacement therapy) remains the gold standard for alleviating menopausal symptoms, particularly VMS. Estrogen therapy is the most effective treatment used to treat VMS due to menopause in the United States and Europe. Although safety issues have been reported in major Women's Health Initiative publications (Non-Patent Document 7), the ongoing demand for treatment of subjects presents a challenge for clinicians to identify the lowest effective dose of estrogen to alleviate menopausal symptoms, especially in subjects with medical prerequisites (Non-Patent Document 8). Furthermore, developing safer estrogen-based treatments than those currently in use remains a general challenge.

[0006] Generally, as with any drug, it is impossible to predict how estrogen is metabolized by subjects with impaired liver function, so the efficacy, safety, and tolerability of these drugs are unknown. Generally, drugs containing estrogen are clearly contraindicated in subjects with impaired liver function due to altered exposure to one or more active pharmaceutical ingredients or their metabolites. See Angeliq™, BIJUVA™, or DUAVEE™ as examples, and such contraindications are clearly stated in the patient labeling approved by the Food and Drug Administration (FDA). In fact, estrogen is poorly metabolized in women with impaired liver function. Therefore, it is unclear whether the use of each drug in these patients is safe or requires adjustment.

[0007] Therefore, providing any estrogen-based drug intended to alleviate estrogen deficiency symptoms that is safe for use in subjects with impaired liver function is of great interest to both subjects and medical professionals and represents an unmet need to date.

[0008] A prerequisite is to achieve good pharmacokinetic parameters, even in the presence of hepatic impairment in subjects. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Almazroo et al., Clin Liver Dis, 2017 [Non-Patent Document 2] Verbeeck, Eur J Clin Pharmacol, 2008 [Non-Patent Document 3] FDA report on pharmacokinetics in patients with impaired hepatic function, Clinical Pharmacology, 2003 [Non-Patent Document 4] Djahanbakhch et al., J Pathol, 2007 [Non-Patent Document 5] Utian et al., Menopause, 2005 [Non-Patent Document 6] Portman et al., Menopause, 2014 [Non-Patent Document 7] Anderson et al., JAMA, 2004 [Non-Patent Document 8] Simon et al., Expert Opin Investig Drugs, 2007 [Summary of the Invention]

[0010] The inventors have observed that estetrol is well tolerated in subjects with impaired hepatic function and therefore provides a safer means of treating estrogen deficiency symptoms (such as menopause-related symptoms) in subjects with impaired hepatic function when compared to currently available products (see the Background section). More specifically, estetrol doses of about 15 mg to about 25 mg, and more specifically, doses of about 15 mg to about 20 mg of the estetrol component, were well tolerated in all subjects tested, and no significant treatment-related adverse events (TEAEs) were observed. All subjects maintained optimal vital signs and laboratory values, as further described in the Examples section.

[0011] Indeed, the hormone replacement therapy of the present invention (aimed at alleviating menopausal-related symptoms, and more broadly, symptoms of estrogen deficiency) has been found to be particularly beneficial, having a very limited effect on a number of hepatic, hemostatic, endocrine, and metabolic parameters in subjects with impaired liver function. Surprisingly and highly beneficially, the treatment of the present invention, in contrast to conventional treatments, has been found to result in no or minimal changes in most parameters.

[0012] More specifically, the pharmacokinetic properties of pharmaceutical compositions containing estetrol as an estrogen component for use in alleviating estrogen deficiency symptoms are generally favorable for subjects with various degrees of liver dysfunction when compared with compositions for alleviating estrogen deficiency symptoms, such as hormone replacement therapy, known to date. The favorable pharmacokinetic properties are generally favorable for subjects with various degrees of liver dysfunction when compared with compositions for alleviating estrogen deficiency symptoms, such as hormone replacement therapy, ... max ), the area under the concentration-time curve (AUC) of the estetrol component extrapolated from time zero to infinity (AUC inf ), AUC of E4-3-glucuronide inf , and parameters including the half-lives of the estetrol component and its metabolites.

[0013] Based on these pharmacokinetic findings, it is surprising that estrogen deficiency symptoms can be treated in patients with varying degrees of hepatic dysfunction with the same estetrol dose as used in patients with normal hepatic function, with no significant differences in safety or efficacy. The same endometrial effects were observed in patients with and without hepatic dysfunction, and doses of 15 mg or higher of estetrol required fewer biopsies in both groups than lower doses of 10 mg. Based on these findings, patients with hepatic dysfunction may now be able to treat estrogen deficiency symptoms, particularly menopausal symptoms, with estrogen, i.e., estetrol, alone, without the need to counteract the endometrial effects with progestogens such as drospirenone. Furthermore, hysterectomized patients with impaired liver function benefit from both treatments, with the advantage of not burdening the patient with unnecessary progestogens. Such a treatment, i.e., a treatment suitable for both hysterectomized and non-hysterectomized patients with hepatic dysfunction, has not been described to date. Therefore, the present invention provides the following aspects:

[0014] Aspect 1. A composition for use in alleviating symptoms of estrogen deficiency in a subject with impaired hepatic function, the composition comprising an estetrol component, the composition being administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0015] Aspect 2. Use of a composition for the manufacture of a medicament for alleviating symptoms of estrogen deficiency in a subject with impaired hepatic function, wherein the composition comprises an estetrol component, and the composition is administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0016] Aspect 3. Use of a composition comprising an estetrol component to alleviate symptoms of estrogen deficiency in a subject with impaired hepatic function, wherein the composition is administered in a daily dose equivalent to about 15 mg to about 25 mg of estetrol.

[0017] Aspect 4. A method of alleviating (i.e., treating) estrogen deficiency symptoms in a subject with impaired hepatic function, the method comprising administering a composition comprising an estetrol component in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0018] Aspect 5. A method for improving the safety of treating symptoms of estrogen deficiency in a subject with impaired hepatic function, the method comprising administering a composition comprising an estetrol component in a daily amount equivalent to about 15 mg to about 25 mg.

[0019] Embodiment 6. The composition for use according to embodiment 1, the use according to embodiment 2 or 3, or the method according to embodiment 4 or 5, wherein the subject with liver dysfunction is characterized by a Child-Pugh score of at least 5 (corresponding to Child-Pugh grade A liver dysfunction).

[0020] Aspect 7. The composition for use, use, or method of any one of the preceding aspects, wherein the subject with impaired liver function is characterized by a Child-Pugh score of 5 to 15 (corresponding to Child-Pugh grade A, B, or C liver function impairment).

[0021] Aspect 8. The composition, use, or method for use of any one of the preceding aspects, wherein the subject with hepatic impairment is characterized by mild hepatic impairment (Child-Pugh score of 5 or 6, or designated as "Grade A"), moderate hepatic impairment (Child-Pugh score of 7 to 9, or designated as "Grade B"), or severe hepatic impairment (Child-Pugh score of 10 to 15, or designated as "Grade C"), as classified by the Child-Pugh scoring system.

[0022] Aspect 9. The composition, use, or method for use according to any one of the preceding aspects, wherein the subject with hepatic impairment is characterized by mild hepatic impairment (Grade A) or moderate hepatic impairment (Grade B) as classified by the Child-Pugh scoring system.

[0023] Aspect 10. The composition, use, or method for use according to any one of the preceding aspects, wherein the estrogen deficiency symptoms are menopause-related symptoms.

[0024] Aspect 11. The composition, use, or method of use according to any one of the preceding aspects, wherein the estrogen deficiency symptoms are psychological aspects of the menopausal transition.

[0025] Aspect 12. The composition, use, or method for use according to Aspect 11, wherein the psychological aspects of the menopausal transition are selected from the group consisting of depression, irritability, mood changes, insomnia, sleep disorders, anxiety, nervous tension, and any combination thereof.

[0026] Aspect 13. The composition, use, or method of use according to any one of the preceding aspects, wherein the symptoms of estrogen deficiency are physiological aspects of the menopausal transition.

[0027] Aspect 14. The composition, use, or method for use according to aspect 13, wherein the physiological aspects of the menopausal transition are selected from the group consisting of joint pain, loss of bone density, urinary tract infections, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, dyspareunia, cardiovascular disease, diabetes, and any combination thereof.

[0028] Aspect 15. A composition for use, use, or method according to any one of the preceding aspects for use in reducing VMS frequency, VMS severity, weighted hot flash weekly score, vaginal dryness, dyspareunia, or any combination thereof, or for use in improving quality of life according to the Menopause Rating Scale (MRS) and / or Menopause-Specific Quality of Life (MENQOL) questionnaire.

[0029] Aspect 16. The composition, use, or method of use of any one of the preceding aspects, wherein the composition is formulated as an oral, sublingual, buccal, or sublabial dosage unit, preferably wherein the composition is formulated as an oral dosage unit.

[0030] Aspect 17. A composition for use, a use, or a method according to aspect 16, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a geometric mean (GM) Cmax of estetrol (E4) that is less than two-fold the corresponding GM Cmax in subjects with normal hepatic function, and preferably, in subjects with normal hepatic function, the geometric mean (GM) Cmax is about 1.7-fold or less the corresponding GM Cmax in subjects with normal hepatic function.

[0031] Aspect 18. A composition for use, a use, or a method according to aspect 16 or 17, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a GM AUCinf for E4 that is less than about 2-fold the corresponding GM AUCinf in subjects with normal hepatic function, and preferably the GM AUCinf for E4 is not more than about 1.1-fold the corresponding GM AUCinf in subjects with normal hepatic function.

[0032] Aspect 19. A composition for use, use, or method according to any one of aspects 16 to 18, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a GM AUCinf for E4-3-glucuronide that is not significantly different from the corresponding GM AUCinf for E4-3-glucuronide in subjects with normal hepatic function.

[0033] Aspect 20. A composition for use, a use, or a method according to any one of aspects 16 to 19, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by similar GM T1 / 2 to E4 when compared to the corresponding GM T1 / 2 in subjects with normal hepatic function.

[0034] Aspect 21. The composition, use, or method for use of any one of the preceding aspects, wherein the number, frequency, and / or severity of adverse effects do not differ between a population of subjects with impaired liver function and a population of subjects with normal liver function.

[0035] Aspect 22. The composition, use, or method for use according to any one of the preceding aspects, wherein the subject is a menopausal, peri-menopausal, or post-menopausal female subject.

[0036] Embodiment 23. The composition, use, or method of use of any one of the preceding embodiments, wherein the composition comprises about 15 mg to about 25 mg of the estetrol component.

[0037] Embodiment 24. The composition, use, or method of use according to any one of the preceding embodiments, wherein the composition comprises about 15 mg to about 20 mg of the estetrol component.

[0038] Embodiment 25. The composition, use, or method of use according to any one of the preceding embodiments, wherein the composition comprises about 15 mg of the estetrol component.

[0039] Embodiment 26. A composition, use, or method for use according to any one of embodiments 1 to 24, wherein the composition comprises about 20 mg of the estetrol component.

[0040] Aspect 27. A composition, use, or method for use according to any one of the preceding aspects, wherein the estetrol component is estetrol or an ester thereof.

[0041] Aspect 28. A composition, use, or method for use according to any one of Aspects 1 to 26, wherein the estetrol component is estetrol monohydrate.

[0042] Embodiment 29. The composition, use, or method for use according to any one of the preceding embodiments, wherein the composition further comprises a progestogen component.

[0043] Aspect 30. A composition, use, or method for use according to Aspect 29, wherein the progestogen component is selected from the group consisting of progesterone, drospirenone, norethisterone, norethisterone acetate (NETA), dydrogesterone, levonorgestrel (LNG), etonogestrel, norgestrel, nomegestrol, nomegestrol acetate (NOMAC), trimegestone, nestrone, dydrogesterone, gestodene, desogestrel, norgestimate, cyproterone acetate, dienogest, and chlormadinone.

[0044] Aspect 31. A composition, use, or method for use according to aspect 29 or 30, wherein said progestogen component is selected from the group comprising drospirenone, progesterone, or dydrogesterone.

[0045] Aspect 32. A composition, use, or method for use according to any one of Aspects 29 to 31, wherein the progestogen component is drospirenone, preferably from about 0.25 mg to about 10 mg of drospirenone, more preferably from about 1 mg to about 4 mg of drospirenone, more preferably about 3 mg of drospirenone, or the progestogen component is administered in an amount equivalent to from about 0.25 mg to about 10 mg of drospirenone, preferably an amount equivalent to from about 1 mg to about 4 mg of drospirenone, more preferably an amount equivalent to about 3 mg of drospirenone.

[0046] Aspect 33. The composition for use, use, or method of any one of Aspects 29 to 32, wherein the progestogen component is progesterone, preferably about 25 mg to about 300 mg of progesterone, more preferably about 100 mg to about 200 mg of progesterone, or the progestogen component is administered in an amount equivalent to about 25 mg to about 300 mg of progesterone, preferably an amount equivalent to about 100 mg to about 200 mg.

[0047] Aspect 34. The composition, use, or method for use according to any one of Aspects 29 to 33, wherein the progestogen component is dydrogesterone, preferably from about 1 mg to about 20 mg of dydrogesterone, more preferably from about 5 mg to about 10 mg of dydrogesterone, or the progestogen component is administered in an amount equivalent to from about 1 mg to about 20 mg of dydrogesterone, preferably an amount equivalent to from about 5 mg to about 10 mg of dydrogesterone.

[0048] Embodiment 35. A composition, use, or method for use according to any one of embodiments 1 to 28, wherein the composition further comprises bazedoxifene.

[0049] Aspect 36. A composition, use, or method for use according to any one of aspects 1 to 28, wherein the estetrol component is the sole (i.e., only) pharmaceutically active ingredient in the composition.

[0050] Embodiment 37. The composition, use, or method of use according to any one of the preceding embodiments, wherein the composition is formulated to correspond to a daily dosage unit.

[0051] Embodiment 38 The composition, use, or method of use according to any one of the preceding embodiments, wherein the composition is used in a once-daily multiple dose regimen.

[0052] Embodiment 39. In any one of the embodiments defined herein, the dosage units may be provided as a kit of parts, including packaging units, e.g., blister packs, containing daily oral dosage units containing the estetrol component. Those skilled in the art will further appreciate that within the scope of the present invention, each packaging unit, e.g., blister pack, may be numbered or otherwise marked.

[0053] Within the scope of the present invention, each such packaging unit may be a sealed blister pack with a cardboard, paperboard or foil plastic backing and enclosed within a suitable cover.

[0054] Also contemplated in any one of the aspects of the packaging unit as defined herein is a bottle. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle characterized by a color that can reduce or prevent degradation of the contents of the bottle, for example, by UV light, while maintaining a degree of transparency that allows visual inspection of the contents of the bottle. Suitable colors include, but are not limited to, amber, cobalt, or vintage green.

[0055] Aspect 40. In certain embodiments of the kit-of-parts according to aspect 39, the packaging unit includes 28 containers, or a multiple of 28 containers, such as 2 to 12 times 28 containers.

[0056] The above and further aspects and preferred embodiments of the present invention are set out in the following sections and in the appended claims, the subject matter of which is specifically incorporated into this specification. [Brief explanation of the drawings]

[0057] [Figure 1] Arithmetic mean (+standard deviation (SD)) plasma concentration versus time profile (linear scale) for E4 up to 24 hours post-dose (pharmacokinetic set). SD = standard deviation; LLOQ = lower limit of quantification. Note: LLOQ = 0.025 ng / mL. X-axis: time after dosing (hours); Y-axis: plasma concentration (ng / mL). Circles: normal liver function group; filled circles: mild liver dysfunction group; triangles: moderate liver dysfunction group; filled triangles: severe liver dysfunction group. [Figure 2] Geometric mean plasma concentration versus time profile (semi-logarithmic scale) for E4 (pharmacokinetic set). LLOQ = lower limit of quantitation. Note: LLOQ = 0.025 ng / ml. X-axis: time after dosing (hours); Y-axis: plasma concentration (ng / ml). Circles: normal liver function group; filled circles: mild liver impairment group; triangles: moderate liver impairment group; filled triangles: severe liver impairment group. [Figure 3]Arithmetic mean (+SD) plasma concentration versus time profile (linear scale) for E4-3-glucuronide up to 24 hours post-dose (pharmacokinetic set). SD = standard deviation; LLOQ = lower limit of quantification. Note: LLOQ = 0.250 ng / ml. X-axis: time post-dose (hours); Y-axis: plasma concentration (ng / ml). Circles: normal liver function group; filled circles: mild liver impairment group; triangles: moderate liver impairment group; filled triangles: severe liver impairment group. [Figure 4] Geometric mean plasma concentration versus time profile (semi-logarithmic scale) for E4-3-glucuronide (pharmacokinetic set). LLOQ = lower limit of quantitation. Note: LLOQ = 0.250 ng / ml. X-axis: time after dosing (hours); Y-axis: plasma concentration (ng / ml). Circles: normal liver function group; filled circles: mild liver impairment group; triangles: moderate liver impairment group; filled triangles: severe liver impairment group. [Figure 5] Arithmetic mean (+SD) plasma concentration versus time profile (linear scale) for E4-16-glucuronide up to 24 hours post-dose (pharmacokinetic set). SD = standard deviation; LLOQ = lower limit of quantification. Note: LLOQ = 0.500 ng / ml. X-axis: time post-dose (hours); Y-axis: plasma concentration (ng / ml). Circles: normal liver function group; filled circles: mild liver impairment group; triangles: moderate liver impairment group; filled triangles: severe liver impairment group. [Figure 6] Geometric mean plasma concentration versus time (semi-logarithmic scale) for E4-16-glucuronide (pharmacokinetic set). LLOQ = lower limit of quantitation. Note: LLOQ = 0.500 ng / ml. X-axis: time after dosing (hours); Y-axis: plasma concentration (ng / ml). Circles: normal liver function group; filled circles: mild liver impairment group; triangles: moderate liver impairment group; filled triangles: severe liver impairment group. [Figure 7] Main pharmacokinetic parameters and Child-Pugh score for E4 (pharmacokinetic set). AUCinf = area under the concentration-time curve extrapolated from time zero to infinity; Cmax = maximum plasma concentration. Open circles: normal liver function group; filled circles: mild liver dysfunction group; triangles: moderate liver dysfunction group; triangles: severe liver dysfunction group. X-axis: Child-Pugh score; Y-axis: Cmax (ng / mL); AUCinf (h*ng / mL). [Figure 8]Geometric LS mean ratios of Cmax for E4. X-axis: Geometric LS mean ratio (Cmax (ng / ml)) and 90% CI; Y-axis: Comparison (Test vs. Reference). Top comparison: Mild vs. Normal. Middle comparison: Moderate vs. Normal. Bottom comparison: Severe vs. Normal. [Figure 9] Geometric LS mean ratio of AUCinf for E4. X-axis: Geometric LS mean ratio (AUCinf (h*ng / mL)) and 90% CI; Y-axis: Comparison (Test vs. Reference). Top row comparison: Mild vs. Normal. Middle row comparison: Moderate vs. Normal. Bottom row comparison: Severe vs. Normal. [Figure 10] Vasomotor symptoms (VMS) (measured as number of hot flashes per week) for the estetrol monohydrate 15 mg, estetrol monohydrate 20 mg, and placebo treatment groups. Statistical analysis by MMRM model of change from baseline in weekly frequency of moderate to severe VMS to weeks 4 and 12; Intent-to-treat (ITT) population; p-value (LS mean difference) for E4 treatment group vs. placebo for change from baseline vs. placebo. [Figure 11] Proportion of subjects achieving at least a 50% or 75% reduction from baseline in weekly frequency of moderate to severe VMS over time; Efficacy Study Part - Intent to Treat (ITT) population; *: p-value<0.05; **: p-value<0.01; ***: p-value<0.001; ****: p-value<0.0001. [Figure 12] Severity of VMS in the estetrol monohydrate 15 mg, estetrol monohydrate 20 mg, and placebo treatment groups. Statistical analysis using the MMRM model of change from baseline in weekly severity of moderate to severe VMS by FDA method through weeks 4 and 12; intention-to-treat (ITT) population; p-value (LS mean difference) for E4 treatment group vs. placebo for change from baseline versus placebo. [Figure 13]Treatment with 15 mg and 20 mg estetrol monohydrate after 12 weeks reduces hemoglobin A1C levels in subjects. (A) Hemoglobin A1C levels. Left state = baseline, right state = week 12. (B) Change from baseline. *: p-value < 0.05; **: p-value < 0.01; ***: p-value < 0.001; ****: p-value < 0.0001. [Figure 14] Treatment with estetrol monohydrate 15 mg and 20 mg after 12 weeks reduces fasting blood glucose levels in subjects. (A) Fasting blood glucose levels. Left state = baseline, right state = week 12. (B) Change from baseline. *: p-value < 0.05; **: p-value < 0.01; ***: p-value < 0.001; ****: p-value < 0.0001. DETAILED DESCRIPTION OF THE INVENTION

[0058] As used herein, the singular forms "a," "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0059] The terms "comprising," "comprises," and "comprised of," as used herein, are synonymous with "including," "includes," or "containing," and these terms are inclusive or open-ended and do not exclude additional, unrecited components, elements, or method steps. These terms also encompass "consisting of" and "consisting essentially of," which enjoy well-established meanings in patent terminology.

[0060] The recitation of numerical ranges by endpoints includes all numbers and fractions falling within the particular range, as well as the recited endpoints. This applies to numerical ranges whether the numerical range is introduced by the phrase "from to," or "between," or otherwise.

[0061] The terms "about" or "approximately," as used herein, when referring to a measurable value such as a parameter, amount, time interval, etc., are meant to encompass variations from the value relative to the specified value, such as variations of ±10% or less, preferably ±5% or less, more preferably ±1% or less, and even more preferably ±0.1% or less, from the value relative to the specified value, provided that such variations are appropriate for practicing the disclosed invention. It will be understood that values ​​modified by "about" or "approximately" are themselves specifically and preferably disclosed.

[0062] On the other hand, the term "one or more" or "at least one," e.g., one or more members or at least one member of a group of members, is self-explanatory and, by way of further example, encompasses, among other things, reference to any one of said members, or any two or more of said members, e.g., any three or more, four or more, five or more, six or more, seven or more, etc. of said members, up to all of said members. As another example, "one or more" or "at least one" may refer to 1, 2, 3, 4, 5, 6, 7, or more.

[0063] The background discussion to the invention herein is included to explain the context of the invention and is not an admission that any of the material referred to was published, known, or common general knowledge in any country as of the priority date of any of the claims.

[0064] Throughout this disclosure, various publications, patents, and published patent specifications are referenced with an identifying citation. All publications cited herein are incorporated by reference in their entirety. In particular, the teachings or sections of such publications specifically mentioned herein are incorporated by reference.

[0065] Unless otherwise defined, all terms used in disclosing the present invention, including technical and scientific terms, have the meanings commonly understood by those skilled in the art to which this invention belongs. For further guidance, definitions of terms are included so that the teachings of the present invention can be better understood. When a particular term is defined in relation to a particular aspect of the present invention or a particular embodiment of the present invention, such relation or meaning is meant to apply throughout this specification, i.e., in the context of other aspects or embodiments of the present invention, unless otherwise defined. For example, an embodiment relating to a product is also applicable to corresponding features of the method and use.

[0066] In the following sections, different aspects or embodiments of the invention are defined in more detail. Each aspect or embodiment so defined can be combined with any other aspect(s) or embodiment(s), unless expressly stated to the contrary. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature or features indicated as being preferred or advantageous.

[0067] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, even if some embodiments described herein include some features but not other features included in other embodiments, combinations of features from different embodiments are intended to be within the scope of the present invention and form different embodiments, as would be understood by one of ordinary skill in the art. For example, the appended claims encompass alternative combinations of the claimed embodiments, as would be understood by one of ordinary skill in the art.

[0068] Unless otherwise specified, all methods, steps, techniques and operations not described in detail can be carried out as is clear to those skilled in the art and are carried out in a manner known per se. In addition to the general background art mentioned in this specification and the further references cited therein, reference is also made, for example, to standard handbooks.

[0069] The term "estetrol component" as used throughout this specification includes substances selected from the group consisting of estetrol, estetrol esters in which at least one hydrogen atom of a hydroxyl group is replaced by an acyl radical of a hydrocarbon carboxylic acid, sulfonic acid, or sulfamic acid of 1 to 25 carbon atoms, estetrol hydrates, e.g., estetrol monohydrate, and combinations thereof. Reference to estetrol throughout any portion of this specification is understood to contemplate any estetrol-containing component (i.e., compound) and / or estetrol derivative (e.g., estetrol ester). More preferably, in the context of this disclosure, a particularly preferred estetrol component suitable for the dosage units or medical uses and treatment methods described herein is estetrol (including estetrol hydrate). Most preferably, the estetrol component is estetrol monohydrate.

[0070] The term "estetrol" as used herein refers to 1,3,5(10)-estratriene-3,15α,16α,17β-tetrol or 15α-hydroxyestriol, as well as estetrol hydrates, such as estetrol monohydrate. "Estetrol" or "E4" for short is an estrogenic steroid produced by fetal human liver (PubChem CID: 27125). Estetrol can be described as a 3-hydroxysteroid corresponding to 17β-estradiol, with two additional hydroxyl groups substituted at the 15α and 16α positions. Estetrol is known to be an estrogen receptor agonist (Coelingh Bennink et al., Climacteric, 2008). Estetrol may be synthesized chemically, by the use of (mutant) recombinant enzymes, or any combination thereof. It is therefore clear that the terms "estetrol" and "estetrol moiety" equally encompass further chemically modified estetrol. Estetrol has the molecular formula: C 18 H24 O4 or structural formula (I). TIFF2026501201000001.tif49170

[0071] In a preferred embodiment, the estetrol component is estetrol or its ester. In a further embodiment, the estetrol component is estetrol monohydrate. Those skilled in the art will understand that estetrol monohydrate corresponds to estetrol containing one molecule of water, and the core structural formula of estetrol is no different from Formula (I). By way of example and not limitation, the structural formula of estetrol monohydrate is shown by Formula (II). TIFF2026501201000002.tif51170

[0072] As used herein, the term "subject" or "patient" refers to a female human subject, preferably a peri- and / or post-menopausal female subject. A female subject as contemplated herein may be one who is in need of, or is deemed to be in need of, treatment to alleviate estrogen deficiency symptoms (e.g., menopause-related symptoms), or who is predicted to be in need of such treatment at some point in the foreseeable future, for example, by entering perimenopause.

[0073] As will be appreciated by those skilled in the art, terms such as "quantity," "amount," and "level" are synonymous and have clearly defined meanings in the art. As used herein, these terms may refer specifically to the absolute amount of a molecule, such as a steroid, in a subject (a sample taken from the subject), or may refer to the relative amount of a molecule or analyte in a sample, i.e., a relative value relative to another value, such as a reference value or a range of values ​​representing the baseline of a particular parameter as taught herein. These values ​​or ranges of values ​​may be obtained from a single subject or from a group of subjects (i.e., at least two subjects). Furthermore, the AUC or C maxWhen referring to the (absolute or relative) quantity of a parameter such as, these quantities should be interpreted as the quantity as measured in (a sample of) one or more subjects' plasma. Both "plasma" and "serum plasma" are commonly accepted terms in medical and clinical contexts, and there is no ambiguity regarding their interpretation by those skilled in the art (Matthew and Varacallo, Physiology, blood plasma, StatPearls, 2019).

[0074] The term "dosage unit," used interchangeably herein and in the art with "dosage form," refers to a physical preparation suitable for administration to a subject without the need for formulation, i.e., final beneficial product, prior to administration. Thus, a dosage unit refers to a composition ready for administration. This term does not imply any limitations on any other details of the treatment, such as the frequency of administration and / or any characteristics of the dosage unit (e.g., taste, appearance, size, etc.). In the context of the present invention, each dosage unit preferably contains, as a pharmaceutically acceptable component, an amount of estetrol component equivalent to about 15 mg to about 25 mg of estetrol. The presence of an estetrol component as a pharmaceutically acceptable component does not preclude the presence of one or more additional medicinal and / or pharmaceutically acceptable components in the dosage unit. As used herein, the term "pharmaceutically acceptable" means consistent with art-wide usage, compatible with other components of a pharmaceutical composition, and not harmful to the recipient. Non-limiting suitable excipients are further described throughout this disclosure.

[0075] Those of ordinary skill in the art will understand the meanings of the following abbreviations used throughout this disclosure, which should each be interpreted in accordance with their generally accepted meaning: C max maximum plasma concentration; AUC inf area under the concentration-time curve (AUC) extrapolated from time zero to infinity; AUC 0-24h AUC from 0 to 24 hours after administration; AUC lastAUC to the end at concentrations above the lower limit of quantification; t max time to reach Cmax; t 1 / 2 Terminal elimination half-life; C L / F Apparent clearance (for E4 only); λ z Elimination rate constant of the terminal elimination phase; Vz / F Terminal apparent volume of distribution (for E4 only).

[0076] Through extensive clinical trials, the present inventors have observed that estetrol offers a surprisingly excellent safety profile when used to treat estrogen deficiency symptoms, including but not limited to menopause-related symptoms, in subjects with impaired hepatic function. This is in contrast to existing marketed products such as Angeliq™ (containing 1 mg estradiol and 0.5 mg drospirenone), which is clearly contraindicated for use in subjects with impaired hepatic function. Notably, this improved safety was achieved while maintaining satisfactory efficacy. The degree of hepatic impairment possessed by the subject is not particularly limiting to the present invention, and while favorable pharmacokinetic properties can be identified to some extent in either group, as stratified by the Child-Pugh classification, unexpected properties are most pronounced in subjects characterized by mild or moderate hepatic impairment. Particularly preferred parameters include the peak plasma concentration (C ) of the estetrol component. max ), the area under the concentration-time curve (AUC) of the estetrol component extrapolated from time zero to infinity (AUC inf ), AUC of E4-3-glucuronide inf and the half-lives of the estetrol component and its metabolites obtained after administration to subjects with impaired hepatic function.

[0077] Thus, in a first aspect, the present invention relates to a composition for use in alleviating symptoms of estrogen deficiency (as may occur in the context of menopause) in a subject with impaired liver function, the composition comprising an estetrol component, the composition being administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

[0078] Those skilled in the art will understand that the phrase "administered in a daily amount equivalent to about x mg to about y mg of estetrol" refers to the administration of a substance (the estetrol component, in the context of the present invention) that achieves the same physiological and / or psychological effect in a subject as would occur if x mg to y mg of estetrol were administered. Furthermore, the term "daily" indicates that the stated amount is the cumulative amount administered to a subject per day. Those skilled in the art will understand that if the estetrol component is administered only once per day (i.e., daily), the amount of estrogen administered in that single administration is the daily dose. Alternatively, those skilled in the art will understand that if the estetrol component is administered more than once per day (e.g., twice or three times), the daily dose corresponds to the sum of the estetrol component administered during each administration event within a 24-hour total time frame. In embodiments in which different estetrol components are included in the composition (e.g., estetrol monohydrate and estetrol ester), it is within the ability of those skilled in the art to determine the amount of estetrol to which each estetrol component corresponds. Preferred embodiments in the context of the present invention include the administration of a single estetrol component, such as, but not limited to, estetrol monohydrate.

[0079] Furthermore, the present invention contemplates the use of a composition comprising an estetrol component for the manufacture of a pharmaceutical for alleviating estrogen deficiency symptoms, such as menopause-related symptoms, in a subject with impaired liver function, wherein the pharmaceutical is formulated so that the daily dose of the estetrol component is administered in an amount equivalent to about 15 mg to about 25 mg of estetrol.

[0080] Furthermore, the use of a composition containing an estrogen component to alleviate estrogen deficiency symptoms, such as menopause-related symptoms, in a subject with impaired liver function is contemplated, and the composition is used so that the estetrol component is administered to the subject in a daily dose equivalent to about 15 mg to about 25 mg of estetrol.

[0081] Further contemplated is a method for alleviating (i.e., treating) symptoms of estrogen deficiency, such as menopause-related symptoms, in a subject with impaired liver function, comprising administering to the subject a composition comprising an estetrol component in a daily dose equivalent to about 15 mg to about 25 mg of estetrol.

[0082] "Estrogen deficiency symptoms" are described in the art and encompass any symptoms a subject may experience due to estrogen deficiency (i.e., "hyposerogenism" or "estrogen deficiency syndrome"). In a preferred embodiment of the present invention, the estrogen deficiency symptoms occur in the context of menopause, and therefore the symptoms may be referred to as menopause-related symptoms. The phrase "alleviating menopause-related symptoms" used throughout this specification has a well-established meaning within the art and refers to the treatment of undesirable physical or psychological symptoms associated with menopause or the onset of menopause. Thus, the compositions disclosed herein are typically used as (therapeutic) treatments for menopause-related symptoms, i.e., as compositions administered to a subject in a therapeutic context. The use of the compositions described herein to prevent the onset of estrogen deficiency symptoms, or more specifically, menopause-related symptoms, is also envisioned.

[0083] Furthermore, those skilled in the art will understand that the phrase "alleviating menopausal-related symptoms" combined with the characteristics of the estetrol-containing composition means that the uses and methods of the present invention described herein further encompass the medical indications of hormone replacement therapy. Hormone replacement therapy (hereinafter abbreviated as "HRT") is generally accepted in the pharmaceutical and medical arts to involve the use of one or more medications (i.e., one or more compositions) designed to increase or replace hormone levels in women with insufficient hormone production. HRT can alleviate and prevent symptoms caused by a decrease in circulating estrogen (and progesterone hormones), regardless of whether the subject is premenopausal, perimenopausal, menopausal, or postmenopausal. Hormone replacement therapy (HRT) is used to describe either the use of unopposed estrogen (in female subjects who have undergone hysterectomy) or estrogen-progestin combination therapy (in female subjects who still possess a uterus). Additional specific pathologies have been reported for each stage of menopausal progression.

[0084] The term "treatment" or "treating" should be interpreted as both therapeutic treatment of already existing symptoms, diseases, or conditions that lead to (clinical) manifestations, and as prophylactic or preventative measures, where the goal of treatment is to prevent, alleviate, or reduce the likelihood of the occurrence of unwanted suffering, such as preventing the onset, development, and progression of (clinical) conditions associated with menopause. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, improvement of one or more biological markers, reduction in the degree (i.e., reduction in severity) of menopausal-related symptoms, stabilization (i.e., non-worsening) of menopausal symptoms, delay or slowing of the onset of menopausal-related symptoms, etc. As used in the context of the present invention, "prevention" or "preventing" refers to the avoidance of the onset of a condition or disease state in a subject, i.e., the establishment of preventative or prophylactic measures. Preventative treatment refers to treatment aimed at preventing the subject's body or its components from exhibiting (worsening) symptoms of undesirable physiological or psychological changes induced by menopause. As used herein, "therapeutic treatment" or "treatment" and the like refers to treatment aimed at changing a subject's body, or a part of a subject's body, from an undesirable physiological condition, disease, or disorder associated with aging to a desirable condition, e.g., a less severe condition (e.g., improving or even returning to a normal, healthy state (e.g., restoring the subject's health, physical integrity, and physical well-being), maintaining (i.e., not worsening) (e.g., stabilizing) the undesirable physiological state, or slowing progression to a more severe or worse condition compared to the undesirable physiological change or disorder). A measurable decrease includes a statistically significant lowering of a measurable marker or symptom. As used herein, statistically significant refers to a p-value of less than 0.05, which, as one of ordinary skill in the art will understand, is a commonly accepted cutoff value in statistical analysis. "Treatment" encompasses both curative treatments and therapies aimed at alleviating and / or slowing the progression of and / or stabilizing estrogen deficiency symptoms.

[0085] Subjects contemplated by the present invention are preferably female subjects characterized (diagnosed, deemed, or predicted (i.e., prognosed)) by liver dysfunction and experiencing or predicted (i.e., prognosed) to experience one or more symptoms of estrogen deficiency, optionally considered to be one or more menopause-related symptoms.

[0086] In embodiments in which the subject has already experienced one or more menopause-related symptoms, the subject may be a hormone dysregulation subject. In the context of the present invention, dysregulation is determined or established by comparing the subject's hormone levels with those representative of healthy adult female subjects. The cause of hormone dysregulation is specifically limited in this disclosure and may be natural (e.g., menopausal hormone changes), but may also be caused by a pathological condition or deficiency. In certain embodiments, the hormone dysregulation is estrogen dysregulation, such as 17β-estradiol dysregulation. In such embodiments, the 17β-estradiol differs from the representative 17β-estradiol value for female adult subjects by at least 15%, preferably at least 25%, and more preferably at least 50%. If the female subject's endogenous estrogen production is reduced, the subject may be considered to be suffering from estrogen deficiency syndrome.

[0087] The term "17β-estradiol" refers to (17beta)-estra-1,3,5(10)-triene-3,17-diol, and is referred to interchangeably with the terms "estradiol" or "E2," and is an estrogen produced endogenously by the human body. More specifically, estradiol is the primary estrogenic hormone produced by the human ovaries during the first half of the menstrual cycle (i.e., the follicular phase). Estradiol is also involved in maintaining bone density, reducing vasomotor symptoms, and maintaining the normal structure of the female reproductive tract in menopausal subjects.

[0088] Embodiments relating to subjects characterized by estrogen depletion (i.e., hypoestrogenism, or estrogen deficiency syndrome) are contemplated by the present invention. While the present invention is primarily directed to alleviating menopause-related symptoms, those skilled in the art will appreciate that many of these symptoms may also be present in female subjects who are not menopausal but who have a medical condition that results in one or more menopause-related symptoms. Accordingly, the present invention is also directed to alleviating estrogen deficiency symptoms that may be present in individuals who have not undergone menopause and / or are not predicted by the impending onset of menopause. The cause of hypoestrogenism is not particularly limited and, therefore, may be caused by, but is not limited to, menopause, hypogonadism, castration, primary ovarian failure, and aromatase inhibitor or gonadotropin-releasing hormone analog breast cancer treatment.

[0089] In certain embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject. In certain embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject with a 17β-estradiol level of less than 100 pg / ml, preferably less than 50 pg / ml, preferably less than 30 pg / ml, more preferably less than 20 pg / ml, more preferably less than 20 pg / ml, and most preferably less than 10 pg / ml. In alternative embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal subject characterized by a follicle-stimulating hormone concentration of at least 20 milli-international units per milliliter (mIU / ml), preferably at least 25 mIU / ml, more preferably at least 30 mIU / ml, more preferably at least 35 mIU / ml, and most preferably at least 40 mIU / ml.

[0090] A "menopausal subject," which is used interchangeably in the art with a "postmenopausal subject" or a "menopausal subject," is a female subject who has not had menstrual bleeding for one year, accompanied by a decline or cessation of hormone (e.g., 17β-estradiol) production by the ovaries.

[0091] According to the US FDA, the criteria for postmenopausal status are: Spontaneous amenorrhea for at least 12 months, or Spontaneous amenorrhea for at least 6 months with a serum FSH level greater than 40 mIU / mL, or Bilateral oophorectomy with or without hysterectomy at least 6 weeks postoperatively.

[0092] Alternatively, "menopause" can be described as a biological state characterized by the impairment or cessation of primary ovarian function. Menopause may be accompanied by a wide range of clinical symptoms of varying severity, including, but not limited to, vascular dysfunction, vaginal dryness, mood changes, sleep disturbances, urinary incontinence, cognitive changes, physical complaints, and sexual dysfunction. Methods for diagnosing menopause have been described in the art and are therefore known to those skilled in the art (Nelson, Menopause, Lancet, 2008).

[0093] "Perimenopause" refers to the period of life beginning approximately 3 to 4 years before menopause and ending one year after the last menstrual period. It is characterized by persistently irregular menstrual cycles, extreme fluctuations in hormone levels, frequent anovulation, and the onset of vasomotor symptoms (Harlow et al., Executive summary of the Stages of Reproductive Aging Workshop+10: addressing the unfinished agenda of staging reproductive aging, Menopause, 2012). The term "postmenopausal" or "postmenopausal" refers to a female subject characterized by the permanent cessation of menstruation. This permanent cessation is determined retrospectively after 12 months of amenorrhea without any other apparent pathological or physiological cause. The term "postmenopausal" also includes menopause as a result of premature ovarian failure, surgery (e.g., oophorectomy), chemotherapy or radiation therapy for cancer, and certain diseases (e.g., infection or hypothyroidism).

[0094] Thus, in the context of the present invention, a female subject is a menopausal, peri-menopausal or post-menopausal subject.

[0095] Preferably, the subject is an adult-aged female subject. More preferably, the subject is a middle-aged or elderly female subject. Even more preferably, the subject is at least 40 years old, preferably at least 50 years old, preferably at least 55 years old, more preferably at least 60 years old, more preferably at least 65 years old. Alternatively, the subject may be a female subject aged 40-90 years, preferably 45-85 years, preferably 50-80 years, more preferably 55-75 years, more preferably 60-70 years, or 65-75 years old. In certain embodiments, the female subject is at most 90 years old, preferably at most 85 years old, more preferably at most 80 years old, more preferably at most 75 years old, more preferably at most 70 years old, more preferably at most 65 years old, and more preferably at most 60 years old. "Diagnosed," "diagnosing," and diagnosis refer to the process of recognizing, determining, or concluding on a disease, condition, or (adverse side effect) in a subject based on symptoms and signs and / or the results of various diagnostic procedures (e.g., from knowing the presence or absence and / or quantity of one or more biomarkers or clinical symptoms characteristic of the diagnosed disease or condition). A "diagnosis" of one or more estrogen deficiency symptoms may particularly mean that the subject has at least one estrogen deficiency symptom as determined by a skilled medical professional. The subject may exhibit one or more conventional symptoms or signs indicative thereof, but the absence of symptoms may be conclusively diagnosed. As used herein, a "diagnosis" of one or more estrogen deficiency symptoms may particularly mean that the subject has at least one physiological estrogen deficiency symptom and / or at least one psychological estrogen deficiency symptom. In the context of the present invention, "prognosing" refers to a prediction regarding the progression of, and outlook for recovery from, one or more estrogen deficiency symptoms (e.g., the probability, duration, and / or extent of recovery) in a subject, and / or the severity or improvement of the experience of said one or more estrogen deficiency symptoms. The term can also encompass a prediction that there will be no further deterioration or exacerbation thereof, preferably within a given period of time.A "poor prognosis" for the disease or condition typically encompasses a prediction of insufficient and / or unsatisfactorily slow recovery, or no recovery at all, or further worsening of one or more symptoms of estrogen deficiency, including physiological symptoms, psychological symptoms, or a combination of both.

[0096] In the foregoing context, "predict" or "prediction" generally refers to the statement, declaration, indication, or forecast of a disease or condition in a subject who does not (yet) exhibit any one or more symptoms of estrogen deficiency or limiting clinical symptoms. A prediction of one or more symptoms of estrogen deficiency in a subject may indicate a probability, chance, or risk that the subject will develop the clinical symptom, condition, or (adverse) side effect, for example, within a certain period of time after diagnosis of one or more symptoms of estrogen deficiency. The probability, chance, or risk may be expressed as any appropriate qualitative or quantitative expression; non-limiting examples of quantitative expressions include absolute values, ranges, or statistics. Alternatively, the probability, chance, or risk may be expressed relative to a suitable control subject or group of control subjects (i.e., compared to a control subject population (e.g., compared to a general, normal, or healthy subject or subject population)). Thus, any probability, chance, or risk may advantageously be expressed as a doubling or doubling, an increase or decrease, an up-regulation or a down-regulation, compared to an appropriate control subject or population of subjects, or compared to a baseline value, which may be derived from either a control subject (population), a textbook reference value, etc. When a population of subjects is used to define a baseline value, it will be apparent that the baseline value will be the median (e.g., the mean or median) of one or more values ​​(parameters) of the population. Furthermore, those skilled in the art will understand that monitoring may be applied during the course of a subject's medical treatment. Such monitoring may be involved, for example, in determining whether a patient can be discharged from a controlled clinical or health care setting, requires a treatment or change in treatment, or requires hospitalization.

[0097] In each of the embodiments disclosed herein, the composition is intended to alleviate estrogen deficiency symptoms, such as menopause-related symptoms, by providing an amount of estetrol component equivalent to about 15 mg to about 25 mg of estetrol. This means that the estetrol component in the composition is present in a pharmaceutically effective amount, and in such embodiments, a daily equivalent is achieved by multiple administrations of the composition. A "pharmaceutically effective amount" refers to the amount required to achieve a physiological effect and may refer to a therapeutically effective amount and / or a prophylactically effective amount. The physiological effect may be achieved by a single dose or multiple doses. A "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of the estetrol component that, when administered, results in a favorable clinical response in the treatment of a subject suffering from estrogen deficiency symptoms. Similarly, a "prophylactically effective amount" or "prophylactically effective dose" refers to the amount of the estetrol component that inhibits or delays the onset of clinical symptoms of the condition as desired by a subject, veterinarian, physician, or other clinician. Those skilled in the art will recognize that terms such as "quantity," "amount," and "level" are synonymous and have well-defined meanings in the art, and will understand that they may refer to an absolute quantification of the estetrol component, or a relative quantification of the estetrol component, which is believed to be an effective amount for the uses described herein. A suitable value or range of values ​​may be obtained from one subject or a group of subjects (i.e., at least two subjects).

[0098] A further aspect of the present invention relates to a method for improving the safety of treating estrogen deficiency symptoms (such as, but not limited to, menopause-related symptoms) in a subject with impaired liver function, comprising administering a composition containing an estetrol component in a daily dose equivalent to about 15 mg to about 25 mg. As illustrated by the examples enclosed herein, it is clear that administration of the estetrol component improves the safety of treatment for estrogen deficiency symptoms by reducing the liver burden in the subject, compared to existing estrogen replacement therapies that rely on the administration of estrogens other than the estrogen component contemplated herein. Thus, the present invention also relates to a method for improving the pharmacokinetic profile of a drug for treating estrogen deficiency symptoms, and a method for improving the safety of treatment for alleviating estrogen deficiency symptoms in a subject with impaired liver function through an improved pharmacokinetic profile.

[0099] The subject described herein is a subject with liver dysfunction. Unless otherwise specified, the degree of liver dysfunction is not particularly limited in the context of the present invention. Throughout this specification, liver dysfunction can be expressed by the Child-Pugh score. Alternative names for this scoring system are used in the art, including, but not limited to, the "Child-Turcotte-Pugh score" or the "Child criteria." The Child-Pugh score is widely used throughout the art (Tsoris and Marlar, updated March 18, 2022, StatPearls), and the classification schedule for liver dysfunction, as known to those skilled in the art, is summarized below.

[0100] TIFF2026501201000003.tif132170

[0101] Liver function groups are defined as follows: Group 1: normal liver function Group 2: Mild liver dysfunction (Child-Pugh score 5-6) Group 3: Moderate liver dysfunction (Child-Pugh score 7-9) Group 4: Severe liver dysfunction (Child-Pugh score 10-14)

[0102] Preferred subjects in the context of the present invention are subjects with an encephalopathy grade of grade 2 or less, preferably subjects with an encephalopathy grade of grade 1 or less, more preferably subjects with an encephalopathy grade of grade 0.

[0103] Optionally, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by liver dysfunction corresponding to a Child-Pugh score of at least 5. In a preferred embodiment, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by liver dysfunction corresponding to a Child-Pugh score of at least 6, preferably at least 7, preferably at least 8, preferably at least 9, preferably at least 10, preferably at least 11, preferably at least 12, preferably at least 13, preferably at least 14. Thus, the subject may be a menopausal, peri-menopausal, or post-menopausal female subject characterized by liver dysfunction corresponding to Child-Pugh Grade A, Grade B, or Grade C. In certain embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by liver dysfunction with a Child-Pugh score of 5 to 15, preferably 5 to 14, preferably 5 to 13, preferably 5 to 12, preferably 5 to 11, preferably 5 to 9, preferably 5 to 8, preferably 5 to 7, preferably 5 to 6.

[0104] In an alternative embodiment, the subject is a menopausal, peri-menopausal or post-menopausal female subject characterized by liver dysfunction corresponding to a Child-Pugh score of 5 to 15, preferably 6 to 15, preferably 7 to 15, preferably 8 to 15, preferably 9 to 15, preferably 10 to 15, preferably 11 to 15, preferably 12 to 15, preferably 13 to 15, preferably 14 to 15.

[0105] In certain embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by mild liver dysfunction (i.e., a Child-Pugh score corresponding to "Grade A"). In alternative embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by moderate liver dysfunction (i.e., a Child-Pugh score corresponding to "Grade B"). In further alternative embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by severe liver dysfunction (i.e., a Child-Pugh score corresponding to "Grade C"). In preferred embodiments, the subject is a menopausal, peri-menopausal, or post-menopausal female subject characterized by mild or moderate liver dysfunction (i.e., a Child-Pugh score corresponding to "Grade A" or "Grade B").

[0106] It is clear that both the terms "estrogen deficiency symptoms" and "menopause-related symptoms" include psychological symptoms, physiological symptoms, and any combination thereof.

[0107] Psychological estrogen deficiency symptoms and menopause-related symptoms include, by way of example and not limitation, depression, irritability, mood changes, insomnia, sleep disturbances, anxiety, nervous tension, and any combination thereof. It is understood that the term "psychological menopause-related symptoms" also encompasses any form or degree of emotional distress due to one or more physical menopause-related symptoms occurring in the subject.

[0108] Physiological estrogen deficiency symptoms and menopause-related symptoms include, by way of example and not limitation, joint pain, loss of bone density, urinary tract infections, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, dyspareunia, cardiovascular disease, diabetes, and any combination thereof. Optionally, the diabetes is type 2 diabetes (e.g., as described in Mauvais-Jarvis et al., Endocr Rev, 2017).

[0109] Preferably, the compositions, uses and methods described herein are for use in reducing VMS frequency, VMS severity, weighted hot flash weekly score, vaginal dryness, dyspareunia, or any combination thereof, or for use in improving quality of life according to the Menopause Rating Scale (MRS) and / or Menopause-Specific Quality of Life (MENQOL) questionnaire.

[0110] As used herein, the term "VMS" (or, in its unabbreviated form, "vasomotor symptoms") corresponds to thermoregulatory disturbances characteristic of menopause. The term VMS encompasses hot flashes (equivalently referred to as "hot flushes"), bouts of sweating, e.g., night sweats, chills, and increased sweating, and palpitations. VMS are bouts of profuse heat accompanied by sweating and flushing, experienced primarily around the head, neck, chest, and upper back. VMS are classified into mild, moderate, and severe categories. In certain embodiments, VMS is selected from the group consisting of hot flashes, night sweats, sleep disturbances, mood swings, and any combination thereof.

[0111] Severity scoring systems that define different severity categories of VMS are commonly used in the technical field: A mild score (1) was given for heat sensation without sweating; Heat sensation due to sweating / moderate score (2) if the subject is able to continue activity, and Severe score (3) if causing heat / inactivity with sweating.

[0112] Additionally, a severity score of 0 is attributed to a patient who experienced 100% VMS relief in a given week. From these scoring records, baseline VMS severity is calculated, typically considering only moderate and severe VMS, by multiplying the total number of moderate VMSs over a 7-day period during the baseline week by 2 and adding that to the total number of severe VMSs over a 7-day period during the baseline week multiplied by 3. This sum is then divided by the total number of moderate and severe VMSs over the baseline week.

[0113] Severity at weeks 4 and 12 will be calculated for each of these weeks using the following formula: Multiply the number of mild VMS in 7 days by 1; Multiply the number of moderate VMS in 7 days by 2; Multiply the number of severe VMS in 7 days by 3; The three numbers obtained are then added together and this total is divided by the total number of mild, moderate, and severe VMS for the seven days of that week.

[0114] VMS severity will be assessed as follows: baseline severity will be calculated, taking into account only moderate and severe VMS, by multiplying the total number of moderate VMS over 7 days during the baseline week by 2 and adding it to the total number of severe VMS over 7 days during the baseline week multiplied by 3. This sum will be divided by the total number of moderate and severe VMS over the baseline week.

[0115] However, the severity at weeks 4 and 12 will be calculated for each of these weeks using the following formula: Multiply the number of moderate VMS in 7 days by 2; Multiply the number of severe VMS in 7 days by 3; The two numbers obtained are then added together and this sum is divided by the total number of moderate and severe VMS during the seven days of that week.

[0116] In another embodiment, the severity score can be calculated according to the method described by Archer et al. (Menopause, 2014), where for each day of the seven-day period, a daily severity score is calculated using the following formula: Multiply the number of moderate VMS during the day by two; Multiply the number of severe VMS during a day by 3; Add the two resulting numbers together; The combined result is then divided by the total number of VMS (moderate and severe) on that day.

[0117] The same formula is applied for seven consecutive days, and the resulting seven numbers are summed and divided by seven to calculate a "weekly average daily severity" score for moderate to severe VMS.

[0118] Furthermore, as used herein, "Hot Flush Weekly Weighted Score" corresponds to a score that takes into account frequency and severity calculated using the 7-day severity score (calculated above) [(1 x number of mild VMS) + (2 x number of moderate VMS) + (3 x number of severe VMS)].

[0119] Such weighted scores were used, for example, by Notelovitz et al. (Obstetrics and Gynaecology, 2000).

[0120] In yet another embodiment, any combination of the above methods may be used to assess the weekly severity and / or frequency of VMS.

[0121] As used herein, the term "quality of life" (and the abbreviation "QoL") may refer to, for example, by way of example and not limitation, 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, further detailed in Example 1, section C below), or the MENQOL questionnaire (Menopause-specific quality of life (MENQOL) questionnaire, Hilditch et al., Maturitas 1996; A menopause-specific quality of life questionnaire: development and These refer to parameters that can be assessed using questionnaires such as the Psychometric Properties; 24(3); p.161-175.

[0122] In certain embodiments, the compositions described herein are advantageously administered to take advantage of the smoking status of the subject and do not affect the treatment of the present invention.For example, as reported in the analysis of clinical trials by Bjarnason et al. (Bjarnason et al.; Climacteric 2012; Acute and long-term estradiol kinetics in smoking postmenopausal women; 15:5; p.449-454), smoking has long been known to significantly reduce serum estrogen levels, and in estrogen group, smoking significantly reduces both serum estrone and serum estradiol levels at all time points after randomization, while in placebo, no difference is found between smokers and non-smokers. Bjarnason et al. concluded that smoking reduces serum estrogen both at the trough and 2 hours after estrogen treatment in postmenopausal women, that the effect of smoking on estrogen concentrations is fully expressed in women who smoke 10 or fewer cigarettes daily, that the effect of smoking on the metabolism of estrogen therapy is consistent, and that there is no dose-response across standard smoking intensities.

[0123] In this particular embodiment, based on the surprising finding that the treatment of the present invention is not affected by the smoking status of the subject, the composition is optionally administered to a patient population who smokes 5 or more cigarettes daily, a patient population who smokes 10 or more cigarettes daily, or a patient population who smokes 15 or more cigarettes daily.

[0124] In yet another specific embodiment of the present invention, the compositions described herein are advantageously administered to take advantage of the fact that the subject's BMI does not affect the treatment of the present invention. Indeed, it has surprisingly been found that, contrary to hormone replacement therapies described in the art, the effectiveness of the treatment of the present invention is not affected by the subject's BMI value. In this specific embodiment, the hormone therapy of the present invention is preferably administered to subjects with a BMI of 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 administered to overweight or obese subjects. As used herein, "BMI" (or its unabbreviated form, "Body Mass Index") refers to an index related to a subject's weight and height, calculated by dividing the subject's weight in kilograms by the subject's height in square meters. A female subject is classified as "overweight" if her BMI is 27.3 or more, and as "obese" if her BMI is 30 or more.

[0125] It will be apparent that both the compositions and dosage units may suitably contain one or more pharmaceutically acceptable excipients. As used herein, the term "pharmaceutically acceptable" means consistent with usage in the art, compatible with the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof.

[0126] The subject matter of the composition of the present invention is particularly suitable for formulation as an oral dosage unit, which provides favorable pharmacokinetic properties in subjects with impaired liver function, as evidenced by the examples enclosed herein.Preferably, the oral dosage unit for use according to the present invention is swallowed.More preferably, the oral dosage unit for use according to the present invention is swallowed as a whole.However, dosage units formulated for other administration methods, such as, but not limited to, sublingual, buccal, or sublabial dosage units, are also envisioned.

[0127] "Oral dosage unit" encompasses any dosage unit intended and / or suitable for administration to a subject via the oral cavity. As described in more detail below, for oral dosage units of the present invention, without limitation, ingestion (immediate or near-immediate) of the dosage unit is contemplated.

[0128] The oral dosage units described herein may be solid or semi-solid dosage units such as tablets, capsules, cachets, pellets, pills, powders, or granules, or any combination thereof. For example, the oral dosage unit of the present subject matter may be a tablet containing estetrol component-containing granules or a capsule containing estetrol component-containing granules. The term "solid or semi-solid dosage unit" also encompasses capsules containing a liquid, such as an oil, in which the estetrol component and / or any progestogen component is dissolved or dispersed.

[0129] Tablets and equivalent solid and semi-solid dosage units may suitably contain materials such as binders (e.g., hydroxypropyl methylcellulose, polyvinylpyrrolidone (povidone, PVP), other cellulose materials and starches), diluents (e.g., lactose (monohydrate) and other sugars, starches (e.g., corn starch), dicalcium phosphate and cellulose materials), disintegrants (e.g., starch polymers and cellulose materials (e.g., sodium starch glycolate)), and lubricants (e.g., magnesium stearate and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means well described in the art (e.g., Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing the estetrol component in manufacturing dosage units include wet granulation (e.g., using aqueous or organic solutions), direct compression, 3D printing, or by coating carrier particles with the estetrol component using organic or inorganic solvents.

[0130] As mentioned above, the composition, and thus the (oral) dosage unit, may comprise one or more suitable excipients. The term "excipient", which is used interchangeably herein and in the art with "carrier", refers to any solvent, diluent, buffer (including but not limited to neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate buffer, or phosphate buffer), solubilizer (Tween 80 or polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (including, but not limited to, EDTA or glutathione), amino acids, proteins, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, sweeteners, colorants, flavors, fragrances, thickeners, any agents suitable for achieving a depot effect, coating agents, antifungal agents, any preservatives (including, but not limited to, Thimerosal™, benzalkonium chloride, or benzyl alcohol), antioxidants (including, but not limited to, ascorbic acid, sodium metabisulfite), isotonicity agents, absorption delaying agents, adjuvants, bulking agents (including, but not limited to, lactose, mannitol), and any other ingredients that may affect any parameter or characteristic of the oral dosage units of the present subject matter. Those skilled in the art will understand that one or more excipients may be used in an oral dosage unit, provided that the one or more excipients are compatible with one or more pharmaceutical ingredients (i.e., in the context of the present invention, at least the estetrol ingredient) and result in a pharmaceutically acceptable formulation.

[0131] In certain embodiments, the excipient is an active pharmaceutical ingredient excipient, a binder excipient, a carrier excipient, a co-processing excipient, a coating system excipient, a controlled release excipient, a diluent excipient, a disintegrant excipient, a dry powder inhalation excipient, an effervescent system excipient, an emulsifier excipient, a lipid excipient, a lubricant excipient, a modified release excipient, a penetration enhancer excipient, a permeation enhancer excipient, a pH adjuster excipient, a plasticizer excipient, a preservative excipient, a preservative excipient, a The excipient may be a vehicle, a solubilizer excipient, a solvent excipient, a sustained-release excipient, a sweetener excipient, a taste-forming excipient, a thickener excipient, a viscosity-improving excipient, a filler excipient, a compression excipient, a dry granulation excipient, a hot-melt extrusion excipient, a wet granulation excipient, a rapid-release excipient, a bioavailability-enhancing excipient, a dispersing excipient, a solubility-enhancing excipient, a stabilizer excipient, a capsule-filling excipient, or any combination thereof.Those skilled in the art will recognize that the use of such vehicles and agents for pharmaceutically active substances is common practice, and therefore the incorporation of these excipients is well known in the art.It is clear that all components used should be non-toxic at the concentration contained in the final pharmaceutical composition, and in this respect, at least the estetrol component, should not adversely affect the activity of one or more pharmaceutically active ingredients.

[0132] Optionally, the composition is contained in a tablet and includes, in addition to estetrol, excipients that perform the functions of a first or additional filler, superdisintegrant, binder, disintegrant, and lubricant. An excipient can perform several of these functions. Thus, a binder can also be a disintegrant. A tablet can also contain two or more excipients that perform the same function, such as two different binders. In a preferred embodiment, the composition is contained in a tablet containing estetrol, lactose, sodium starch glycolate, corn / cornstarch, povidone, and magnesium stearate. Preferably, the composition is contained in a tablet containing estetrol monohydrate, lactose monohydrate, type A sodium starch glycolate, corn / cornstarch, povidone K30, and magnesium stearate. Optionally, the tablet is coated with a coating agent. In a further optional embodiment, the coating agent includes hypromellose, hydroxypropyl cellulose, titanium dioxide, red iron oxide, hydrogenated cottonseed oil, and talc. By way of example and not limitation, suitable coatings are AquaPolish Orange 034.23MS, AquaPolish P Blue 064.65MS, AquaPolish Yellow 024.15MS, or AquaPolish Pink 044.08MS. One skilled in the art will recognize that such coatings may be used in combination with an appropriate amount of purified water. Furthermore, one skilled in the art will understand that any excipients present in any dosage unit, such as an oral dosage unit, should comply with pharmaceutical-grade industry quality standards, such as the European Pharmacopoeia and the United States Pharmacopoeia-National Formulary (USP-NF).

[0133] The oral dosage unit may be suitable for, or even specifically manufactured for, sublingual, buccal, and / or sublabial administration. In such embodiments, the solid dosage unit can rapidly release the estetrol component upon contact with an aqueous solvent such as saliva. Thus, in these embodiments, the solid dosage unit is an orally dispersible dosage unit that releases at least about 50%, preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 80%, and most preferably more than about 80% of the estetrol component within about 5 minutes, preferably within about 3 minutes, more preferably within about 2.5 minutes, more preferably within about 90 seconds, and most preferably within about 90 seconds. The oral dosage unit may be an orally dispersible dosage unit. In such embodiments, the dosage unit rapidly disintegrates in the oral cavity upon contact with saliva, dispersing the estetrol component in the saliva and allowing it to be absorbed through the mucosal lining of the oral cavity. Those skilled in the art will know how to determine the release rate of the estetrol component from a dosage unit. Non-limiting standardized tests generally accepted in this field include European Pharmacopoeia 2.9.1 ("Disintegration of Tablets and Capsules") and United States Pharmacopoeia <701> ("Disintegration") (for example, using water as the disintegration medium).

[0134] As used herein, the term "sublingual" refers to a pharmacological route of administration in which the estetrol component diffuses through the tissues under the tongue into the blood.

[0135] As used herein, the term "buccal" refers to the pharmacological route of administration whereby the estetrol component diffuses into the blood through the tissues of the oral vestibule, the area of ​​the mouth between the inner lining of the buccal mucosa (buccal mucosa) and the teeth / gingiva.

[0136] As used herein, the term "sublabial" refers to a pharmacological route of administration in which the estetrol component is placed between the lip and gum.

[0137] In certain embodiments, the estetrol component is contained in an immediate release dosage unit or composition.

[0138] In certain embodiments, the estetrol component is formulated into a solid dosage unit, including, but not limited to, a hard capsule, a soft capsule, a tablet, a coated tablet such as a lacquer tablet or a dragee, a granule, an aqueous or oily solution, a syrup, an emulsion, a suspension, an ointment, a paste, a lotion, a gel, an inhalant, or a suppository. In embodiments in which an effective amount of the estetrol component is administered orally, the oral dosage unit according to the present invention is preferably a solid or semi-solid dosage unit, such as a tablet, a capsule, a cachet, a pellet, a pill, a powder, or a granule. The term "solid or semi-solid dosage unit" also includes a capsule containing a liquid, such as an oil, in which the estetrol component and / or any progestogen component is dissolved or dispersed. Tablets and equivalent solid and semi-solid dosage units may suitably contain materials such as binders (e.g., hydroxypropylmethylcellulose, polyvinylpyrrolidone, other cellulose materials and starches), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulose materials), disintegrants (e.g., starch polymers and cellulose materials), and lubricants (e.g., stearic acid and talc). These tablets and equivalent solid dosage units may be prepared by any suitable means well described in the art (e.g., Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing the estetrol component when producing dosage units include wet granulation (e.g., using an aqueous or organic solution), direct compression, 3D printing, or coating carrier particles with the estetrol component using an organic or inorganic solvent.

[0139] By way of example and not limitation, oral dosage units containing the compositions of the presently disclosed subject matter can be manufactured by a process involving wet granulation. Those skilled in the art will understand that the wet granulation process may suitably include the following sequential steps: splitting and sieving the active ingredient(s) and excipients, blending the sieved material in a processor, granulating the granules, screening (i.e., further sieving), and one or more blending steps of blending the sieved granules with one or more additional excipients. Thereafter, if desired in consideration of the final dosage unit, the granules can be compressed, for example, into tablets (optionally including a tablet coating step).

[0140] As described above, the compositions described herein unexpectedly provide a favorable pharmacokinetic profile in female subjects with impaired liver function. The compositions are particularly suitable for oral use to alleviate estrogen deficiency symptoms (e.g., but not limited to, menopause-related symptoms) in this subject population. The favorable pharmacokinetic profile includes numerous parameters, including, but not limited to, the geometric mean (GM) plasma concentration of estetrol, Cmax, AUCinf, and GM T1 / 2. Additionally, metabolites of estetrol also exhibit favorable pharmacokinetic properties, as reflected, for example, by the AUCinf of E4-3-glucuronide. "E4-3-glucuronide," also referred to interchangeably by its formal name "estetrol-3-glucuronide," is a known and well-known metabolite of estetrol.

[0141] Those skilled in the art will recognize the commonly accepted meaning of the term "geometric mean," so that the geometric mean is the product of those values ​​(i.e., n Recognize that the use of √x1.x2....xn) indicates a typical value for a set of numbers.

[0142] When the abbreviation "AUC" is used herein, it means "area under the curve" and should be understood to be interpreted as commonly used in the art, i.e., as the definite integral of the curve describing the variation of drug concentration in plasma as a function of time. As used herein, AUC0-24 represents the AUC from time "0", which is the time of administration of the COC to the subject, to the 24-hour time point. In the context used herein, "AUC" can be interpreted as bioavailability. Accordingly, AUCinf indicates the sum of AUC (from measurement time "0" to infinity). "Cmax" referred to herein is the maximum or peak plasma concentration reached by a drug, e.g., drospirenone. Unless otherwise specified, AUC and Cmax values ​​can be measured by radioimmunoassay and / or HPLC and LC MS / MS, assays known to those skilled in the art (see, e.g., Jaffe, Methods of Hormone Radioimmunoassay, 2002). nd edition, Academic press, 1979, and Chen and Hsu, Development of a LC-MS / MS-based method for determining metolazone concentrations in human plasma: Application to a pharmacokinetic study, J of Food and Drug Anal, 2013). As used herein, "T" refers to the amount of time required for the drug concentration measured in plasma (or other biological matrix) to decrease to exactly half of its starting concentration or amount.

[0143] In the following embodiments, certain parameters that define a particular pharmacokinetic profile are discussed. It should be understood that these parameters are defined relatively and expressed as values ​​and / or ranges relative to subjects with normal liver function. It is clear that in the context of the present invention, a "subject with normal liver function" generally corresponds to a subject with impaired liver function (e.g., age, menopausal status, ethnicity, BMI, etc.) and relates to a subject who differs from the subject with impaired liver function only by the absence of substantial liver dysfunction. It is within the capabilities of a medical professional to classify a subject as having normal liver function or impaired liver function using any means or method deemed necessary by the medical professional, such as, but not limited to, one or more biomarkers. Optionally, a subject with normal liver function in the context of the present invention may be defined as a subject having a Child-Pugh score of less than 5, preferably less than 4, more preferably less than 3, even more preferably less than 2, and most preferably a Child-Pugh score of 1. Optionally, a subject with normal liver function in the context of the present invention may be defined as a subject with a Child-Pugh score of 1 to a maximum of 4, preferably a Child-Pugh score of 1 to a maximum of 3, more preferably a Child-Pugh score of 1 to a maximum of 2.

[0144] Thus, in certain embodiments, the composition formulated as an oral dosage unit provides a pharmacokinetic profile in subjects with hepatic impairment upon single administration characterized by a geometric mean Cmax of estetrol that is less than three times the corresponding GM Cmax in subjects with normal hepatic function. Preferably, the GM Cmax of estetrol is provided in subjects with hepatic impairment that is 2.5 times or less, more preferably 3 times or less, and even more preferably 1.7 times or less the corresponding GM Cmax in subjects with normal hepatic function. Optionally, the hepatically impaired subject is a subject characterized by mild, moderate, or severe hepatic impairment as defined by the Child-Pugh score. In a further embodiment, the composition formulated as an oral dosage unit provides a pharmacokinetic profile in subjects with mild hepatic impairment upon single administration characterized by a GM Cmax of estetrol that is about 1.5 to about 2.0 times, preferably about 1.7 times the corresponding GM Cmax in subjects with normal hepatic function. In a further alternative embodiment, the composition formulated as an oral dosage unit provides a pharmacokinetic profile in subjects with moderate hepatic impairment upon single administration, characterized in that the GM Cmax of estetrol is about 1.8 to about 2.5 times, preferably about 1.9 times, the corresponding GM Cmax in subjects with normal hepatic function. In a further alternative embodiment, the composition formulated as an oral dosage unit provides a pharmacokinetic profile in subjects with severe hepatic impairment upon single administration, characterized in that the GM Cmax of estetrol is about 5 to about 6 times, preferably about 4.5 times, the corresponding GM Cmax in subjects with normal hepatic function.

[0145] A further preferred pharmacokinetic parameter following single administration of a composition formulated as an oral dosage unit to subjects with impaired hepatic function is no or generally no difference in peak exposure levels of the estetrol metabolite E4-3-glucuronide. Accordingly, optionally, the composition is characterized by a peak E4-3-glucuronide exposure level that is not significantly different from the peak E4-3-glucuronide exposure level following single administration of a composition formulated as an oral dosage unit to subjects with normal hepatic function. In a further embodiment, the peak E4-3-glucuronide exposure level in subjects with impaired hepatic function is about 90% to about 110% of the peak E4-3-glucuronide exposure level in subjects with normal hepatic function. Preferably, the peak E4-3-glucuronide exposure level in subjects with impaired hepatic function is about 95% to about 105%, preferably about 97% to about 102.5%, of the peak E4-3-glucuronide exposure level in subjects with normal hepatic function.

[0146] Another preferred pharmacokinetic parameter is a GM AUC of estetrol and / or E4-3-glucuronide upon single administration of the composition formulated as an oral dosage unit to a subject with hepatic impairment that is not significantly different from (i.e., similar to) the GM AUC of estetrol and / or E4-3-glucuronide upon single administration of the composition formulated as an oral dosage unit to a subject with normal hepatic function. Optionally, the GM AUC of estetrol and / or E4-3-glucuronide in subjects with mild or moderate hepatic impairment is about 90% to about 110% of the GM AUC of estetrol and / or E4-3-glucuronide in subjects with normal hepatic function. Preferably, the GM AUC of estetrol and / or E4-3-glucuronide in subjects with mild or moderate hepatic impairment is not more than about 1.1 times the GM AUC of estetrol and / or E4-3-glucuronide in subjects with normal hepatic function. Preferably, the GM AUC of estetrol and / or E4-3-glucuronide in subjects with severe hepatic impairment is not more than about 2 times the GM AUC of estetrol and / or E4-3-glucuronide in subjects with normal hepatic function.

[0147] An even more preferred pharmacokinetic parameter upon single administration of the composition formulated as an oral dosage unit to a subject with hepatic impairment is a similar GM T1 / 2 of metabolites such as estetrol and / or E4-3-glucuronide when compared to the respective GM T1 / 2 upon single administration of the composition as an oral dosage unit to a subject with normal hepatic function. Preferably, the GM T1 / 2 of metabolites such as estetrol and / or E4-3-glucuronide in a subject with mild hepatic impairment is similar when compared to the respective GM T1 / 2 upon single administration of the composition as an oral dosage unit to a subject with normal hepatic function.

[0148] In combination with one or more favorable pharmacokinetic profile parameters described herein, the number, frequency, and / or severity of adverse effects (AEs) do not differ between a subject population with hepatic impairment and a subject population with normal hepatic function. In a further embodiment, the number, frequency, and / or severity of treatment-emergent adverse effects (TEAEs) do not differ between a subject population with hepatic impairment and a subject population with normal hepatic function. It should be recognized that a treatment-emergent adverse effect is an adverse event that occurs between the time of the first intake of the clinical trial and the final visit, or any pre-existing event that worsens in either intensity or frequency after exposure to treatment. Thus, TEAEs encompass not only newly emerging treatment-emergent adverse events, but also worsening of existing adverse events that result from treatment with the compositions described herein. Treatment-emergent adverse effects are not particularly limited in the context of the present invention and include, by way of example and not limitation, bloating, breast tenderness, breast swelling, swelling in other parts of the body, generalized feeling of illness, leg cramps, headache, indigestion, diarrhea, and vaginal bleeding.

[0149] It is noteworthy that when using the subject compositions of the present invention, the number, frequency, and / or severity of adverse effects are not different between a subject group with hepatic dysfunction and a subject group with normal hepatic function.Therefore, the compositions described herein are safe and well tolerated in subjects characterized by normal hepatic function, mild hepatic dysfunction, moderate hepatic dysfunction, and severe hepatic dysfunction.Optionally, the risk of a subject experiencing one or more treatment-emergent adverse events is not different between a subject group with hepatic dysfunction and a subject group with normal hepatic function.Optionally, the subject is a subject with hepatic dysfunction that is not considered to be severe hepatic dysfunction (i.e., a subject with mild or moderate hepatic dysfunction).

[0150] As detailed above, the compositions that are the subject of the present invention contain an estetrol component equivalent to a daily dose of about 15 mg to about 25 mg of estetrol. Obviously, this includes embodiments in which the composition contains about 15 mg to about 25 mg of estetrol component (those skilled in the art will understand that this is encompassed by the definition "equivalent to about 15 mg to about 25 mg of estetrol"). In a further embodiment, the composition contains about 15 mg to about 20 mg of estetrol component, preferably, the estetrol component is estetrol, estetrol monohydrate, or an ester of estetrol. Preferably, the composition contains about 15 mg to about 25 mg of estetrol monohydrate, more preferably about 15 mg to about 20 mg of estetrol monohydrate. In an alternative embodiment, the composition contains about 15 mg to about 25 mg of estetrol or an ester thereof, preferably about 15 mg to about 20 mg of estetrol or an ester thereof.

[0151] Optionally, the composition contains about 17 mg of the estetrol component, or an amount of the estetrol component equivalent to a daily dose of about 17 mg of the estetrol component. In a further embodiment, the composition contains about 17 mg of estetrol monohydrate, or an amount of the estetrol component equivalent to a daily dose of about 17 mg of estetrol monohydrate. In an alternative further embodiment, the composition contains about 17 mg of estetrol or an ester thereof, or an amount of the estetrol component equivalent to a daily dose of about 17 mg of estetrol or an ester thereof.

[0152] In an alternative embodiment, the composition comprises about 12 mg to about 28 mg of the estetrol component, or an amount of the estetrol component equivalent to a daily dose of about 12 mg to about 28 mg of estetrol. In a preferred alternative embodiment, the composition comprises about 12 mg to about 28 mg of estetrol monohydrate, or an amount of the estetrol component equivalent to a daily dose of about 12 mg to about 28 mg of estetrol monohydrate. In a further alternative embodiment, the composition comprises about 12 mg to about 28 mg of estetrol or an ester thereof, or an amount of the estetrol component equivalent to a daily dose of about 12 mg to about 28 mg of estetrol or an ester thereof.

[0153] Optionally, the composition contains about 15 mg of the estetrol component, or an amount equivalent to about 15 mg of estetrol. Optionally, the composition can contain about 15 mg of estetrol. In a further optional embodiment, the composition contains about 15 mg of estetrol monohydrate.

[0154] Alternatively, the composition contains about 20 mg of the estetrol component, or an amount equivalent to about 20 mg of estetrol. Optionally, the composition can contain about 20 mg of estetrol. In a further optional embodiment, the composition contains about 20 mg of estetrol monohydrate.

[0155] The estetrol component may contain multiple particles in the composition. The particle size of the estetrol component is not particularly limited. By way of example and not limitation, suitable particle sizes can be expressed using particle size distribution values ​​such as, but not limited to, D(10), D(50), and D(90). Those skilled in the art will be familiar with how to interpret these parameters. "Particle size distribution," commonly abbreviated as "PSD," is a numerical value that represents the relative amount of particles according to size, preferably expressed by mass. For example, the value "D10" or "Dv(10)" indicates the point in the size distribution that occupies 10% of the total volume (i.e., the particle population) of the sample, counting from the smallest. For example, a D10 of 10 μm means that 10% of the sample has a size up to 10 μm. The D10, D50, and D90 values ​​are routinely used in the art to calculate the span of a sample, which indicates the width of the size distribution. Span is calculated according to the following formula: (D90-D10) / D50. Those skilled in the art will appreciate that representative particle size distribution values ​​can only be derived from representative samples.

[0156] Optionally, the estetrol particles have a D(10) of about 0.5 μm to about 10 μm, preferably about 1 μm to about 5 μm, and more preferably about 1.5 μm to about 2.5 μm. Optionally, the estetrol particles have a D(50) of less than 20 μm, preferably less than 12 μm, more preferably about 5 μm to about 15 μm, preferably about 6 μm to about 12 μm, more preferably about 7 μm to about 11 μm, and most preferably about 8 μm to about 12 μm. Optionally, the estetrol particles have a D(90) of about 15 μm to about 50 μm, preferably about 20 μm to about 30 μm, and more preferably about 22 μm to about 28 μm.

[0157] Numerous measurement techniques are available for determining particle size distribution values, including sieve analysis, air sieve analysis, photoanalysis, optical counting, electrical resistance counting, sedimentation, laser diffraction, laser obscuration, transit time, acoustic spectroscopy, ultrasonic attenuation microscopy, cascade impactor, or any combination thereof. Unless otherwise specified, the particle size distribution values ​​in this disclosure are obtained by laser diffraction analysis. Laser diffraction analysis, interchangeably referred to in the art as laser diffraction spectroscopy, is a particle measurement technique based on the interpretation of the diffraction pattern of a laser passed through an object. Laser diffraction can measure the geometric dimensions of particles. Laser diffraction protocols have been described in detail many times in the art (e.g., reviewed in detail in Eshel et al., Soil Science Society of America Journal, 2004, in the context of particle analysis).

[0158] Optionally, the estetrol particles are further granulated to form larger granules. In certain embodiments, the estetrol component is contained in the composition as a multiplicity of larger granules having a volume median diameter of from about 100 μm to about 4000 μm, preferably from about 200 μm to about 1000 μm, and more preferably from about 200 μm to about 600 μm.

[0159] In certain embodiments, the estetrol component is the sole (i.e., single, only) pharmaceutically active component of the composition. The term "pharmacologically active component" is used interchangeably with "pharmacologically active agent" throughout this disclosure and should be interpreted in accordance with the World Health Organization's definition of the term: "a substance used in a finished pharmaceutical product (FPP) that is intended to exhibit pharmacological activity or that is otherwise intended to have a direct effect on the diagnosis, cure, mitigation, treatment, or prevention of disease, or that is intended to have a direct effect on the restoration, correction, or modification of a physiological function in humans." More specifically, in certain embodiments, the progestogen component is not co-administered with the estetrol component (not in the same composition or oral dosage unit, nor in a co-administered additional composition or dosage unit). In embodiments in which a subject with impaired liver function has undergone a hysterectomy, the estetrol component is preferably administered as the sole pharmaceutically active component.

[0160] In an alternative embodiment, the composition comprises at least one further pharmaceutically active ingredient in addition to the estetrol component.

[0161] Optionally, the oral dosage form includes a progestogen component as an additional pharmaceutically active ingredient, or the method of treatment includes co-administering a progestogen component to a subject. While embodiments in which the progestogen component is included in the same composition as the estetrol component are preferred, embodiments in which the progestogen component is administered in a separate composition or dosage unit are also envisioned.

[0162] The terms "progestogen," "gestagen," or "gestogen," as well as the derivative term "progestogen component," used both herein and in the art, refer to any molecule that produces an effect similar to that of the natural female sex hormone progesterone in a subject's body. Progestogens are thought to be agonists of the progesterone receptor, and their function has been thoroughly investigated in the art (especially as discussed in Kuhl, Climacteric, 2005). Progestins are a subgroup of progestogens, including synthetic progestogens. The above terms can be used interchangeably in the art, but it is generally understood that when referring to progestins, synthetic progestogens are meant.

[0163] Examples of progestogen components contemplated by the present invention include, but are not limited to, levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol, mesirogestron, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone ... Luetynodrel, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17α)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one, tibolone, trimegestone, algestone-acetophenide, nestrone, promegestone, 17-hydroxyprogesterone ester, 19- nor-17hydroxyprogesterone, 17alpha-ethynyltestosterone, 17alpha-ethynyl-19-nortestosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethynylgon-4-en-3-one oxime, 6beta,7beta;15beta,16beta-dimethylene-3-oxo-17-pregna-4,9(11)-diene-21,17beta-carbolactone or tanaproget, and precursors of these components that can liberate these progestogens in vivo.

[0164] The progestogen component may be selected from the group comprising progesterone, drospirenone, norethisterone, norethisterone acetate (NETA), dydrogesterone, levonorgestrel (LNG), etonogestrel, norgestrel, nomegestrol, nomegestrol acetate (NOMAC), trimegestone, nestorone, dydrogesterone, gestodene, desogestrel, norgestimate, cyproterone acetate, dienogest, and chlormadinone. Particularly preferred progestogens in this context include, but are not limited to, drospirenone, progesterone, and dydrogesterone.

[0165] In certain embodiments, the progestogen is a naturally occurring progestogen, hi other embodiments, the progestogen is a progestin.

[0166] "Drospirenone" (abbreviated as DRSP, PubChem CID: 68873) is an example of a progestogen component, and is widely used in combined oral contraceptives (commonly abbreviated as COCs) due to its combination of antimineralocorticoid and antiandrogenic activity with generally low off-target activity. Drospirenone-containing COCs are generally referred to as fourth-generation COCs. Non-limiting examples of commercially available COCs containing drospirenone are known as "Yaz™" and "Yasmin™." An example of a drospirenone-only progestogen pill is "Slynd™," which is also commercially available. Additionally, hormone replacement therapy compositions containing estradiol and estrogens, such as drospirenone, are available, such as "Angeliq™." Alternatively, drospirenone can be expressed by its molecular formula C 24 H 30 O3 or may be represented in the art by structural formula (III): TIFF2026501201000004.tif59170

[0167] It is understood that when the term "drospirenone" is used herein, any drospirenone derivative is also envisaged.

[0168] The methods described herein may include administering drospirenone to a subject receiving an estetrol component. In certain embodiments, the composition may contain about 0.25 mg to about 10 mg of drospirenone, or an amount of the progestogen component equivalent to a daily dose of about 0.25 mg to about 10 mg of drospirenone. Preferably, the composition may contain about 1 mg to about 4 mg of drospirenone, or an amount of the progestogen component equivalent to a daily dose of about 1 mg to about 4 mg of drospirenone. More preferably, the composition may contain about 1 mg to about 3 mg of drospirenone, or an amount of the progestogen component equivalent to a daily dose of about 1 mg to about 3 mg of drospirenone. Even more preferably, the composition may contain about 2.5 mg to about 3.5 mg of drospirenone, or an amount of the progestogen component equivalent to a daily dose of about 2.5 mg to about 3.5 mg of drospirenone.

[0169] Optionally, the composition contains an estetrol component, preferably estetrol monohydrate, in an amount of about 15 mg to about 25 mg, and drospirenone in an amount of about 0.25 mg to about 10 mg. In a further optional embodiment, the composition contains about 15 mg to about 20 mg of an estetrol component, preferably estetrol monohydrate, and about 1 mg to about 4 mg of drospirenone. In yet a further optional embodiment, the composition contains about 15 mg or about 20 mg of an estetrol component, preferably estetrol monohydrate, and about 3 mg of drospirenone.

[0170] "Progesterone" (commonly abbreviated as "P4"; PubChem CID 5994) is an endogenous steroid and progestogenic hormone involved in the female menstrual cycle, pregnancy, and embryonic development, and constitutes the body's major progestogen. Progesterone is a well-documented substance used in the art for indications including, but not limited to, contraception, female hormone replacement therapy, and feminizing hormone therapy. Progesterone is a compound represented by its structural formula C 21 H 30O2 or can be shown in the art by reference to structural formula (IV): TIFF2026501201000005.tif53170

[0171] It is understood that when the term "progesterone" is used herein, any progesterone derivative is also contemplated.

[0172] In certain embodiments, the composition may contain about 10 mg to about 500 mg, preferably about 25 mg to about 300 mg, of progesterone, or an amount of the progestogen component equivalent to a daily dose of about 10 mg to about 500 mg, preferably about 25 mg to about 300 mg, of progesterone. Preferably, the composition may contain about 100 mg to about 200 mg of progesterone, or an amount of the progestogen component equivalent to a daily dose of about 100 mg to about 200 mg of progesterone.

[0173] Optionally, the composition contains an estetrol component, preferably estetrol monohydrate, in an amount of about 15 mg to about 25 mg, and progesterone in an amount of about 25 mg to about 300 mg. In a further optional embodiment, the composition contains about 15 mg to about 20 mg of an estetrol component, preferably estetrol monohydrate, and about 100 mg to about 200 mg of progesterone. In yet a further optional embodiment, the composition contains about 15 mg or about 20 mg of an estetrol component, preferably estetrol monohydrate, and about 100 mg to about 200 mg of progesterone. In another embodiment, progesterone is used in a daily dose of 100 mg to 200 mg when used sequentially, for example, administered for about 14 days each month. In yet another embodiment, progesterone is used in a daily dose of 100 mg to 200 mg when it is used sequentially, for example, when the estetrol component is orally administered at a dose of 15 mg or 20 mg once daily for at least 12 weeks, but not more than 13 weeks, for about 14 days after the estetrol component is orally administered. Preferably, progesterone is used once daily for 14 consecutive days after completion of treatment with the estetrol component.

[0174] The progestin "dydrogesterone" (PubChem CID 9051), referred to interchangeably in the art as "isopregnenone" and "dydrogesterone," is used for a number of medical indications, including dysfunctional bleeding, infertility, dysmenorrhea, endometriosis, and menopausal hormone therapy. Dydrogesterone has the structural formula C 21 H 28 O2 or structural formula (V): TIFF2026501201000006.tif58170

[0175] It is understood that when the term "dydrogesterone" is used herein, dydrogesterone derivatives are also contemplated.

[0176] In certain embodiments, the composition may contain a progestogen component in an amount equivalent to a daily dose of about 1 mg to about 20 mg of dydrogesterone, or about 5 mg to about 10 mg of dydrogesterone. Preferably, the composition may contain a progestogen component in an amount equivalent to a daily dose of about 1 mg to about 20 mg of dydrogesterone, or about 5 mg to about 10 mg of dydrogesterone.

[0177] Optionally, the composition contains an estetrol component, preferably estetrol monohydrate, in an amount of about 15 mg to about 25 mg, and dydrogesterone in an amount of about 1 mg to about 20 mg. In a further optional embodiment, the composition contains about 15 mg to about 20 mg of an estetrol component, preferably estetrol monohydrate, and about 5 mg to about 10 mg of dydrogesterone. In yet a further optional embodiment, the composition contains about 15 mg or about 20 mg of an estetrol component, preferably estetrol monohydrate, and about 5 mg to about 10 mg of dydrogesterone.

[0178] In the context of the present invention, other compounds (i.e., ingredients, drugs) may be used in conjunction with the estetrol component for administration to a woman with a uterus. Selective estrogen receptor modulators (SERMs) are contemplated as useful complements to the estetrol component in the methods of the present invention and define a category of such compounds. A preferred SERM for use in the context of the present invention is bazedoxifene. In the methods and compositions further described herein, when a "progestogen component" is referenced, it should be understood that such reference includes SERMs and, in particular, bazedoxifene. 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 15 mg to about 25 mg. Most preferably, bazedoxifene is administered in a daily dose of about 20 mg.

[0179] The composition can be formulated into a dosage unit that is administered to a subject at any time interval deemed appropriate by those skilled in the art. A preferred administration scheme in the context of the present invention is a daily administration scheme (i.e., approximately once every 24 hours). Thus, in such an embodiment, the composition described herein is a daily composition, a daily dosage unit. In another embodiment, the composition is formulated for a multiple-dose administration scheme per day, which is then accumulated to achieve a dose consistent with the present invention, for example, 15 mg to 25 mg of estetrol component.

[0180] Optionally, the dosage units are administered to the subject according to a continuous administration schedule. The terms "continuous" and "successively" as used herein mean that the dosage units are administered at relatively regular intervals without any significant (therapeutic) interruptions. Of course, minor interruptions that do not affect the overall effectiveness of the method of the present invention may occur, and indeed, such deviations are encompassed by the present invention. In a preferred embodiment, more arithmetically, if the longest interval between two subsequent administrations is 3.5 times or less than the average interval, the administration regimen is considered continuous. More preferably, the longest interval is 2.5 times or less, and most preferably 1.5 times or less, of the average interval. By way of example and not limitation, the treatment strategies and methods described herein employ continuous administration of the estetrol component, preferably for a period of at least 10 days, preferably at least 20 days.

[0181] Alternatively, the dosage units are administered to the subject according to a sequential administration schedule. The term "sequentially" should be understood to mean, for example, administration for 10 to 14 days every month or for 14 days every three months. Sequential administration schedules are particularly contemplated when a progestogen component is part of the compositions or treatments described herein.

[0182] A further aspect of the present invention relates to packaging units containing the dosage units described herein. The packaging unit may include at least 14, preferably at least 21, and more preferably at least 28 containers for holding separately packaged, individually removable dosage units, each container containing at least one dosage unit containing about 15 mg to about 25 mg of the estetrol component. Preferably, the separately packaged, individually removable dosage units are oral dosage units. More preferably, each separately packaged, individually removable dosage unit contains about 15 mg or about 20 mg of the estetrol component, preferably about 15 mg or about 20 mg of estetrol monohydrate.

[0183] Optionally, the packaging unit further comprises at least 10, preferably 12, more preferably 14 additional containers for holding separately packaged and individually removable dosage units, each additional container containing at least one dosage unit containing a progestogen component. Optionally, each additional container for holding dosage units containing a progestogen component is visually arranged separately next to the container holding the dosage unit containing the estetrol component if these two dosage units are to be administered on the same day. Optionally, the packaging unit further comprises an equal number of additional containers for holding separately packaged and individually removable oral dosage forms, each additional container containing at least one daily, preferably solid, oral dosage form containing a progestogen, preferably the progestogen being selected from drospirenone, progesterone, and dydrogesterone.

[0184] Those skilled in the art will understand that the above-described embodiments relating to packaging units may equivalently be presented as a kit of parts, including a first packaging unit, e.g., a blister pack, containing a daily oral dosage unit comprising an estetrol component, and a second, separate packaging unit, e.g., a second, separate blister pack, containing a daily oral dosage unit comprising a progestogen.

[0185] Those skilled in the art will further appreciate that within the scope of the present invention, each packaging unit, e.g., a blister pack, may be numbered or otherwise marked.

[0186] The packaging unit may be provided in any suitable packaging means known in the art, non-limiting examples being a troche, sachet, pouch, bottle, film, spray, microcapsule, implant, rod or blister pack.

[0187] By way of example and not limitation, each packaging unit may be a sealed blister pack with a cardboard, paperboard, or foil plastic backing and enclosed in a suitable cover. Also contemplated in any one of the aspects defined herein are packaging units such as bottles. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle characterized by a color that can reduce or prevent degradation of the contents of the bottle, for example, by UV light, while maintaining a degree of transparency that allows visual inspection of the contents of the bottle. Suitable colors include, but are not limited to, amber, cobalt, or vintage green.

[0188] In certain embodiments of the invention, the packaging unit comprises 28 containers, or a multiple of 28 containers, for example, 2 to 12 times 28 containers.

[0189] While the present invention has been described in conjunction with detailed embodiments thereof, it is evident from the foregoing description that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims. Aspects and embodiments of the invention disclosed herein are further supported by the following non-limiting examples. The following specific experimental examples are provided in support of the claimed invention, but should not be construed as limiting the scope of the invention. [Example]

[0190] Example 1. Clinical Study Report (CSR) in Subjects with Hepatic Dysfunction 1. Purpose of the clinical trial 1.1 Main purpose The PK of E4 will be assessed in subjects with different categories of hepatic impairment and in subjects with normal hepatic function. 1.2 Secondary Objectives The PK of E4 metabolites will be assessed in subjects with different categories of hepatic impairment and in subjects with normal hepatic function. To assess the safety of E4 in subjects with different categories of hepatic impairment and in subjects with normal hepatic function.

[0191] 2. Research Plan 2.1 Clinical trial design and planning in general The following section summarizes the study design and plan. See also Tables 2 and 3 in Section 2.5.1 for a summary of clinical procedures and assessments.

[0192] 2.1.1 Types of clinical trials This was a phase 1, multicenter, open-label, PK and safety study of a single oral dose of E4 monohydrate 20 mg in female subjects with normal hepatic function (Group 1), mild hepatic impairment (Group 2), moderate hepatic impairment (Group 3), and severe hepatic impairment (Group 4) as defined using the Child-Pugh classification at screening.

[0193] The study consisted of an eligibility screening period (within 28 days prior to study drug administration), an assessment period (home stay period and outpatient visits (including a single oral dose of 20 mg E4 on Day 1)), and a follow-up visit. All subjects were restricted to the study site from Day -1 (the day before dosing) through Day 4 and returned to the site daily from Day 5 through Day 9. Alternatively, with agreement with the investigator, subjects could remain at home for an extended period. A follow-up visit occurred on Day 14 (± 2 days).

[0194] 2.1.2 Screening Period All subjects were screened within 28 days prior to receiving study drug.

[0195] Subjects signed a study-specific informed consent form (ICF) prior to the study-specific screening procedures being conducted. Written informed consent was obtained for all subjects, regardless of study eligibility, and the signed ICF was stored at the CRO and provided to the subjects. Liver function was assessed for subjects with liver impairment according to the Child-Pugh classification during the screening period. The results of this assessment were used to classify subjects into groups with mild, moderate, and severe liver impairment (see Section 2.3). Subjects with liver impairment were assigned to these groups based on results obtained within 15 days prior to dosing. If screening was performed 15 days prior to dosing, the assessment used for the Child-Pugh classification was repeated, and the most recent results were used to classify each subject into the corresponding liver impairment group. If this assessment was performed on day -2, subjects could choose to begin their inpatient period thereafter or attend the unit as an outpatient.

[0196] After signing the ICF, eligibility screening consisted of the assessments shown in Table 2.

[0197] 2.1.3 Evaluation Period All subjects arrived at the study site in the morning of Day -1 in a fasted state (no food for at least 8 hours, water was permitted) and underwent scheduled assessments to confirm eligibility as outlined in the inclusion and exclusion criteria (Sections 2.3.1 and 2.3.2, respectively). On the morning of Day 1, after an overnight fast, subjects received an oral dose of 20 mg of E4 monohydrate and remained at the study site. Study-related assessments were conducted at the time points indicated in the schedule of assessments in Table 2.

[0198] Serial blood sampling for PK assessment began on Day 1 and continued through Day 9 according to the pharmacokinetic sampling schedule shown in Table 3.

[0199] On day 4, subjects could leave the study site and return to outpatient care from days 5 through 9. Alternatively, at the investigator's discretion, subjects could extend their stay at home until day 9.

[0200] For a detailed overview of the evaluation, see Section 2.5.1 and the evaluation schedule (Table 2).

[0201] 2.1.4 Follow-up A follow-up examination was performed on day 14 (± 2 days). For a detailed overview of assessments, see Section 2.5.1 and the schedule of assessments (Table 2).

[0202] 2.2 Clinical trial design considerations This clinical trial complied with the guidelines for clinical trials involving subjects with hepatic impairment, as recommended by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

[0203] According to the objectives, a parallel design was used to examine potential differences in PK profiles between subjects with different stages of hepatic impairment and subjects with normal hepatic function. Liver function was scored according to the Child-Pugh classification recommended in the FDA and EMA guidelines (FDA Guidance for Industry, Pharmacokinetics in Patients with Impaired Hepatic Function, 2003; EMA Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function, 2005).

[0204] Initially, two subjects were enrolled in the hepatic impairment groups (Groups 2, 3, and 4). Upon completion of those two subjects in a particular group on Day 5, a review of the safety laboratory data for that group was performed. The results of this data review were satisfactory (see Section 2.8), allowing the remaining subjects in that group to be enrolled.

[0205] This was an open-label trial, which required all subjects to receive the same treatment and be assigned to the appropriate liver function group.

[0206] 2.3 Selection of study population Approximately 32 female subjects were planned to be enrolled in the trial: 24 subjects with liver dysfunction (8 in each severity group: mild, moderate, and severe), and 8 subjects with normal liver function as a control group. Subjects could be rotated or additional subjects enrolled to ensure a minimum of 6 evaluable subjects per group and sufficient subjects for matching.

[0207] Liver function was assessed in subjects with liver dysfunction (cirrhosis) using the Child-Pugh scoring system (Table 1) and clinical test results at screening.

[0208] TIFF2026501201000007.tif107170

[0209] Liver function groups are defined as follows: Group 1: normal liver function Group 2: Mild liver dysfunction (Child-Pugh score 5-6) ** ) Group 3: Moderate liver dysfunction (Child-Pugh score 7-9) * ) Group 4: Severe liver dysfunction (Child-Pugh score 10-14) * ) ** Subjects with encephalopathy greater than grade 2 were not enrolled.

[0210] The control group (Group 1) was matched with the liver dysfunction population in terms of age, body mass index (BMI), and smoking habits. Subjects with normal liver function were enrolled after dosing at least 50% of the liver dysfunction subjects in each group, and the median, minimum, and maximum age and BMI of Groups 2 to 4 were determined. Enrollment of subjects with normal liver function was performed within the calculated age and BMI range (approximately 50% of subjects on either side of the median, including extreme values ​​whenever possible). Approximately equal proportions of smokers and non-smokers were enrolled.

[0211] 2.3.1 Selection Criteria To be eligible for inclusion in the study, subjects had to meet the following inclusion criteria:

[0212] 2.3.1.1 All subjects 1. Understand and willing to sign the ICF and comply with the study restrictions. 2. Adult female subjects aged 18 to 75 years at the time of informed consent. 3. BMI 18.0 kg / m 2 ~35.0kg / m 2 (inclusive) (BMI (kg / m 2 ) = weight (kg) / height 2 (m 2 )). 4. Subjects were eligible to enroll if: a. Documented surgical infertility or postmenopausal (amenorrhea for >1 year and FSH ≥ 30 mU / mL), OR b. Negative serum pregnancy test at screening and negative urine pregnancy test on day -1 and willingness to use non-hormonal contraception (i.e., non-hormonal intrauterine device, vasectomized partner, sexual abstinence, male or female condom with or without spermicide, cap, diaphragm, or spermicide-impregnated sponge) throughout the study (from screening to follow-up). 5. Willing and able to sign the ICF. 6. Willingness and ability to comply with clinical trial procedures

[0213] 2.3.1.2 Subjects with Hepatic Dysfunction (Addition) 7. Diagnosis of cirrhosis due to parenchymal liver disease confirmed and documented by at least one of liver ultrasound, computerized axial tomography (CT) scan, magnetic resonance imaging (MRI), and / or liver biopsy. 8. Stable liver dysfunction as determined by the investigator, defined as no clinically significant change in disease status for one month.

[0214] 2.3.1.3 Subjects with normal liver function (additional) 9. Subjects who have no liver disease and normal liver function as determined by the investigator. 10. In the opinion of the investigator, the participant is in good physical and mental health based on a medical evaluation that reveals no medical history or clinically relevant abnormalities (including physical examination, medical history, vital signs [systolic blood pressure ≥ 100mmHg and ≤ 140mmHg, diastolic blood pressure ≥ 60mmHg and ≤ 90mmHg], and results of biochemistry, coagulation and hematology tests, and urinalysis performed at screening and on Day 1).

[0215] Subjects with chronic (greater than 3 months) stable non-oncological conditions under clinical control (e.g., hypertension, diabetes) may be enrolled.

[0216] 2.3.2 Exclusion criteria Subjects who met any of the following exclusion criteria were not eligible for inclusion in the study:

[0217] 2.3.2.1 All subjects 1. Clinically relevant abnormal medical history, abnormal findings on physical examination (including gynecological examination), vital signs, or clinical laboratory tests at screening that the investigator determines may interfere with the objectives of the study or the safety of the volunteer, except for symptoms related to liver dysfunction in subjects with impaired liver function (Groups 2 to 4). 2. Surgery (e.g., gastric bypass) or medical condition (e.g., pancreatic injury or pancreatitis, gastritis) that, in the investigator's judgment, may significantly affect drug absorption. 3. Documenting congenital QT syndrome. 4. Unstable ischemic heart disease or severe heart failure (New York Heart Association class III or IV). 5. Uncontrolled / untreated hypertension (defined as an average of three repeated measurements of systolic blood pressure ≥ 180 mmHg and / or diastolic blood pressure ≥ 110 mmHg); current or documented history of repeated clinically significant hypotension or severe episodes of orthostatic hypotension (systolic blood pressure < 90 mmHg and / or diastolic blood pressure < 50 mmHg). 6. Primary biliary cirrhosis. 7. History of hormone-related (estrogen / progestin) cancer or other cancer not in complete remission or determined to be cancerous (excluding basal cell skin cancer or squamous cell carcinoma). 8. Acute illness within 14 days prior to administration of the investigational product, unless mild in severity and approved by the investigator and sponsor's medical personnel. 9. Presence of active infection requiring antibiotics. 10. Consumption of Seville oranges, grapefruit or grapefruit juice, pomelo, starfruit, cranberry, or menthol (drinks or foods) within 7 days prior to administration of the study drug through the end of the evaluation period. 11. Use of prescription medications or herbal supplements (e.g., St. John's wort) that act as strong inducers or inhibitors of CYP3A4 function within 14 days prior to Day 1 and through follow-up. For the treatment of pain, such as headache or musculoskeletal pain, first-line medications including acetaminophen, ibuprofen, indomethacin, and metamizole with pitofenone were permitted. The dose of analgesics was determined by the investigator. The sponsor reserved the right to review the chronic use of medications by subjects with hepatic impairment in consideration of their eligibility for the study. 12. Any over-the-counter medication or dietary supplement (vitamin) within 14 days prior to study drug administration through completion of the study. 13. Alcohol consumption within 48 hours prior to study drug administration and through Day 9. Outside of this period, regular alcohol consumption of less than 17 units per week (1 unit is equivalent to 250 mL of beer, 75 mL of wine, or 25 mL of spirits) was permitted. 14. Smoking more than 10 cigarettes per day (or equivalent nicotine consumption). Intake of menthol-containing cigarettes was not permitted. 15. Exposure to another investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to study drug administration, or exposure to 4 or more new investigational drugs within 12 months prior to study drug administration. Previous participation in a clinical trial due to E4 exposure. 16. Donated blood or had bleeding exceeding 450 mL within 3 months prior to screening. 17. Non-hysterectomized female subjects who are pregnant, nursing, or planning to become pregnant during the study. 18. Clinically significant renal disease (creatinine clearance [CLCr] less than 60 mL / min calculated by the Cockcroft-Gault formula at screening; see Table 4). 19. Positive serological test for human immunodeficiency virus antibody (anti-HIV)-1 / 2 at screening. 20. History of drug addiction (including soft drugs such as cannabis products). 21. Positive urine drug (opiates, methadone, cocaine, amphetamines [including methamphetamine], cannabinoids, barbiturates, benzodiazepines, and tricyclic antidepressants) screening (excluding cannabinoid-containing drugs, which are not permitted in any case if not medically indicated and prescribed), or a breath alcohol test on screening and / or day -1. 22. History of relevant drug and / or food allergies. 23. Lack of legal capacity or limited legal capacity. 24. Undiagnosed vaginal bleeding in the past 12 months. 25. History of venous or arterial thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.) or known coagulation disorder. 26. Papanicolaou smear for subjects with cervical abnormalities and clinically significant cervixes with evidence of cervical dysplasia (documented record from a previous trial within 12 months or documented record at screening examination). Women diagnosed with atypical squamous cells of undetermined significance (ASCUS) were allowed. 27. Subjects who were not euthyroid (hyperthyroid or hypothyroid), including subjects receiving medication (e.g., L-thyroxine or antithyroid drugs).

[0218] 2.3.2.2 Subjects with Hepatic Dysfunction (Addition) 28. History of esophageal bleeding within 3 months prior to administration of the study drug 29. Severe hepatic encephalopathy (greater than Grade 2) or central nervous system dysfunction of a degree that, in the opinion of the Investigator without informed consent, is so severe as to interfere with the conduct, completion, or results of this trial or to pose an unacceptable risk to the subject. 30. History of liver transplantation. 31. Progressive ascites and ascites requiring emptying and albumin supplementation as determined by the investigator. Hemoglobin concentration less than 32.105 g / L.

[0219] 2.3.2.3 Subjects with normal liver function (additional) 33. Positive serological test for hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) unless the absence of active hepatitis B / C infection is confirmed by polymerase chain reaction (PCR) testing.

[0220] 2.3.3 Exclusion of Subjects from Rating Participation in the study was strictly voluntary, and subjects had the right to withdraw from the study at any time for any reason without any repercussions.

[0221] The investigator had the right to terminate a subject's participation either due to difficulty obtaining a blood sample, a protocol violation, a serious adverse event (AE) or serious adverse event (SAE), or any other reason related to the subject's safety or the integrity of the trial data.

[0222] If a subject discontinued the study, he or she must notify the sponsor immediately. If there was a medical reason for discontinuation, the subject was to remain under the supervision of the investigator until his or her health condition improved.

[0223] A subject was dropped if the investigator discontinued the subject (at the investigator's discretion) for reasons related to the study drug. Dropouts were to be replaced if deemed necessary by the sponsor.

[0224] If a subject did not complete the study for reasons unrelated to the drug, the subject was considered a non-completer and was replaced to ensure a sufficient number of six evaluable subjects.

[0225] Decisions regarding subject substitution were to be documented.

[0226] The CRO would make every effort to ensure that non-completers and dropouts who received study drug completed safety follow-up assessments.

[0227] 2.3.4 Early Termination of a Clinical Trial The procedure for early discontinuation of the trial was detailed in the trial protocol.

[0228] 2.4 Treatment 2.4.1 Treatment administered Each enrolled subject received a single oral dose of 20 mg of E4 (estetrol) as the monohydrate as a film-coated tablet.

[0229] 2.4.2 Identification of the Investigational Product Active drug therapy Active substance: Estetrol as the monohydrate Activity: Estrogen receptor (ER) agonist with high affinity for ERα Indications: Not applicable Dose: 20mg Strength: 1 x 20mg Dosage form: Film-coated tablets for oral administration

[0230] Packaging and labeling were in accordance with European Union Regulations governing medical supplies for human use, Volume 4: Good Manufacturing Practice (GMP). The investigational medicinal product (IMP) label contained all information required by Annex 13 of the GMP.

[0231] 2.4.3 Method of assigning subjects to liver function groups After obtaining verbal and written informed consent, subjects with liver dysfunction and normal liver function were screened according to the inclusion and exclusion criteria. Subjects with liver dysfunction were assigned to one of three liver dysfunction groups based on the Child-Pugh classification (see Section 2.2). If liver function tests were repeated during screening, the most recent results were used for group assignment. Subjects in the control group were required to be free of liver disease and have normal liver function, as determined by the investigator.

[0232] Subjects who met all inclusion criteria received a unique subject number upon enrollment in the study. Subject numbers were assigned sequentially in the order in which subjects were enrolled. The investigator or designee entered the appropriate subject number on each subject's electronic case report form (eCRF). Subject numbers ensured identification until follow-up visits.

[0233] Subjects who dropped out or withdrew for any reason prior to enrollment were considered to have failed screening. Such subjects did not receive a subject number. The investigators kept screening records of all subjects screened to assess the number and characteristics of excluded subjects and the reasons for exclusion.

[0234] 2.4.4 Dose Selection in Clinical Trials E4 is well tolerated and safe up to 100 mg given as a single dose and up to 40 mg given once daily for 28 days, and a mass balance study in humans showed that hepatic excretion contributed approximately 20% of overall excretion. An oral dose of 20 mg E4 was hypothesized to provide an adequate safety margin, even when exposure was expected to be five times higher in subjects with severe hepatic impairment than in subjects with normal hepatic function.

[0235] 2.4.5 Timing of Medication in Clinical Trials Subjects were administered the study drug in the morning after an overnight fast of at least 8 hours.

[0236] The study medication was swallowed with 240 mL of tap water (room temperature). The medication was not to be chewed. Fasting continued for 4 hours after drug administration. During the fasting period, no fluids other than water were permitted, except for water 2 hours before dosing and 1 hour after dosing (excluding fluids ingested with the medication mentioned above). When not fasting, fluids were permitted ad libitum, taking into account the restrictions described in section 2.4.8.

[0237] Administration of the study drug was supervised by the investigator or his / her representative. After drug administration, mouth and hand examinations were performed.

[0238] Whenever possible, administration of routine medications should be avoided 2 hours before and 2 hours after IMP dosing, except for medications prescribed at specific times or administered with meals.

[0239] 2.4.6 Meals during the clinical trial At all time points, i.e., before screening, on admission day −1, 2, 3, 5, 9, and follow-up, a fasting period of at least 8 hours was required before obtaining laboratory samples.

[0240] There were no special requirements regarding food and beverage intake, except for the restrictions on beverages or foods containing caffeine and alcohol described in Section 2.4.8. If not fasting, meals and snacks were provided according to clinic standards.

[0241] 2.4.7 Blinding This was an open-label trial.

[0242] 2.4.8 Previous and Concomitant Therapies and Other Restrictions During the Study All medications (prescription and over-the-counter) taken from 30 days before screening through follow-up were recorded in the appropriate section of the eCRF.

[0243] Except for the limitations listed in the inclusion and exclusion criteria (section 2.3), the following limitations had to be adhered to: All subjects: Alcohol consumption within 48 hours prior to administration of the study drug was not permitted until the end of the evaluation period. Foods or beverages containing grapefruit, Seville oranges, pomelos, starfruit, or cranberries were not permitted from 7 days before study drug administration until the end of the evaluation period. No caffeine-containing foods or beverages were permitted from 48 hours before administration of the study drug until the end of the evaluation period. Postmenopausal women had to use the same contraceptive methods as described for non-hysterectomized women, unless their postmenopausal status was confirmed by FSH testing and they had been menstruating for more than 12 months. No strenuous activity, sun exposure, or contact sports were permitted from 96 hours (4 days) prior to enrollment at the clinical trial center until the final follow-up visit. Smoking was prohibited during the stay at the home. For the treatment of pain, such as headache or musculoskeletal pain, first-line medications were acetaminophen, ibuprofen, indomethacin, and metamizole with pitofenon. The dose of analgesic medication was determined by the investigator. Subjects with hepatic dysfunction (additional): Initiation of new medications (other than pain treatment) or changes in current doses within 14 days prior to study drug administration was not permitted.

[0244] 2.4.9 Treatment Adherence Accountability and subject compliance were assessed by maintaining adequate dispensing records for study medication. The investigator was responsible for ensuring that medication was administered according to the study protocol. Delegation of this task had to be clearly documented and approved by the investigator. Compliance was further confirmed by bioanalysis of E4 in plasma samples (see Section 2.5.5.1).

[0245] 2.5 Pharmacokinetics, Safety, and Exploratory Endpoints and Variables This study was conducted to assess the safety and PK parameters of E4 after a single dose; the study did not include efficacy or pharmacodynamic evaluations.

[0246] 2.5.1 Grading Schedule The assessment schedule is shown in Table 2. PK sampling is shown in Table 3.

[0247] TIFF2026501201000008.tif245170TIFF2026501201000009.tif245170

[0248] TIFF2026501201000010.tif152170

[0249] 2.5.2 Pharmacokinetic measurements The assessment schedule is shown in Table 2. PK sampling is shown in Table 3.

[0250] 2.5.2.1 Blood collection Details regarding sample collection, handling, storage, and shipping were provided in a laboratory manual prepared by the CRO.

[0251] 2.5.3 Safety and Tolerability Measures Safety and tolerability assessments consisted of treatment-emergent AEs (TEAEs), clinical laboratory tests, vital signs, physical examination, and gynecological examination. Assessments were performed according to Tables 2 and 3 in Section 2.5.1.

[0252] 2.5.3.1 Adverse Events AEs / TEAEs were recorded after ICF signing until the end of the follow-up visit. Any clinically significant finding in the results of laboratory tests, vital signs, or physical examination was recorded as an AE.

[0253] A TEAE is defined as any event that was not present before study drug administration or any pre-existing event that worsened in either severity or frequency after exposure to the study drug.

[0254] Adverse events (AEs) that occurred after ICF signing but before administration of the study drug were considered pretreatment AEs.

[0255] At several time points before and after drug administration, subjects were asked non-leading questions to determine the occurrence of AEs / TEAEs. Subjects were asked in general terms about any AEs / TEAEs at regular intervals during the study. In addition, all spontaneously reported AEs / TEAEs during the course of the study were recorded.

[0256] All responses were interpreted by the investigator for AEs / TEAEs using the Medical Dictionary for Regulatory Activities (MedDRA; version 22.1) and recorded in the AE record.

[0257] Pregnancy was to be monitored with follow-up as needed.

[0258] 2.5.3.2 Laboratory Tests The following tests were to be performed by local laboratories at the times indicated in the assessment schedule (Table 2).

[0259] TIFF2026501201000011.tif221170

[0260] Laboratory testing clearly demonstrated laboratory values ​​outside the normal range and were to be designated by the investigator as clinically significant according to the applicable CRO standard operating procedures (SOPs). Procedures for collection, handling, and shipping of laboratory samples were specified in the laboratory manual(s) provided to the study site.

[0261] An estimated total blood volume of 285 mL was collected per subject throughout the trial.

[0262] 2.5.3.3 Vital signs At the time points indicated in the assessment schedule (Table 2), after the subjects had rested in the supine position for at least 5 minutes, systolic and diastolic blood pressure and pulse were recorded. These assessments were performed using automated devices. Body temperature and respiratory rate were then measured.

[0263] 2.5.3.4 Physical Examination A complete physical examination consisting of a general system examination was performed at the time points indicated in the assessment schedule (Table 2). A symptom-specific physical examination could be performed at any time at the discretion of the investigator.

[0264] Height was recorded only at the screening visit. Weight was measured and BMI was calculated at the time points indicated in the assessment schedule (Table 2).

[0265] A gynecological examination (consisting of a breast examination, transvaginal ultrasound, and Papanicolaou smear [Papanicolaou smear only if not performed within 1 year prior to screening]) was performed according to the assessment schedule in Table 2 .

[0266] 2.5.4 Measurement Appropriateness The assessments performed in this trial are standard and generally recognized as reliable, accurate, and relevant. Validated PK assays are standard methods for measuring a drug's pharmacological effects, including changes in blood levels and liver function. AE / TEAE collection, safety laboratory tests, and physical examinations are standard methods for evaluating the safety of new drugs. Overall, these are appropriate measures to address the trial's objectives.

[0267] All procedures are documented in the CRO SOP.

[0268] 2.5.4.1 Timing of assessment For PK, pre-dose samples were collected after an overnight fast within 60 minutes before dosing, and post-dose samples were obtained well in advance, as described in Table 3.

[0269] For safety assessments, predose assessments were to be conducted between awakening and dosing. A ±15-minute window was allowed for safety assessments up to 2.5 hours after dosing. Thereafter, consecutive postdose assessments (e.g., multiple assessments on any given day) were to be conducted within a ±10% window of the time elapsed since the (last) dose, with concomitant postdose assessments (e.g., one or two assessments on a given day) occurring within ±3 hours of the scheduled scheme time (provided that assessments remained within the same time slot on the dosing day and did not shift from predose to postdose, or vice versa). If event assessments were scheduled at the same scheme time, the following sequence was to follow: (1) physical examination, (2) vital sign assessment, (3) blood draw (PK blood draws to be performed at the correct time), and (4) meal (if applicable).

[0270] 2.5.5 Pharmacokinetic and Safety Variables 2.5.5.1 Pharmacokinetic variables Calculations of non-compartmental PK parameters were performed using WinNonlin™ Professional, version 6.3 or higher.

[0271] 2.5.5.1.1 Primary Pharmacokinetic Parameters Key PK parameters analyzed for E4 in plasma: Cmax=maximum plasma concentration AUCinf = area under the concentration-time curve (AUC) extrapolated from time zero to infinity

[0272] 2.5.5.1.2 Secondary Pharmacokinetic Parameters Secondary PK parameters analyzed for E4 and its metabolites in plasma: Cmax = maximum plasma concentration (for metabolites only) AUCinf = AUC extrapolated from time zero to infinity (for metabolites only) AUC0-24h = AUC from 0 to 24 hours after administration AUClast = AUC up to the end at concentrations above the lower limit of quantification Tmax = time to reach Cmax T1 / 2 = terminal elimination half-life CL / F = apparent clearance (for E4 only) Λz = terminal elimination rate constant Vz / F = Terminal apparent volume of distribution (for E4 only) If necessary, additional PK parameters may be calculated.

[0273] 2.5.5.2 Safety Variables Safety variables measured include, but are not limited to, the following: Laboratory tests Vital signs Physical examination TEAE

[0274] 2.5.6 Drug concentration measurements Analysis of E4 and the metabolites E4-3-glucuronide and E4-16-glucuronide in plasma samples was performed in the CRO's bioanalytical laboratory using a validated liquid chromatography-mass spectrometry / mass spectrometry method.

[0275] 2.6 Protocol-Planned Statistical Methods and Sample Size Determination 2.6.1 Analysis Sets 2.6.1.1 Safety Set All subjects receiving E4 monohydrate medication.

[0276] 2.6.1.2 Pharmacokinetic Set All subjects who received at least one dose of E4 monohydrate and provided sufficient bioanalytical assessment results to allow reliable estimates of PK parameters to be calculated.

[0277] 2.6.2 Statistical Analysis Plan for Pharmacokinetic, Safety, and Exploratory Evaluations Statistical analyses were performed using appropriate procedures in SAS™ Version 9.4 or later.

[0278] All data were summarized using descriptive statistics and were listed and summarized in tabular and / or graphical format.

[0279] 2.6.2.1 Pharmacokinetic evaluation Individual and mean plasma concentrations of E4 at each sampling time point are presented by summary and descriptive summary statistics, including mean, geometric mean (GM), median, range, standard deviation (SD), and coefficient of variation (CV). Individual, mean, and / or median concentrations per hepatic function group were plotted against time on a semi-logarithmic scale.

[0280] PK parameters were calculated using non-compartmental analysis and analyzed using descriptive statistics and presented by hepatic function group.

[0281] Summary statistics of PK parameters, including mean, GM, median, range, SD, and CV, were presented by hepatic function group.

[0282] In an exploratory approach, to compare the major PK parameters of E4 (Cmax and AUCinf) between subjects with hepatic impairment and those with normal hepatic function, analysis of variance (ANOVA) was used with the log-transformed value of each PK parameter as the dependent variable and hepatic impairment group (normal, mild, moderate, and severe) as a fixed classification factor. Geometric least-squares means were used to calculate the ratios of the major PK parameters in each hepatic impairment group to those in the control group, along with 90% confidence intervals (CI).

[0283] In addition, the influence of age and BMI on the effect of liver dysfunction was assessed using an ANOVA model similar to that described above, but with the interaction of each factor with liver dysfunction group as an additional factor.

[0284] The relationship between log-transformed PK parameters (Cmax and AUCinf) used in the Child-Pugh score and continuous parameters (albumin, total bilirubin, and prothrombin time) was extrapolated using a linear regression approach. Additional linear regressions stratified by BMI or age group could be performed in case of significant interactions with hepatic dysfunction group identified using the ANOVA model. Further exploratory analyses of the relationship between hepatic dysfunction and PK could be performed if indicated.

[0285] Secondary PK parameters were analyzed descriptively.

[0286] 2.6.2.2 Safety and Tolerability Assessment Safety and tolerability were assessed by TEAEs, clinical laboratory tests, vital signs, and physical examination findings, as well as other parameters relevant to safety assessment.

[0287] All individual safety outcomes were listed and descriptive statistics, including change from baseline, were calculated where applicable.

[0288] 2.6.2.2.1 Adverse Events A list of all individual AEs will be provided. Summary tables of TEAEs will be presented based on System Organ Class (SOC) based on the MedDRA terminology list (preferred terms), with tables including the number of subjects experiencing AEs by hepatic function, tables including the number of subjects experiencing SAEs by hepatic function (if applicable), tables by hepatic function and relatedness, and tables by hepatic function and severity.

[0289] All TEAE summaries are presented alphabetically by SOC, and preferred terms (PTs) are sorted in descending order of frequency within each SOC according to MedDRA.

[0290] A summary of the number and percentage of subjects reporting TEAEs, SAEs, TEAEs leading to study drug discontinuation, or TEAEs by severity will be presented by hepatic function group.

[0291] A summary of the number and percentage of subjects reporting each TEAE is shown by hepatic function group. Counts were performed only by subject, not by event, and subjects were counted only once within each body system or PT.

[0292] A summary of the number and percentage of subjects reporting each TEAE is presented by relationship to study drug (as recorded on the eCRF) and by hepatic function group. Subjects with multiple events within a particular SOC or PT will be counted as related events unless there are no events related to that SOC / PT.

[0293] A summary of the number and percentage of subjects reporting each TEAE is presented by severity (as recorded on the eCRF) and by hepatic function group. Subjects with multiple events within a particular SOC or PT will be counted in the most severe event category within that SOC or PT.

[0294] All AEs (including non-treatment-emergent events) recorded on the eCRF will be listed by subject.

[0295] A separate list of AEs leading to discontinuation of study drug will be provided for each subject.

[0296] 2.6.2.2.2 Laboratory Tests All laboratory data were converted to the International System of Units for reporting and processing purposes.

[0297] Laboratory data were annotated with indications if parameters were outside the reference range, and a summary listing of all data assessed by the investigator as clinically significant was generated.

[0298] Summary descriptive statistics of serial laboratory results for hematology, coagulation, and clinical chemistry, including derived changes from baseline, will be provided by liver function group and scheduled time points.

[0299] All laboratory data will be listed by subject.

[0300] Provide a separate list of clinically significant abnormalities.

[0301] 2.6.2.2.3 Physical Examination Physical examination data are listed by subject.

[0302] 2.6.3 Sample size determination Because no prior information was available about the variability of E4 PK in subjects with hepatic impairment, a formal sample size calculation was not performed. The number of subjects to be enrolled was chosen based on practical considerations in accordance with the guidelines for clinical trials involving subjects with hepatic impairment.

[0303] 2.7 Review of Safety Laboratory Data Safety laboratory results from the first two subjects in each group were reviewed to assess the potential effect of E4 on liver function (elevated liver enzymes) before enrolling the next subject(s). Results from days 2, 3, and 5 were considered and compared with results from day -1 (baseline).

[0304] Potential fluctuations in liver function were anticipated: if liver enzyme results exceeded 1.5 times the baseline value (either the upper limit of normal or the actual value, if above the upper limit of normal on day -1), the case was reviewed further within the CRO, and the situation was followed up by the sponsor before subjects were enrolled in that group.

[0305] 2.8. Demographics 48 to 70 years old, BMI 18.5 kg / m 2 ~34.7kg / m 2 A total of 32 female subjects participated in this study. All subjects were Caucasian, not multiracial, and not of Hispanic or Latino ethnicity (Table 7).

[0306] TIFF2026501201000012.tif185170

[0307] The medical history of subjects with normal liver function was appropriate for the age of this population. Subjects with liver dysfunction exhibited disease characteristics consistent with the origin of the underlying liver dysfunction or secondary to this condition. Of the 32 female subjects, 3 were of childbearing potential.

[0308] 3. Pharmacokinetic results 3.1 Pharmacokinetic results 3.1.1 E4 plasma concentration E4 was rapidly absorbed, reaching peak plasma concentrations within 30 minutes (mean 15 minutes) after administration in subjects with severe hepatic impairment, and within 2 hours in all subjects. Subsequently, plasma E4 concentrations rapidly declined, producing a smaller secondary peak in all groups except for those with severe hepatic impairment. Approximately 12 hours later, E4 entered a log-linear terminal elimination phase (Figures 1 and 2).

[0309] The groups with moderate and severe liver impairment showed a more rapid decline than the groups with mild liver impairment and normal liver function. E4 concentrations remained above the LLOQ in at least half of the subjects for up to 48 hours after dosing in the group with severe liver impairment, up to 96 hours in the group with moderate liver impairment, and up to 144 hours after dosing in the group with mild liver impairment and subjects with normal liver function, respectively (Figure 2).

[0310] 3.1.2 E4-3-glucuronide plasma concentration The arithmetic mean plasma concentrations of E4-3-glucuronide versus time are shown in Figure 3, and GM plasma concentrations are shown in Figure 4. GM plasma concentrations reached a primary peak of similar values ​​within approximately 1 hour in all groups, and showed a secondary peak in all groups except the severe liver dysfunction group.

[0311] The group with severe hepatic impairment showed the most rapid decline compared with the groups with moderate, mild, and normal liver function. E4-3 concentrations remained above the LLOQ in at least half of the subjects for up to 36 hours after dosing in the group with severe hepatic impairment, up to 48 hours in the group with moderate hepatic impairment, and up to 96 hours in the group with mild hepatic impairment and subjects with normal liver function.

[0312] 3.1.3 E4-16-glucuronide plasma concentration The time course of the arithmetic mean plasma concentrations of E4-16-glucuronide and GM are shown in Figures 5 and 6, respectively. GM plasma concentrations reached a primary peak within approximately 1 hour in all groups. The peak values ​​were similar among the three groups of subjects with hepatic dysfunction and higher than those in subjects with normal liver function. In the groups with normal liver function and mild hepatic dysfunction, a secondary peak was reached before the excretion phase.

[0313] The group with severe hepatic impairment showed the most rapid decline compared with the groups with moderate, mild, and normal liver function. E4-16 concentrations remained above the LLOQ in at least half of the subjects for up to 48 hours after dosing in the group with severe hepatic impairment, up to 72 hours in the group with moderate hepatic impairment, and up to 96 hours in the group with mild hepatic impairment and subjects with normal liver function.

[0314] 3.1.4 Pharmacokinetic parameters of E4 in plasma The effect of hepatic impairment on individual Cmax and AUCinf values ​​is displayed in relation to the Child-Pugh score in Figure 7. Inter-individual variability was large in all groups, with Cmax and AUCinf values ​​spanning the widest range in the moderate hepatic impairment group. In all subjects with severe hepatic impairment, Cmax exceeded the maximum value measured in the control group. In the mild and moderate hepatic impairment groups, the maximum Cmax was higher than in the control group. The minimum AUCinf measured in the severe hepatic impairment group was similar to the maximum AUCinf measured in the control group. In the mild and moderate hepatic impairment groups, the maximum AUCinf was higher than in the control group.

[0315] Summary statistics for the primary and secondary PK parameters of E4 are shown in Table 8.

[0316] Compared with normal liver function, the GM values ​​of Cmax of parent compound E4 were increased in all groups with hepatic impairment, the effect was most pronounced in the severe hepatic impairment group and less pronounced in mild or moderate impairment, the latter of which was inconclusive due to high variability.

[0317] The mean, median, and GM AUCinf values ​​were elevated in the severe impairment group (GM AUCinf approximately 1.9-fold), but were similar in the mild and normal liver function groups, and apparently also in the moderate liver impairment group; however, the results are inconclusive due to the high variability within this group (Table 12). The median Tmax ranged from 0.25 to 0.50 hours, suggesting no association with the degree of liver impairment. GM T1 / 2 values ​​were similar in subjects with normal liver function, mild impairment, and moderate impairment with high variability. Only subjects with severe liver impairment exhibited significantly lower GM T1 / 2 values ​​compared with the other groups. The final measurable E4(Clast) concentration was obtained 192 hours after dosing (last measurement time point) in subjects with normal liver function or mild liver impairment, 144 hours in subjects with moderate liver impairment, and 168 hours in subjects with severe liver impairment. The apparent clearance CL / F was similar in the groups with normal liver function and mild and moderate impairment, and showed a slight decrease in the group with severe impairment.

[0318] In subjects with normal liver function, the GM of Vz / F was 5996.6 L and decreased to 1201.4 L in subjects with severe liver dysfunction.

[0319] The variability of the major PK parameters of E4 was moderate to high (Figure 7).

[0320] TIFF2026501201000013.tif230170TIFF2026501201000014.tif185170

[0321] 3.1.5 Pharmacokinetic parameters of E4-3-glucuronide in plasma Summary statistics for the metabolite E4-3-glucuronide are shown in Table 9.

[0322] Cmax and AUC0-24 of E4-3-glucuronide GM were similar in all hepatic function groups. AUCinf of GM showed a slight decrease in the moderate and severe hepatic impairment groups compared with the normal hepatic function group.

[0323] The median Cmax increased in the groups with hepatic impairment compared with the group with normal liver function. The median AUCinf decreased slightly in the groups with moderate and severe hepatic impairment compared with the group with normal liver function. The median AUCinf was lowest in the group with severe hepatic impairment. The median AUC0-24h was similar in the groups with mild and moderate hepatic impairment compared with the group with normal liver function and slightly decreased in the group with severe hepatic impairment. The median AUClast decreased in the groups with hepatic impairment compared with the group with normal liver function, with the greatest decrease in the group with severe hepatic impairment.

[0324] The maximum values ​​of Cmax, AUCinf, AUC0-24h, and AUClast were similar between the group with severe hepatic impairment and the control group.

[0325] Tmax was reached within approximately 1 hour in the group with severe hepatic impairment, within approximately 2 hours in the groups with mild and moderate hepatic impairment, and approximately 6 hours in the group with normal hepatic function due to abnormal values, with a median of approximately 0.5 hours in all groups except the group with moderate hepatic impairment (1 hour).

[0326] GM T1 / 2 was decreased in the moderate and severe liver dysfunction groups and increased in the mild liver dysfunction group compared with the normal liver function group. The mean and GM T1 / 2 were lowest in the severe liver dysfunction group.

[0327] TIFF2026501201000015.tif230170TIFF2026501201000016.tif96170

[0328] 3.1.6 Pharmacokinetic parameters of E4-16-glucuronide in plasma Summary statistics for the metabolite E4-16-glucuronide are shown in Table 10.

[0329] In the hepatic impairment groups, the median, mean, and GM of E4-16-glucuronide for Cmax, AUCinf, and AUC0-24h were elevated, most significantly in the severely impaired group. The %CV was higher for Cmax in normal subjects and for AUC in the severely impaired group.

[0330] The maximum values ​​of Cmax, AUCinf, AUC0-24h, and AUClast were doubled in the severe hepatic impairment group compared with the control group (Cmax: approximately 2-fold, AUCinf: approximately 4-fold, AUC0-24h: approximately 5-fold, and AUClast: approximately 4-fold).

[0331] The median Tmax was approximately 0.5 hours in all groups except for the moderate hepatic impairment group (approximately 1.0 hour).

[0332] Compared with the normal liver function group, GM T1 / 2 decreased in the moderate and severe liver dysfunction groups and increased in the mild liver dysfunction group.

[0333] TIFF2026501201000017.tif225170TIFF2026501201000018.tif134170

[0334] 3.1.7 Pharmacokinetic statistical analysis Linear regression of E4 Cmax and AUCinf against laboratory parameters used to grade the severity of liver dysfunction according to the Child-Pugh classification showed an inverse correlation with albumin and a direct relationship with bilirubin and prothrombin time (Table 11). The 90% CIs suggest an association in all regressions (excluding 0).

[0335] TIFF2026501201000019.tif135170

[0336] In the severe hepatic impairment group, AUCinf was approximately 1.9-fold higher than in the control group (90% CI: 1.367-2.625) (Table 12, Figure 9). There were no relevant differences in AUCinf in the mild and moderate hepatic impairment groups compared with the control group (approximately 1.1-fold (90% CI: 0.808-1.552) and approximately 1.0-fold (90% CI: 0.745-1.431), respectively).

[0337] TIFF2026501201000020.tif95170

[0338] Two-way ANOVA compared four liver function groups (mild, moderate, severe, and normal) and two BMI groups (18.5 kg / m 2 ~25kg / m 2 Less than 25kg / m 2 The above values ​​were compared with the primary PK parameters (Cmax and AUCinf) (Table 13). These results suggested a relevant effect of liver function on the PK parameters, but there was no effect of BMI on these PK parameters. Furthermore, no interaction was observed between liver function and BMI groups, suggesting that liver function was not associated with BMI. As this trial was exploratory and underpowered, p values ​​should be interpreted with caution.

[0339] TIFF2026501201000021.tif67170

[0340] 3.2 Pharmacokinetic evaluation 3.2.1 E4 Pharmacokinetics GM Cmax was approximately 1.7-fold higher in the group with mild hepatic impairment, approximately 1.9-fold higher in the group with moderate hepatic impairment, and approximately 5.4-fold higher in the group with severe hepatic impairment than in the control group (Table 12). GM AUCinf increased approximately 1.1-fold (116.80 h*ng / mL) in the group with mild hepatic impairment, approximately 1.0-fold (107.64 h*ng / mL) in the group with moderate hepatic impairment, and approximately 1.9-fold (197.53 h*ng / mL) in the group with severe hepatic impairment (Table 12). Compared to the normal liver function group, the 90% CIs for the estimates of Cmax and AUCinf in the severe group and Cmax in the moderate group did not contain unity, i.e., a ratio of 1, suggesting relevant differences (Table 12). In fact, the 90% CIs completely exceeded the usual bioequivalence limits (0.80 to 1.25). GM T1 / 2 was similar in normal liver function, mild impairment, and moderate impairment. Significantly lower T1 / 2 was observed in the severe liver impairment group compared to the other groups (Table 8). Median Tmax was similar across all hepatic function groups (Tmax range, 0.23 to 1.92 hours) (Table 8). The apparent clearance GM of E4 (CL / F) was similar between the normal liver function group and the mild and moderate liver dysfunction groups, and was approximately half in the severe liver dysfunction group (191.77 L / h) compared with the normal liver function group (101.25 L / h) (Table 8). GM Vz / F was comparable between liver function groups, except for the severe liver dysfunction group, which had a GM Vz / F of 1201.4 L compared with 5996.6 L in the normal liver function group. Two-way ANOVA confirms that hepatic function, but not BMI, is a variable that influences the PK parameters Cmax and AUCinf (Table 13).

[0341] 3.2.2 Pharmacokinetics of E4-3-glucuronide GM Cmax was similar across all hepatic function groups (Table 9). GM AUCinf showed a slight decrease in the moderate and severe hepatic impairment groups compared with the group with normal liver function, but GM AUC0-24 was comparable between groups (Table 9). The median Tmax appeared to be similar in all but one hepatic function group, being 1 hour in the moderate hepatic impairment group compared with approximately 0.5 hours in the other three groups (Table 9). Compared with the normal liver function group, GM T1 / 2 decreased in the moderate and severe liver dysfunction groups and increased in the mild liver dysfunction group (Table 9).

[0342] 3.2.3 Pharmacokinetics of E4-16-glucuronide GM Cmax increased in all groups with hepatic impairment, most significantly in the group with severe impairment (Table 10). GM AUCinf and GM AUC0-24 showed increases in the hepatic dysfunction groups, most notably in the severely impaired group (Table 10). Median Tmax appeared to be similar across all hepatic function groups (Table 10). GM T1 / 2 appeared to be similar in groups with normal liver function, mild or moderate liver dysfunction, and appeared to be decreased in groups with severe liver dysfunction.

[0343] 4. Safety Assessment 4.1 Exposure Levels All subjects in all groups received 20 mg of E4 as specified in the protocol.

[0344] 4.2 Adverse events 4.2.1 Brief summary of adverse events In this trial, 9 subjects (28.1%) had at least 1 TEAE: 2 subjects each in the normal hepatic function and mild hepatic impairment groups; 4 subjects in the moderate hepatic impairment group; and 1 subject in the severe hepatic impairment group.

[0345] No subjects had an SAE.

[0346] Six subjects (18.8%) had TEAEs considered to be mild in severity, and three subjects (9.4%) had TEAEs of moderate severity. Eight subjects (25.0%) had TEAEs considered unrelated to the study drug by the investigator, and one subject (3.1%) had a TEAE considered related to the study drug (Table 14).

[0347] The most commonly reported TEAE was diarrhea in 3 subjects (9.4%), followed by headache, back pain, and hypertension in 2 subjects each (6.3%).

[0348] TIFF2026501201000022.tif123170

[0349] 4.2.2 Display of Adverse Events Table 15 provides a summary of TEAEs by SOC and preferred term. Table 16 provides a summary of TEAEs by severity.

[0350] TIFF2026501201000023.tif152170

[0351] TIFF2026501201000024.tif154170

[0352] 4.2.3 Analysis of adverse events AE data were analyzed by frequency, severity, outcome, and relationship to study drug. No further analyses of AEs were performed. The most common TEAE was diarrhea (gastrointestinal disorder) reported by three subjects. Additionally, back pain (musculoskeletal and connective tissue disorder), headache (nervous system disorder), and hypertension (vascular disorder) were reported by two subjects each (Table 15).

[0353] Eleven TEAEs were considered mild in intensity, and four were considered moderate in intensity. Diarrhea was reported by one subject in the normal group and two subjects in the moderate group. These events were considered moderate in intensity in the normal group and mild in intensity in the moderate group. Headache was reported by two subjects in the moderate group, one of whom was moderate in intensity and the other mild in intensity. Back pain was reported by one subject in the normal group and one subject in the severe group. These events were considered moderate in intensity in the normal group and mild in the moderate group. Hypertension was recorded in two subjects in the mild group, and the intensity in both subjects was considered mild (Table 16).

[0354] All TEAEs reported during this study were considered unrelated to the study drug, except for one TEAE of diarrhea, which was reported by one subject in the moderate group and was considered mild in intensity.

[0355] 4.3 Deaths, other serious adverse events, and other significant adverse events No deaths, SAEs, or other serious AEs occurred during this study. No patients discontinued the study due to TEAEs.

[0356] 4.3.1 Evaluation of each clinical test parameter 4.3.1.1 Changes in test values A summary of laboratory values, changes from baseline, and shifts from baseline revealed no deviations or trends in hematology and clinical chemistry parameters after E4 administration that raised safety concerns in subjects with mild, moderate, or severe hepatic impairment and in subjects with normal hepatic function.

[0357] 4.3.1.2 Individual subject changes The majority of laboratory values ​​were within the normal range throughout the clinical trial (screening, day -1, and follow-up). Many of the individual variations from the normal range of clinical laboratory parameters assessed during the trial were already present at screening or baseline and may be attributable to the overall health of the study population or the underlying disease(s). With the exception of two subjects with out-of-range values ​​judged to be clinically significant in hematology, clinical chemistry, coagulation, and urinalysis, deviations from the normal range of individual subject laboratory values ​​were judged not to be clinically significant because the out-of-range values ​​were minor.

[0358] 4.3.1.3 Individual clinically significant abnormalities Subject 3022, a patient with normal liver function and no history of gallbladder infection or pancreatitis, had clinically significant elevations in amylase levels on days 3 and 5, lipase levels on day 9 and at follow-up, and clinically significant elevations in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyltransferase, and lactate dehydrogenase at follow-up, leading to a diagnosis of asymptomatic pancreatitis. The subject remained asymptomatic throughout the event and was not treated or hospitalized. The subject was monitored until all parameters returned to near baseline levels (determined not to be clinically significant) within 9 days of follow-up.

[0359] In subject 3028, elevated creatinine and urea levels were observed isolated on day -1 in the group with severe hepatic impairment.

[0360] 4.4 Vital Signs, Physical Examination, and Other Safety Observations 4.4.1 Vital signs Although some individual changes from baseline were noted, blood pressure, pulse rate, respiratory rate, and temperature showed no trends or clinically significant changes.

[0361] 4.4.2 Physical Examination All but one of the observed abnormalities was considered clinically unrelated. One subject in the mild hepatic impairment group had a diffuse hemorrhage (diffuse hematoma) in the left elbow on Day 3 that was considered clinically significant and reported as a TEAE (MedDRA Preferred Term: hemarthrosis). The severity of this event was mild and determined by the investigator to be unrelated to the study drug. The diffuse hemorrhage resolved without additional treatment.

[0362] 4.5 Safety Conclusions A single oral dose of 20 mg E4 monohydrate was safe and well tolerated in female subjects with normal hepatic function and mild, moderate, or severe hepatic impairment. No deaths, SAEs, or other serious AEs occurred during this study. The most common TEAE was diarrhea (gastrointestinal disturbance) in three subjects. Diarrhea was reported by one subject in the group with normal hepatic function and two subjects in the group with moderate hepatic impairment. This event was considered moderate in intensity in subjects with normal hepatic function and mild in subjects with moderate hepatic impairment. All TEAEs reported during this study were considered unrelated to the study drug, except for one TEAE of diarrhea, which was reported by one subject in the group with moderate hepatic impairment and was considered mild in intensity. A summary of laboratory values, changes from baseline, and shifts from baseline revealed no deviations or trends in hematology or clinical chemistry parameters that raised safety concerns following administration of E4 monohydrate in subjects with mild, moderate, or severe hepatic impairment and in subjects with normal hepatic function. The results of the physical examination were generally unremarkable.

[0363] 5. Discussion and Overall Conclusions This was a phase 1, multicenter, open-label, PK and safety study of a single oral dose of 20 mg E4 monohydrate in female subjects with varying degrees of hepatic impairment and normal hepatic function. Previous studies of absorption, distribution, metabolism, and excretion suggest involvement of the liver, a well-known pathway for other estrogens.

[0364] 5.1 Pharmacokinetics E4 was readily absorbed, with Cmax reaching within the first 2 hours after oral administration regardless of hepatic function status. Mean Cmax ranged from approximately 24 ng / mL in subjects with normal hepatic function to approximately 38 ng / mL in subjects with mild hepatic impairment, approximately 52 ng / mL in subjects with moderate hepatic impairment, and approximately 117 ng / mL in subjects with severe hepatic impairment.

[0365] Comparison of Cmax in subjects with moderate and severe hepatic impairment with Cmax in subjects with normal liver function showed relevant differences (1.896-fold, 90% CI: 1.132-3.178 and 5.359-fold, 90% CI: 3.198-8.981, respectively), but this was not the case when comparing mild hepatic impairment with normal liver function (1.661-fold, 90% CI: 0.991-2.783).

[0366] Finally, the distribution and reabsorption phases resulted in an increase in AUC0-24 depending on the degree of hepatic impairment, with GM of 69.7554 h*ng / mL, 88.7526 h*ng / mL, and 179.0494 h*ng / mL in subjects with mild, moderate, and severe hepatic impairment, respectively, compared to 60.4146 h*ng / mL in subjects with normal hepatic function.

[0367] For AUCinf, these differences were not significant for mild and moderate vs. normal (1.120-fold, 90% CI: 0.808-1.552 and 1.032-fold, 90% CI: 0.745-1.431, respectively), but were significant for severe vs. normal (1.894-fold, 90% CI: 1.367-2.625).

[0368] The elimination phase of the concentration-time profiles revealed a decreasing half-life of E4 that ordered along the degree of hepatic impairment, with a GM T of 21.67 hours in subjects with normal liver function, followed by 20.07 hours in subjects with mild hepatic impairment, 14.79 hours in subjects with moderate hepatic impairment, and 8.22 hours in subjects with severe hepatic impairment. Correspondingly, the final measurable concentration of E4(Clast) was obtained 192 hours after dosing (last measurement time point) in subjects with normal liver function or mild hepatic impairment, 144 hours in subjects with moderate hepatic impairment, and 168 hours in subjects with severe hepatic impairment.

[0369] The present results are consistent with the effect of liver dysfunction on the distribution and reabsorption cycle, particularly the effect of severe liver dysfunction on enterohepatic recycling.

[0370] Notably, E4 plasma levels 24 hours after administration were in the same range among different liver function groups, potentially resulting in similar accumulation after multiple daily dose regimens.

[0371] 5.2 Safety In this trial, a single oral dose of 20 mg of E4 monohydrate was administered to female subjects with normal liver function, mild, moderate, or severe liver impairment and was safe and well tolerated.

[0372] The most common TEAE was diarrhea (gastrointestinal disturbance) in three subjects. Diarrhea was reported by one subject in the normal group and two subjects in the group with moderate hepatic impairment. These events were considered moderate in intensity for subjects in the normal group and mild in intensity for subjects with moderate hepatic impairment.

[0373] All TEAEs reported during this study were considered unrelated to the study drug, except for one TEAE of diarrhea, which was reported by one subject in the moderate hepatic impairment group and was considered mild in intensity.

[0374] A summary of laboratory values, changes from baseline, and shifts from baseline revealed no deviations or trends in hematology and clinical chemistry parameters after E4 administration that raised safety concerns in subjects with mild, moderate, or severe hepatic impairment and in subjects with normal hepatic function.

[0375] The results of the physical examination were generally unremarkable.

[0376] 5.3 Conclusion 5.3.1 Pharmacokinetics The GM Cmax of E4 after a single 20 mg dose was significantly increased in subjects with moderate (approximately 1.9-fold, 90% CI: 1.132-3.178) and severe hepatic impairment (approximately 5.4-fold, 90% CI: 3.198-8.981), but was not significantly different in subjects with mild hepatic impairment and normal liver function (approximately 1.7-fold and 90% CI: 0.991-2.783). Although the peak exposure of metabolites correlated with the degree of liver dysfunction, the changes were negligible due to the low potency and small proportion of pharmacological compounds. The GM AUCinf of E4 was similar in the groups with mild hepatic impairment (approximately 1.1-fold, 90% CI 0.808-1.552) and moderate hepatic impairment (approximately 1.0-fold, 90% CI 0.745-1.431), and was approximately 1.9-fold higher in the group with severe hepatic impairment (90% CI 1.367-2.625) compared with normal liver function. The GM AUCinf of E4-3-glucuronide appeared to be slightly decreased in moderate and severe liver impairment compared with normal liver function, but the results show a lot of variability.For E4-16-glucuronide, the GM AUCinf showed an increase in the liver impairment groups, most significantly in the severe group. GM T1 / 2 was highly variable but appeared to be generally shortened for E4 and metabolites depending on the degree of liver dysfunction.

[0377] 5.3.2 Safety A single oral dose of 20 mg E4 monohydrate was safe and well tolerated in female subjects with normal hepatic function and mild, moderate, or severe hepatic impairment.

[0378] The most common TEAE was diarrhea (gastrointestinal disturbance). Diarrhea was reported by three subjects: one in the normal group and two in the group with moderate hepatic impairment. These events were considered moderate in intensity for subjects in the normal group and mild in intensity for subjects with moderate hepatic impairment.

[0379] All TEAEs reported during this study were considered unrelated to the study drug, except for one TEAE of diarrhea, which was reported by one subject in the moderate hepatic impairment group and was considered mild in intensity.

[0380] Vital signs, laboratory values, and physical examination were unremarkable.

[0381] Example 2. Dose-finding study to select a daily oral dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women Clinical trial enrollment and duration: Enrollment was approximately 18 months. Individual subject participation, for non-hysterectomized subjects only, included up to 6 weeks of pre-screening and washout, up to 4 weeks of screening and run-in, up to 91 days (13 weeks) of E4 monohydrate or placebo treatment followed by 2 weeks (14 days) of progestin therapy, and a follow-up visit 1 week after completion of progestin therapy for up to 27 weeks.

[0382] Primary efficacy objectives: The minimal effective dose (MED) of oral E4 will be defined by assessing changes in the frequency and severity of moderate to severe vasomotor symptoms (VMS).

[0383] Methodology: This was a prospective, multicenter, randomized, placebo-controlled, double-blind, dose-ranging trial.

[0384] Subject population: Eligible subjects were postmenopausal hysterectomized and non-hysterectomized women aged 40-65 years who experienced at least seven moderate-to-severe hot flashes per day or at least 50 moderate-to-severe hot flashes per week.

[0385] Diagnostic and selection criteria: Subjects met all of the following inclusion criteria at the randomization visit. These criteria were assessed during the screening period: 1. 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 during the week prior to randomization. 2. Body mass index (BMI) is 18.0 kg / m 2 ~35.0kg / m 2 (inclusive). 3. Postmenopausal status is defined as a follicle-stimulating hormone (FSH) level greater than 40 IU / L and is as follows: Amenorrhea for at least 12 months, or Estradiol (E2) less than 20 pg / mL and amenorrhea for at least 6 months, or Bilateral oophorectomy with or without hysterectomy at least 6 weeks after surgery, with a copy of the pathology report or statement on letterhead from the subject's physician verifying that both ovaries were removed. 4. For non-hysterectomized women: An intact uterus with a two-layered endometrial thickness of 5 mm or less on TVUS. 5. Negative pregnancy test. 6. In the judgment of the Principal Investigator (PI), be in good physical and mental health based on medical, surgical, and gynecological history, physical examination, gynecological examination, laboratory tests, and vital signs. 7. Subject provided signed and dated informed consent prior to acceptance into the trial. 8. The subject will be able to understand and comply with the requirements, instructions, and limitations set forth in the clinical trial protocol.

[0386] Exclusion criteria: Potential study subjects were excluded if one of the following exclusion criteria was present at the randomization visit. These criteria were assessed during the screening period: 1. For non-hysterectomized women: Uterine disease or medical condition, including: a. Double-layered endometrial thickness greater than 5 mm as determined by TVUS; b.Presence of fibroid(s) with unclear endometrial evaluation by TVUS; c. History or presence of uterine cancer; d. Presence of endometrial hyperplasia; e. Presence of endometrial polyps with hyperplastic or malignant epithelium. 2. Undiagnosed vaginal bleeding in the past 12 months. 3. Any history of malignancy except basal cell carcinoma of the skin (excluded if within the past 2 years) or squamous cell carcinoma (excluded if within the past year). Any clinically significant finding on breast examination and / or mammography suspicious for breast cancer that required additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound were allowed). Note: A screening mammogram was required unless the subject provided written documentation of a mammogram within the past 9 months. 4. Abnormal cervical Pap smear in non-hysterectomized subjects with evidence of cervical dysplasia beyond low-grade squamous intraepithelial lesion (LSIL) (documented record of previous test within 18 months or documented record of test at the time of screening examination). Women diagnosed with atypical squamous cells of undetermined significance (ASCUS) were enrolled. 5. Systolic blood pressure (BP) outside the range of 90mmHg to 140mmHg, diastolic blood pressure outside the range of 60mmHg to 90mmHg, and / or heart rate outside the range of 40bpm to 100bpm. Subjects with mild to moderate hypertension who were controlled on a stable antihypertensive regimen were enrolled if they met the inclusion / exclusion criteria. 6. Any clinically significant abnormality identified on the screening 12-lead ECG. 7. History of venous or arterial thromboembolic disease (e.g., deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), known coagulation disorder, or coagulation factor abnormality. 8. Diabetes mellitus with poor glycemic control in the past 6 months was assessed by blood glucose test values ​​outside the normal range and glycated hemoglobin >7%. 9. Dyslipoproteinemia predisposes subjects to atherosclerotic cardiovascular disease (ASCVD). Subjects were not included in this study if they had a 10-year ASCVD score of 5% or higher, calculated using the ASCVD risk estimate (ACC / AHA Cardiovascular Risk Assessment Guidelines, 2013). All subjects were excluded if they had an LDL cholesterol level of 190 mg / dL or higher or a triglyceride plasma level of 400 mg / dL or higher.

[0387] If subjects were receiving lipid-lowering therapy, they had to be on a stable dose of treatment for at least 1 month before screening, and the same eligibility criteria were used. 10. Smoking more than 10 cigarettes per day and / or using more than 1 ml of nicotine-containing e-liquid per day. 11. Current or history of gallbladder disease unless cholecystectomy has been performed. 12. Systemic lupus erythematosus. 13. Multiple sclerosis. 14. Acute or chronic liver disease. 15. Acute or chronic renal dysfunction, including severe renal dysfunction. 16. Uncontrolled thyroid disorder. 17. Subject has a history of major depression or post-traumatic stress disorder (PTSD) within the past two years, or has had a history of any other significant psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.) at any time. 18. Use of estrogen- or progestin-containing medication(s). A washout period is required before the run-in period if the following are used: a. Vaginal hormone products (rings, creams, gels): at least 4 weeks washout; b. Transdermal estrogen or estrogen / progestin: at least 4 weeks washout; c. Oral estrogen and / or progestin: at least 4 weeks washout; d. Intrauterine progestin therapy: at least 4 weeks washout; Current users of progestin implants or estrogen-only injectable medications were not allowed to participate unless treatment had been discontinued more than 3 months prior. Current users of estrogen pellet therapy or progestin injectable medications were not allowed to participate unless treatment had been discontinued more than 6 months prior. 19. Use of non-hormonal treatments to reduce hot flashes. If non-hormonal prescription and over-the-counter (OTC) treatments for hot flashes (such as the antidepressants paroxetine, escitalopram, venlafaxine, desvenlafaxine, and clonidine; or phytoestrogens, such as black cohosh) were used, a 1-week washout period was required before the run-in period. If one of these treatments was used in combination with an estrogen- or progestin-containing drug, the washout periods could be combined and did not have to be sequential. 20. Use of medications within 28 days prior to the run-in period that may affect the outcome of the VMS endpoint, including (but not limited to): SSRIs [selective serotonin reuptake inhibitors], SNRIs [serotonin and norepinephrine reuptake inhibitors], dopaminergic or antidopaminergic agents, or gabapentin. 21. History or presence of allergy to the investigational drug or this class of drug, or history of drug or other allergy that, in the opinion of the investigator, contraindicates the subject's participation. 22. History or presence of allergy or intolerance to any component of the study drug. 23. A 12-month history of alcohol or drug abuse or dependence as determined by the investigator, i.e., the subject consumed excessive alcohol, abused drugs, or had a condition that, in the investigator's judgment, may impair the subject's ability to comply with the requirements of the study. 24. Employees of the sponsor or contract research organization (CRO), or departmental personnel of the investigator, and their immediate family members related to this clinical trial. 25. Subjects with porphyria and subjects with a known or suspected history of clinically significant systemic illness, unstable medical disorder, life-threatening illness, or current malignancy that, in the opinion of the investigator, poses a risk to the subject. 26. Have participated in a clinical trial of another investigational drug within the past 1 month (30 days) or have received an investigational drug within the past 3 months (90 days). 27. The investigator has determined that the study is inappropriate for any reason.

[0388] Number of subjects: Intention-to-treat principle This principle asserts that the effects of a treatment policy can best be assessed by evaluating subjects based on the intention to treat them (i.e., the planned treatment regimen), rather than the treatment actually administered. Consequently, subjects assigned to a treatment group should be followed up, assessed, and analyzed as members of that group, regardless of their adherence to the planned course of treatment.

[0389] Furthermore, the intention-to-treat principle means that the primary analysis should include all randomized subjects.

[0390] Maintaining the original randomization in the analysis is important to prevent bias and provide a solid basis for statistical testing. In many clinical trials, using the full analysis set offers a conservative strategy. Under many circumstances, it may also provide estimates of treatment effect that are more likely to reflect results observed in subsequent practice.

[0391] The trial included a total of 257 patients in the intention-to-treat group.

[0392] Subjects were randomly assigned to one of five treatment arms in a 1:1:1:1:1 ratio. Randomization was stratified by center.

[0393] TIFF2026501201000025.tif54170

[0394] Study drug and reference treatment, dose, and mode of administration All treatments (estetrol, hereafter E4 as the monohydrate, [2.5 mg, 5 mg, 10 mg, 15 mg] capsules) were administered orally once daily (QD) for at least 12 consecutive weeks until the last biological assessment (maximum day 91) was performed.

[0395] Placebo was administered orally at one capsule QD for at least 12 consecutive weeks until the final biological assessment (maximum day 90).

[0396] During the course of the study, if a bilayered endometrial thickness of 15 mm or greater was detected by TVUS and / or abnormal uterine bleeding (in the opinion of the gynecologist in light of estrogen therapy) was reported by non-hysterectomized women, subjects underwent endometrial biopsy and were treated continuously with progestin (10 mg dydrogesterone) QD until the end of week 11 (i.e., a 14-day progestin treatment period followed by a 14-day progestin break) in addition to E4 / placebo treatment. If endometrial biopsy revealed endometrial hyperplasia, the subject's participation was immediately discontinued, and treatment for hyperplasia was administered according to local guidelines. If abnormal uterine bleeding recurred after the initial normal endometrial biopsy, a thorough gynecological examination and TVUS were performed. If necessary at the gynecologist's discretion, a second endometrial biopsy was performed.

[0397] After the E4 monohydrate or placebo treatment period, all non-hysterectomized subjects (including those who had previously received a progestin) received 14 days of progestin therapy with 10 mg dydrogesterone QD.

[0398] result A. Vasomotor parameters for each of the five treatment groups a.VMS frequency i. Absolute change (mean change from baseline) in weekly frequency of moderate to severe VMS a) Weekly for each group

[0399] TIFF2026501201000026.tif134170

[0400] To analyze the data recorded in this trial, treatment groups were compared using ANCOVA (analysis of covariance) for the change in weekly frequency of moderate to severe VMS from baseline to weeks 4 and 12. The ANCOVA model included treatment ("trt1") and trial site ("SITEPOOL") as fixed effects and baseline ("Base") as a covariate.

[0401] b) Significance of covariates The table below shows the comparison between all treatment groups.

[0402] TIFF2026501201000027.tif41170

[0403] After consideration, it was determined that the effect of the clinical trial site was not very important, and a second ANCOVA was conducted without taking the clinical trial site into account.

[0404] No impact on facilities

[0405] TIFF2026501201000028.tif28170

[0406] c) The following table shows the mean change from baseline by week and treatment:

[0407] TIFF2026501201000029.tif67170

[0408] No impact on facilities

[0409] TIFF2026501201000030.tif68170

[0410] All statistical tests are supported by presenting least squares adjusted means (LS adjusted means: also called group means, marginal means, or estimated marginal means after adjusting for covariates) and 95% confidence intervals for each treatment effect. These LS adjusted means and confidence intervals are based on the statistical model used in the analysis.

[0411] A confidence interval means that if the same population is sampled many times and an interval is estimated each time, the resulting interval will bracket the true population parameter in approximately 95% of cases.

[0412] d) The table below shows the difference from placebo by week and treatment.

[0413] TIFF2026501201000031.tif57170

[0414] No impact on facilities

[0415] TIFF2026501201000032.tif58170

[0416] These tables show that estetrol monohydrate at a daily dose of 15 mg is nearly statistically significantly different from placebo at week 4 (p-value 0.10653 in the initial statistical analysis, p-value 0.06834 in the non-pooled analysis) and at week 12 (p-value 0.10838 in the initial statistical analysis, p-value 0.07057 in the non-pooled analysis).

[0417] ii. Relative change (% from baseline) in weekly frequency of moderate to severe VMS a) Weekly for each group

[0418] TIFF2026501201000033.tif87170

[0419] From this table it can be seen that a daily dose of 15 mg of estetrol monohydrate resulted in a greater than 80% reduction in the frequency of moderate to severe VMS compared to baseline.

[0420] b) Significance of covariates The table below shows the comparison between all treatment groups.

[0421] TIFF2026501201000034.tif38170

[0422] No impact on facilities

[0423] TIFF2026501201000035.tif28170

[0424] c) The table below shows the mean relative change (%) from baseline by week and treatment.

[0425] TIFF2026501201000036.tif73170

[0426] No impact on facilities

[0427] TIFF2026501201000037.tif69170

[0428] d) The table below shows the difference from placebo by week and treatment.

[0429] TIFF2026501201000038.tif62170

[0430] This table shows that a daily dose of 15 mg of estetrol monohydrate produced a statistically significant difference from placebo at week 12 (p-value 0.03771) and a near statistically significant difference from placebo at week 4 (p-value 0.05622).

[0431] In particular, it is noteworthy to observe the low p-value obtained with the 15 mg estetrol monohydrate dose compared to the elevated p-value obtained with the 10 mg estetrol monohydrate dose.

[0432] No impact on facilities

[0433] TIFF2026501201000039.tif58170

[0434] This table shows that in statistical analysis without considering the effect of center, estetrol monohydrate at a daily dose of 15 mg produced a statistically significant difference from placebo at week 4 (p=0.03206) and week 12 (p=0.02210).

[0435] In particular, it is noteworthy to observe the low p-value obtained with the 15 mg estetrol monohydrate dose compared to the elevated p-value obtained with the 10 mg estetrol monohydrate dose.

[0436] iii. Change in the weekly frequency of moderate to severe VMS in the responder group The frequency of VMS was also examined by dividing patients into groups according to the degree of response.

[0437] An initial grouping of patients with a 50% or greater response (relative change from baseline) was performed. According to this analysis, at week 12, the 15 mg daily estetrol monohydrate group contained 91.8% of responders, and the placebo group contained 65.5% of responders. The difference between these two groups was p<0.01, while the difference between the 10 mg daily estetrol monohydrate group and the placebo group was not statistically significant (p>0.1).

[0438] A second grouping of patients who showed a response of 75% or more was performed. According to this analysis, at week 12, the 15 mg daily estetrol monohydrate group contained 77.6% of responders, and the placebo group contained 43.6% of responders. The difference between these two groups was p-value less than 0.001, while the difference between the 10 mg daily estetrol monohydrate group and the placebo group was not statistically significant (p-value > 0.05).

[0439] b. Severity of VMS i. Absolute change (mean change from baseline) in weekly severity of moderate to severe VMS a) Weekly for each group

[0440] TIFF2026501201000040.tif88170

[0441] To better analyze the data recorded in this trial, ANCOVA (analysis of covariance) was used to compare treatment groups for change in severity from moderate to severe VMS at baseline to mild, moderate, and severe VMS at weeks 4 and 12 for each active treatment group versus the placebo group. A value of 0 was assigned for women who experienced 100% VMS relief at weeks 4 and / or 12. The ANCOVA model included treatment ("trt1") as a fixed effect and baseline ("base") as a covariate.

[0442] b) Significance of covariates The table below shows the comparison between all treatment groups.

[0443] TIFF2026501201000041.tif28170

[0444] c) The following table shows the mean change from baseline by week and treatment:

[0445] TIFF2026501201000042.tif68170

[0446] d) The table below shows the difference from placebo by week and treatment.

[0447] TIFF2026501201000043.tif57170

[0448] From this table it can be seen that a daily dose of 15 mg estetrol monohydrate produces a statistically significant difference from placebo at week 4 (p-value 0.0486) and week 12 (p-value 0.0489). Thus, the 15 mg dose of estetrol monohydrate significantly improves the severity of VMS at week 4 and week 12 compared to placebo.

[0449] For severity parameters, the difference between the 10 mg and 15 mg doses of estetrol monohydrate is also striking, as reflected primarily in the mean change from baseline shown in the table in section c) above, where, for example, at week 12, the LS-adjusted mean value for 10 mg is -0.69 (compared to -0.66 seen in the placebo group) and -1.04 for the 15 mg daily dose group. This clear difference is reflected in the p-value at week 4 when switching from 10 mg to 15 mg per day, which resulted in an almost 8-fold improvement, and the p-value at week 12 when switching from 10 mg to 15 mg per day, which resulted in a more than 20-fold improvement.

[0450] ii. Relative change (% from baseline) in weekly severity of moderate to severe VMS a) Weekly for each group

[0451] TIFF2026501201000044.tif87170

[0452] This table shows that a daily dose of 15 mg of estetrol monohydrate resulted in a greater than 40% reduction in the severity of moderate to severe VMS compared to baseline.

[0453] b) Significance of covariates The table below shows the comparison between all treatment groups.

[0454] TIFF2026501201000045.tif28170

[0455] c) The table below shows the mean relative change from baseline by week and treatment.

[0456] TIFF2026501201000046.tif71170

[0457] d) The table below shows the difference from placebo by week and treatment.

[0458] TIFF2026501201000047.tif61170

[0459] From this table, it can be seen that the 15 mg daily dose of estetrol monohydrate is nearly statistically significant compared to placebo at 12 weeks (p-value 0.0568). The 15 mg daily dose of estetrol monohydrate improves VMS severity at weeks 4 and 12 compared to placebo, but again the 10 mg daily dose of estetrol monohydrate is barely distinguishable from placebo, especially at week 12.

[0460] c. Weighted weekly hot flash score i. Absolute change in weekly weighted score (mean change from baseline) a) Weekly for each group

[0461] TIFF2026501201000048.tif87170

[0462] b) Significance of covariates The table below shows the comparison between all treatment groups.

[0463] TIFF2026501201000049.tif28170

[0464] c) The table below shows the mean change from baseline by week and treatment.

[0465] TIFF2026501201000050.tif67170

[0466] d) The table below shows the difference from placebo by week and treatment.

[0467] TIFF2026501201000051.tif57170

[0468] ii. Relative change in weekly weighted score (% from baseline) a) Weekly for each group

[0469] TIFF2026501201000052.tif87170

[0470] b) Significance of covariates The table below shows the comparison between all treatment groups.

[0471] TIFF2026501201000053.tif28170

[0472] c) The table below shows the mean relative change from baseline by week and treatment.

[0473] TIFF2026501201000054.tif71170

[0474] d) The table below shows the difference from placebo by week and by treatment.

[0475] TIFF2026501201000055.tif61170

[0476] From this table it can be seen that estetrol monohydrate at a daily dose of 15 mg produces a statistically significant difference from placebo at weeks 4 (p-value 0.0267) and 12 (p-value 0.0276).

[0477] In particular, it is noteworthy to observe the low p-value obtained with the 15 mg estetrol monohydrate dose compared to the elevated p-value obtained with the 10 mg estetrol monohydrate dose.

[0478] B. Vasomotor parameters of the 10 mg and 15 mg estetrol monohydrate groups compared to placebo, and the ineffective doses grouped together (2.5 mg and 5 mg estetrol monohydrate) The results observed in Section A above revealed that the two lowest doses tested (2.5 mg / day and 5 mg / day estetrol monohydrate) did not demonstrate efficacy. Thus, the results were further analyzed and the data for these two doses were grouped with the placebo dose and compared to the 10 mg and 15 mg estetrol monohydrate doses.

[0479] 1. Relative change (% from baseline) in weekly frequency of moderate to severe VMS a) Weekly for each group

[0480] TIFF2026501201000056.tif87170

[0481] b) Significance of covariates

[0482] TIFF2026501201000057.tif39170

[0483] c) Paired comparison with placebo (containing non-effective doses of 2.5 mg and 5 mg estetrol monohydrate grouped together)

[0484] TIFF2026501201000058.tif52170

[0485] d) Difference from placebo (including non-effective doses of 2.5 mg and 5 mg estetrol monohydrate grouped together)

[0486] TIFF2026501201000059.tif69170

[0487] As already mentioned in section A) above, it is particularly noteworthy to observe the low p-value obtained with the 15 mg daily dose of estetrol monohydrate compared to the increased p-value obtained with the 10 mg daily dose, which indicates that only a relief was obtained with the 15 mg daily dose of estetrol monohydrate.

[0488] 2. Relative change in weekly weighted hot flash score (% from baseline): a) Weekly for each group

[0489] TIFF2026501201000060.tif87170

[0490] b) Significance of covariates

[0491] TIFF2026501201000061.tif44170

[0492] c) Paired comparison with placebo (containing non-effective doses of estetrol monohydrate at 2.5 mg and 5 mg)

[0493] TIFF2026501201000062.tif50170

[0494] d) Difference from placebo (including non-effective doses of 2.5 mg and 5 mg estetrol monohydrate)

[0495] TIFF2026501201000063.tif64170

[0496] As already mentioned in section A) above, a daily dose of 15 mg estetrol monohydrate is found to be statistically significantly different from placebo at week 4 (p-value 0.00178) and week 12 (p-value 0.00097).

[0497] Here too, it is particularly noteworthy to observe the low p-value obtained with the 15 mg estetrol monohydrate dose compared to the elevated p-value obtained with the 10 mg estetrol monohydrate dose.

[0498] C. Menopausal Symptom Assessment Scale The Menopause Rating Scale (MRS) is a health-related quality of life measure that allows for the assessment of the severity of age- / menopausal-related complaints by grading symptom profiles (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).

[0499] For each of the 11 items (severity of each item is expressed as 0 to 4 points), the score increases by a point as the subjectively perceived severity of the complaint increases. For each item in the questionnaire, the respondent provides their personal perception by checking one of five possible boxes for "severity." The total MRS score ranges from 0 (asymptomatic) to 44 (highest severity of complaints). The minimum / maximum score varies across the three dimensions depending on the number of complaints assigned to each symptom dimension (Heinemann et al., 2003, Health Qual Life Outcomes 1: 28): 1. Psychological symptoms: 0 to 16 points (4 symptoms: depression, irritability, anxiety, exhaustion); 2. Somato-vegetative symptoms: 0 to 16 points (4 symptoms: sweating / flushing, heart problems, sleep disorders, joint and muscle problems) 3. Genitourinary symptoms: 0 to 12 points (3 symptoms: sexual problems, urinary tract complaints, vaginal dryness).

[0500] Total MRS score

[0501] TIFF2026501201000064.tif37170

[0502] The Menopausal Rating Scale (MRS), which indicates improvement in overall quality of life, showed the strongest effect with the 15 mg dose of estetrol monohydrate, which showed a statistically significant effect compared to placebo at week 4 (p=0.0113) and a near-statistically significant effect at week 12 (p=0.0694).

[0503] D. Genitourinary symptoms (GSM) Changes from baseline to week 12 in the following GSM symptoms (self-rated by VVA subjects) were recorded:

[0504] a) Vaginal dryness (vaginal dryness or burning sensation; none = 0, mild = 1, moderate = 2, or severe = 3):

[0505] TIFF2026501201000065.tif42170

[0506] b) Vaginal and / or vulvar irritation / itching (unusual vaginal irritation or sensitivity; none = 0, mild = 1, moderate = 2, or severe = 3):

[0507] TIFF2026501201000066.tif38170

[0508] c) Dysuria (pain or difficulty urinating; none = 0, mild = 1, moderate = 2, or severe = 3):

[0509] TIFF2026501201000067.tif38170

[0510] d) Sexually-associated vaginal pain (pain sensation during intercourse; none = 0, mild = 1, moderate = 2, or severe = 3):

[0511] TIFF2026501201000068.tif42170

[0512] e) Sexually Associated Vaginal Bleeding (blood loss due to sexual intercourse; yes = 1 vs. no = 0):

[0513] TIFF2026501201000069.tif51170

[0514] The progression of VVA symptoms showed an overall improvement, with the strongest effect observed at a daily dose of 15 mg estetrol monohydrate. Regarding vaginal pain associated with sexual activity, significant differences from placebo were observed at daily doses of 5 mg, 10 mg, and 15 mg estetrol monohydrate, with p values ​​of 0.0246, 0.0004, and 0.0006, respectively. However, vaginal dryness, generally considered the most troublesome symptom, was significantly improved only at a daily dose of 15 mg estetrol monohydrate, with a p value of 0.0291.

[0515] E. Measurement of side effects of treatment 1. Number of patients with biopsies

[0516] TIFF2026501201000070.tif21170

[0517] 2. Adverse Events (AE)

[0518] TIFF2026501201000071.tif40170

[0519] From the table above, it can be seen that patients in the 15 mg estetrol monohydrate group experienced fewer TEAEs than patients in the 10 mg estetrol monohydrate group. Among patients in the 10 mg estetrol monohydrate group who experienced AEs, the average was 3.2 AEs per patient. In comparison, in the estetrol monohydrate 15 mg group, patients who experienced AEs had an average of 2.6 AEs. Overall, these data demonstrate that a daily dose of 15 mg estetrol monohydrate provides significant relief from VMS without causing additional AEs in patients. Furthermore, there was less need for biopsy in the estetrol monohydrate 15 mg / day group than in the 10 mg / day group.

[0520] This is confirmed by the following statistical analysis: Using a Poisson regression model with random effects for patient and treatment group as a covariate to model the number of TEAEs in the different treatment groups, it is shown that there is no statistical difference between the treatment groups (p-value 0.099). A chi-square test was then used to assess whether the prevalence of patients reporting TEAEs in each treatment group was similar. No statistical difference was found between the two treatment groups (p-value 0.575).

[0521] 3.Patients who have withdrawn from the clinical trial

[0522] TIFF2026501201000072.tif21170

[0523] F. Measurements performed with estetrol monohydrate at daily doses of 15 mg and 20 mg To better assess the possibility of increasing the daily dose beyond the minimum effective dose of 15 mg estetrol monohydrate per day, a number of parameters were followed in a clinical trial in which estetrol monohydrate was administered at increasing doses of 20 mg / day.

[0524] 1. Triglyceride level (mmol / L)

[0525] TIFF2026501201000073.tif50170

[0526] 2. Glucose level (mmol / L)

[0527] TIFF2026501201000074.tif49170

[0528] 3. Cholesterol level (mmol / L)

[0529] TIFF2026501201000075.tif50170

[0530] 4. HDL-cholesterol level (mmol / L)

[0531] TIFF2026501201000076.tif49170

[0532] 5. LDL-cholesterol level (mmol / L)

[0533] TIFF2026501201000077.tif49170

[0534] From the above five tables it can be observed that these lipid parameters and glucose levels do not behave significantly differently when a daily dose of 20 mg estetrol monohydrate is used instead of a daily dose of 15 mg estetrol monohydrate.

[0535] 6. C-terminal telopeptide (CTX-1) (ng / L)

[0536] TIFF2026501201000078.tif49170

[0537] CTX-1 is a specific marker of bone resorption.

[0538] In the above table it can be seen that a daily dose of 15 mg of estetrol monohydrate leads to a slight reduction in bone resorption, and this effect is more pronounced with a daily dose of 20 mg of estetrol monohydrate already after 28 days of treatment.

[0539] G. Measurements performed with estetrol monohydrate at daily doses of 15 mg and 30 mg Healthy women (aged 15 to 50 years, inclusive) were randomized to receive the following treatments according to the randomization code: placebo (n=16); 15 mg group: single oral dose of estetrol monohydrate 15 mg / drospirenone 3 mg (n = 10) followed by a 14-day washout, followed by multiple oral doses of estetrol monohydrate 15 mg / drospirenone 3 mg (n = 10) once daily for 14 days; 30 mg group: A single oral dose of estetrol monohydrate 30 mg / drospirenone 6 mg (n=10) followed by a 14-day washout and multiple oral doses of estetrol monohydrate 30 mg / drospirenone 6 mg (n=10) once daily for 14 days.

[0540] Adverse events were recorded from the first hospital admission until the completion of the follow-up visit (37–42 days after the first day of treatment).

[0541] TIFF2026501201000079.tif48170

[0542] Overall, single dose and once-daily administration of oral estetrol monohydrate / drospirenone ranging from estetrol monohydrate 15 mg / drospirenone 3 mg to estetrol monohydrate 30 mg / drospirenone 6 mg for 14 days was safe and well tolerated in healthy female subjects in this study. There was no increase in either the proportion of subjects reporting TEAEs or the number of TEAEs with single and multiple estetrol monohydrate / drospirenone dose escalations (dose doubling).

[0543] Therefore, it is reasonable to envision hormone replacement therapy for alleviating menopause-related symptoms using a minimum effective daily dose of estetrol monohydrate between 15 mg and 20 mg, or even 25 mg, resulting in a better risk-benefit profile. Increasing the dose of estetrol monohydrate beyond the minimum effective dose of 15 mg / day actually results in better efficacy in parameters such as VMS relief and bone resorption (including, but not limited to, adverse events as described above in Sections E)2) and G), and in particular, lipid parameters and glucose levels as described above in Sections F)1)-5)), while maintaining a good safety profile. Increasing the dose of estetrol monohydrate beyond the minimum effective dose of 15 mg / day also allows for a more rapid onset of relief when patients begin hormone replacement therapy.

[0544] Example 3. Comparison of 15 mg and 20 mg Estetrol Monohydrate Furthermore, a clinical trial was designed to evaluate the effects of 15 mg or 20 mg of estetrol (E4) monohydrate or placebo on the severity and frequency of vasomotor symptoms (VMS) and the safety of E4 20 mg. The inclusion and exclusion criteria described in Example 2 were maintained for this example (i.e., Example 3).

[0545] Endpoint: Primary endpoint 1. Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from baseline to week 4 (efficacy study part) [Time frame: baseline and week 4] Weekly frequency of moderate to severe VMS at baseline and Week 4 was defined as the total recorded number (sum) of moderate to severe VMS experienced during the last 7 consecutive days before randomization at baseline and Week 4. Mean change = mean weekly frequency at Week 4 - mean weekly frequency at baseline.

[0546] 2. Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from baseline to week 12 (efficacy study part) [Time frame: baseline and week 12] Weekly frequency of moderate to severe VMS at baseline and week 12 was defined as the total recorded number (sum) of moderate to severe VMS experienced in the last 7 consecutive days before randomization at baseline and week 12. Mean change = mean weekly frequency at week 12 - mean weekly frequency at baseline.

[0547] 3. Mean change in severity of moderate to severe vasomotor symptoms (VMS) from baseline to week 4 (efficacy study part) [Time frame: baseline and week 4] Severity scores are calculated as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score for VMS at baseline and at week 4 is defined as the arithmetic mean of the daily severity score values ​​for moderate and severe VMS observed in the past 7 days before randomization at baseline and for moderate and severe VMS observed at week 4. Severity score at baseline and at week 4 = [(2 × number of moderate VMS) + (3 × number of severe VMS)] / (total number of moderate + severe VMS). Mean change = mean severity score at week 4 - mean severity score at baseline.

[0548] 4. Mean change in severity of moderate to severe vasomotor symptoms (VMS) from baseline to week 12 (efficacy study part) [Time frame: baseline and week 12] Severity scores are derived as follows: mild = 1, moderate = 2, and severe = 3. The mean severity scores for VMS at baseline and week 12 are defined as the arithmetic mean of the daily severity score values ​​for moderate and severe VMS observed in the past 7 days before randomization for baseline and for moderate and severe VMS observed at week 12. Severity scores at baseline and week 12 = [(2 x number of moderate VMS) + (3 x number of severe VMS)] / (total number of moderate + severe VMS). Mean change = mean severity score at week 12 - mean severity score at baseline.

[0549] 5. Incidence of endometrial hyperplasia with treatment up to 12 months based on endometrial biopsies (endometrial and general safety study part) [Timeframe: Screening and Week 53] Endometrial biopsies were centrally reviewed by three independent pathologists from different institutions, blinded to treatment group and each other's interpretation. Agreement between two of the three pathologists was accepted as the final diagnosis. If there was no agreement between the three pathologists, the most severe pathological diagnosis, i.e., atypical hyperplasia > hybrid hyperplasia > simple hyperplasia > benign endometrium, was used as the final diagnosis.

[0550] Secondary endpoints 1. Mean change from baseline to week n in weekly frequency and severity of moderate to severe vasomotor symptoms (VMS) (efficacy study part) [Time Frame: Baseline and Week n] (n is an integer selected from 1 to 12). The weekly frequency of moderate to severe VMS at baseline and week n is defined as the total recorded number (sum) of moderate to severe VMS experienced during the past 7 consecutive days before randomization at baseline and week n. Mean change = mean weekly frequency at week n - mean weekly frequency at baseline. Severity scores are derived: mild = 1, moderate = 2, and severe = 3. The mean severity score of VMS at baseline and week n is defined as the arithmetic mean of the daily severity score values ​​for moderate and severe VMS observed during the past 7 days before randomization at baseline and for moderate and severe VMS observed at week n. Severity score at baseline and week n = [(2 × number of moderate VMS) + (3 × number of severe VMS)] / (total number of moderate + severe VMS). Mean change = mean severity score at week n - mean severity score at baseline.

[0551] 2. Mean change from baseline to week n in the weekly frequency and severity of mild, moderate, and severe vasomotor symptoms (VMS) (efficacy study part) [Time Frame: Baseline and Week n] (n is an integer selected from 1 to 12). Severity scores are calculated as follows: mild = 1, moderate = 2, and severe = 3. The mean severity score for VMS at baseline and week n is defined as the arithmetic mean of the daily severity score values ​​for mild, moderate, and severe VMS observed in the past 7 days before randomization for baseline and mild, moderate, and severe VMS observed at week n. Severity score at baseline and week n = [(1 × number of mild VMS) + (2 × number of moderate VMS) + (3 × number of severe VMS)] / (total number of mild VMS + moderate VMS + severe VMS). Mean change = mean severity score at week n - mean severity score at baseline.

[0552] 3. Percentage of participants who achieved a 50% reduction from baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (efficacy trial part) [Timeframe: Baseline, Week 1, Week 2, Week 3, 4, Week 5, 6, 7, 8, 9, Week 10, Week 11, and Week 12] The weekly frequency of moderate to severe VMS at baseline and week X was defined as the total recorded number (sum) of moderate to severe VMS experienced during the past 7 consecutive days before randomization (baseline) and during days [(X-1) × 7 + 1] through day X × 7 (week X).

[0553] 4. Percentage of participants who achieved a 50% reduction from baseline in the weekly frequency of mild, moderate, and severe vasomotor symptoms (VMS) at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (efficacy study part) [Timeframe: Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, 6, Week 7, Week 8, Week 9, Week 10, Week 11, and Week 12] The weekly frequency of moderate to severe VMS at baseline and week X was defined as the total recorded number (sum) of moderate to severe VMS experienced during the past 7 consecutive days before randomization (baseline) and during days [(X-1) × 7 + 1] through day X × 7 (week X).

[0554] 5. Percentage of participants who achieved a 75% reduction from baseline in the weekly frequency of moderate to severe VMS at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (efficacy study part) [Timeframe: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12] The weekly frequency of moderate to severe VMS at baseline and week X was defined as the total recorded number (sum) of moderate to severe VMS experienced during the past 7 consecutive days before randomization (baseline) and during days [(X-1) × 7 + 1] through day X × 7 (week X).

[0555] 6. Percentage of participants achieving a 75% reduction from baseline in the weekly frequency of mild, moderate, and severe VMS at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (efficacy study part) [Timeframe: Baseline, Week 1, Week 2, Week 3, 4, Week 5, 6, 7, 8, 9, Week 10, Week 11, and Week 12] The weekly frequency of moderate to severe VMS at baseline and week X was defined as the total recorded number (sum) of moderate to severe VMS experienced during the past 7 consecutive days before randomization (baseline) and during days [(X-1) × 7 + 1] through day X × 7 (week X).

[0556] 7. Percentage of participants who achieved a clinically important difference (CID) compared to baseline in the weekly frequency of moderate to severe VMS at Weeks 4 and 12 using the Clinical Global Impression (CGI) questionnaire (efficacy study part) [Timeframe: Weeks 4 and 12] The CGI score is a 7-point scale that asks subjects to grade their overall improvement, in their judgment, compared to their condition at entry into the trial, whether or not it was entirely due to medication. Scale: very improved, greatly improved, minimally improved, no change, minimally worsened, greatly worsened, very worsened.

[0557] 8. Change in VVA symptoms from baseline to week 12 (efficacy study part) [Time frame: baseline and week 12] GSM is assessed by subjects using the VVA Self-Rating Questionnaire. The following GSM symptoms are assessed: Vaginal dryness Vaginal and / or vulvar irritation / pruritus difficulty urinating Vaginal pain with sexual activity Vaginal bleeding with sexual activity

[0558] All GSM symptoms, except vaginal bleeding associated with sexual activity, are graded by participants using a scale of [0] absent, [1] mild, [2] moderate, or [3] severe. Vaginal bleeding associated with sexual activity is recorded using two categories: [0] absent or [1] present. A negative change from baseline score indicates symptom improvement.

[0559] 9. Change from baseline to week 12 in VVA symptoms initially identified by the participant as most bothersome using the baseline VVA questionnaire (efficacy study part) [Timeframe: baseline and week 12] GSM is assessed by subjects using the VVA Self-Rating Questionnaire. The following GSM symptoms are assessed: Vaginal dryness Vaginal and / or vulvar irritation / pruritus difficulty urinating Vaginal pain with sexual activity Vaginal bleeding with sexual activity

[0560] All GSM symptoms, except vaginal bleeding with sexual activity, were graded by participants using a scale of [0] absent, [1] mild, [2] moderate, or [3] severe. Vaginal bleeding with sexual activity was recorded using two categories: [0] absent or [1] present. A negative change from baseline score indicates symptom improvement. At baseline, participants are asked which of the above-mentioned symptoms they identified as most bothersome.

[0561] 10. Changes from baseline to week 12 in plasma triglyceride concentration, plasma low-density lipoprotein (LDL)-cholesterol concentration, plasma total cholesterol concentration, total cholesterol / high-density cholesterol (HDL)-cholesterol ratio, HDL-cholesterol ratio, plasma lipoprotein concentration (a), fasting blood glucose, plasma insulin concentration, plasma glycated hemoglobin concentration, homeostasis model assessment-estimated insulin resistance (HOMA-IR), and health-related quality of life (HRQoL) using the Menopause-Specific Quality of Life (MENQOL) questionnaire (efficacy study part) [Time frame: baseline and week 12] The MENQOL is a self-administered questionnaire assessing changes in quality of life over a one-month period. It consists of 29 questions (yes / no) indicating whether the subject experienced a problem; if yes, the rating scale ranges from 0 = not bothersome at all to 6 = extremely bothersome. For analysis, the raw scores are converted into an analyzed score ranging from 1 to 8, where no = 1, 0 = 2, 1 = 3, and 6 = 8. The scale includes four domains: vasomotor, psychosocial, physical, and sexual. Each domain is scored separately. The vasomotor domain score is the average of Q1, Q2, and Q3, where 1 is "not bothersome at all" and 8 is "extremely bothersome."

[0562] 11. Total Treatment Satisfaction Score Using the Clinical Global Impression (CGI) Questionnaire (Efficacy Study Part) [Time Frame: Week 4 and Week 12] The CGI score is a 7-point scale that asks subjects to grade their overall improvement, in their judgment, compared to their condition at entry into the trial, whether or not it was entirely due to medication. Scale: very improved, greatly improved, minimally improved, no change, minimally worsened, greatly worsened, very worsened.

[0563] 12. Number of participants with treatment-emergent adverse events (TEAEs) (efficacy study part) [time frame: from baseline to follow-up visit (up to week 16)] A TEAE is an adverse event that occurs between the time of first intake of study drug and the last visit, or any pre-existing event that worsens in either intensity or frequency following exposure to treatment.

[0564] 13. Number of participants with changes in physical and gynecological examination results (efficacy trial part) [Time frame: Screening and Week 13] The physical examination includes an examination of the general appearance, head, eyes, ears, nose, throat, skin, neck, lungs, breasts, lymph nodes, abdomen, and the cardiovascular, musculoskeletal, and nervous systems. The gynecological examination includes a manual pelvic examination.

[0565] 14. Number of participants with changes in vital sign results (Efficacy trial part) [Time frame: Screening to Week 13] Vital signs included height, weight, body mass index, sitting systolic and diastolic blood pressure, and heart rate.

[0566] 15. Number of participants with changes in electrocardiogram (ECG) results (efficacy trial part) [Timeframe: Screening and Week 13] The ECG interpretation scheme includes analysis of morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves, and the presence or absence of pathological changes.

[0567] 16. Number of participants with change in breast exam results (efficacy trial part) [Timeframe: Screening and Week 13] Number of participants with changes in routine clinical laboratory test results (efficacy study part) [Timeframe: Screening, Baseline and Week 13]. Routine clinical laboratory tests include hematology and chemistry.

[0568] 17. Change in endometrial thickness from baseline to each measurement time point (efficacy study part) [Time frame: screening, week 13, week 16] Endometrial thickness will be assessed by transvaginal ultrasound (TVUS). Baseline: Data will be recorded at screening.

[0569] 18. Frequency of subjects with different endometrial categories according to Blaustein's pathology (efficacy study part) [Time frame: Screening and Week 13] Endometrial biopsies were centrally reviewed by three independent pathologists from different institutions, blinded to treatment group and each other's interpretation. Agreement between two of the three pathologists was accepted as the final diagnosis. If there was no agreement between the three pathologists, the most severe pathological diagnosis, i.e., atypical hyperplasia > hybrid hyperplasia > simple hyperplasia > benign endometrium, was used as the final diagnosis.

[0570] 19. Number of participants with vaginal bleeding and / or spotting during each 28-day treatment cycle with E4 (efficacy study part) [Time frame: Baseline to Follow-up (Week 16)] Vaginal bleeding is recorded daily by participants in a diary. The presence or absence of vaginal bleeding / spotting is rated using the following scale: 0 = no vaginal bleeding or spotting; 1 = spotting: minimal evidence of blood loss requiring no pads, tampons, or panty liners or at most one pad, tampon, or panty liner per day; 2 = bleeding: evidence of blood loss requiring two or more pads, tampons, or panty liners per day.

[0571] 20. Number of bleeding and / or spotting days during each 28-day treatment cycle (efficacy study part) [Time frame: Baseline to Follow-up (Week 16)] Vaginal bleeding is recorded daily by participants in a diary. The presence or absence of vaginal bleeding / spotting is rated using the following scale: 0 = no vaginal bleeding or spotting; 1 = spotting: minimal evidence of blood loss requiring no pads, tampons, or panty liners or at most one pad, tampon, or panty liner per day; 2 = bleeding: evidence of blood loss requiring two or more pads, tampons, or panty liners per day.

[0572] 21. Number of participants with amenorrhea (no bleeding or spotting) during each 28-day treatment cycle with E4 (efficacy study part) [Time frame: Baseline to Follow-up (Week 16)] Vaginal bleeding is recorded daily by participants in a diary. The presence or absence of vaginal bleeding / spotting is rated using the following scale: 0 = no vaginal bleeding or spotting; 1 = spotting: minimal evidence of blood loss requiring no pads, tampons, or panty liners or at most one pad, tampon, or panty liner per day; 2 = bleeding: evidence of blood loss requiring two or more pads, tampons, or panty liners per day.

[0573] 22. Cumulative rate of amenorrhea (efficacy trial part) [Time frame: from baseline to follow-up (week 16)] The rate of amenorrhea is defined as the proportion of women who reported amenorrhea in consecutive cycles over a given cycle time.

[0574] 23. Number of participants with treatment-emergent adverse events (TEAEs) (endometrial and general safety part) [Time frame: Baseline to Week 53] A TEAE is an adverse event that occurs between the time of first intake of study drug and the last visit, or any pre-existing event that worsens in either intensity or frequency following exposure to treatment.

[0575] 24. Number of participants with changes in physical and gynecological examination results, changes in vital sign results, changes in breast examination results, changes in electrocardiogram (ECG) results, changes in mammography results, changes in routine clinical laboratory test results (endometrial and general safety part) [Timeframe: Screening and Week 53] The physical examination includes a general appearance, examination of the head, eyes, ears, nose, throat, skin, neck, lungs, breasts, lymph nodes, abdomen, and cardiovascular, musculoskeletal, and nervous systems. The gynecological examination includes a manual pelvic examination. Vital signs include height, weight, body mass index, sitting systolic and diastolic blood pressure, and heart rate. The ECG interpretation scheme includes analysis of morphology, rhythm, conduction, ST segment, PR, QRS, QT and corrected QT (QTc) intervals, T waves, U waves, and the presence or absence of pathological changes. Routine clinical laboratory tests include hematology and chemistry.

[0576] 25. Number of women with vaginal bleeding and / or spotting during a 28-day treatment cycle with E4 (endometrial and general safety part) [Timeframe: Baseline to Week 53] Vaginal bleeding is recorded daily by participants in a diary. The presence or absence of vaginal bleeding / spotting is rated using the following scale: 0 = no vaginal bleeding or spotting; 1 = spotting: minimal evidence of blood loss requiring no pads, tampons, or panty liners or at most one pad, tampon, or panty liner per day; 2 = bleeding: evidence of blood loss requiring two or more pads, tampons, or panty liners per day.

[0577] 26. Number of days with bleeding and / or spotting during each 28-day treatment cycle (endometrial and general safety part) [Timeframe: Baseline to Week 53] Vaginal bleeding is recorded daily by participants in a diary. The presence or absence of vaginal bleeding / spotting is rated using the following scale: 0 = no vaginal bleeding or spotting; 1 = spotting: minimal evidence of blood loss requiring no pads, tampons, or panty liners or at most one pad, tampon, or panty liner per day; 2 = bleeding: evidence of blood loss requiring two or more pads, tampons, or panty liners per day.

[0578] 27. Number of participants with amenorrhea (no bleeding or spotting) during each 28-day treatment cycle with E4 (endometrial and general safety part) [Timeframe: Baseline to Week 53] Vaginal bleeding is recorded daily by participants in a diary. The presence or absence of vaginal bleeding / spotting is rated using the following scale: 0 = no vaginal bleeding or spotting; 1 = spotting: minimal evidence of blood loss requiring no pads, tampons, or panty liners or at most one pad, tampon, or panty liner per day; 2 = bleeding: evidence of blood loss requiring two or more pads, tampons, or panty liners per day.

[0579] 28. Cumulative Rate of Amenorrhea (Endometrial and General Safety Part) [Time Frame: Baseline to Week 53] The rate of amenorrhea is defined as the proportion of women who reported amenorrhea in consecutive cycles over a given cycle time.

[0580] 29. Change from baseline to weeks 12 and 52 in health-related quality of life (HRQoL) assessment using the Menopause-Specific Quality of Life (MENQOL) questionnaire (endometrial and general safety part) [Timeframe: baseline, and weeks 12 and 52] The MENQOL is a self-administered questionnaire assessing changes in quality of life over a one-month period. It consists of 29 questions (yes / no) indicating whether the subject experienced any problems; if yes, the rating scale ranges from 0 = not bothersome at all to 6 = extremely bothersome. For analysis, the original scores were converted into an analytical score ranging from 1 to 8, where no = 1, 0 = 2, 1 = 3, and 6 = 8. The scale includes four domains: vasomotor, psychosocial, physical, and sexual. Each domain is scored separately. The vasomotor domain score is the average of Q1, Q2, and Q3, where 1 is "not bothersome at all" and 8 is "extremely bothersome."

[0581] 30. Total treatment satisfaction score (endometrial and general safety parts) assessed after 4, 12, and 52 weeks of treatment using the Clinical Global Impression (CGI) questionnaire [Timeframe: Week 4, Week 12, and Week 52] The CGI score is a 7-point scale that asks subjects to grade their overall improvement, in their judgment, compared to their condition at entry into the trial, whether or not it was entirely due to medication. Scale: very improved, greatly improved, minimally improved, no change, minimally worsened, greatly worsened, very worsened.

[0582] 31. Changes from baseline to weeks 12 and 52 in plasma triglyceride concentration, plasma high-density lipoprotein (HDL) cholesterol concentration, plasma low-density lipoprotein (LDL) cholesterol concentration, plasma total cholesterol concentration, total cholesterol / high-density cholesterol (HDL) cholesterol ratio, plasma lipoprotein concentration (a), fasting blood glucose, plasma insulin concentration, plasma glycated hemoglobin concentration, homeostasis model assessment-estimated insulin resistance (HOMA-IR), and endometrial thickness (endometrial and general safety part) [Time frame: baseline, and weeks 12 and 52] Endometrial thickness is assessed by transvaginal ultrasound (TVUS).

[0583] 32. Frequency of subjects in different endometrial categories according to Blaustein lesions (endometrial and general safety study part) [Timeframe: Screening and Week 53] Endometrial biopsies were centrally reviewed by three independent pathologists from different institutions, blinded to treatment group and each other's interpretation. Agreement between two of the three pathologists was accepted as the final diagnosis. If there was no agreement between the three pathologists, the most severe pathological diagnosis, i.e., atypical hyperplasia > hybrid hyperplasia > simple hyperplasia > benign endometrium, was used as the final diagnosis.

[0584] result: 1.VMS From the data, it could be inferred that estetrol significantly reduced the frequency of moderate to severe VMS (Figure 10). Furthermore, more women experienced a reduction in VMS frequency as a result of estetrol treatment than placebo (Figure 11). Finally, estetrol monohydrate significantly reduced the severity of moderate to severe VMS (Figure 12).

[0585] 2. Endometrial thickness Comparison of the 15 mg and 20 mg estetrol monohydrate treatment groups showed no significant difference in endometrial thickness, as demonstrated by an adjusted p-value of 0.8560 from ANCOVA analysis, resulting in an equivalent increase in both doses, as expected from estrogen treatment.

[0586] 3. MENQOL The total MENQOL score of subjects treated with estetrol monohydrate was significantly improved compared to placebo treatment. This improvement was attributed to several different parameters that contribute to the total MENQOL score, including, but not limited to, improvements in reported muscle pain, difficulty sleeping, anxiety and / or irritability, impatience, levels of dissatisfaction with personal life, and psychosocial domain scores.

[0587] TIFF2026501201000080.tif121170

[0588] 4. Diabetes Treatment of subjects with 15 mg or 20 mg of estetrol monohydrate had a positive effect on glucose metabolism in terms of a decrease in hemoglobin A1C (FIG. 13) and a decrease in fasting blood glucose levels (FIG. 14).

[0589] Hemoglobin A1C:

[0590] TIFF2026501201000081.tif39170

[0591] TIFF2026501201000082.tif31170

[0592] Fasting blood sugar:

[0593] TIFF2026501201000083.tif39170

[0594] TIFF2026501201000084.tif32170

[0595] Example 4. Dose-finding study selecting daily oral estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women with mild, moderate, or severe hepatic impairment The clinical trial described in Example 2 will be conducted again, including women with mild, moderate, or severe liver dysfunction. There is no statistically significant difference in efficacy and safety in women with mild, moderate, or severe liver dysfunction, preferably women with mild or moderate liver dysfunction, compared with women with normal liver function. In particular, it is highlighted that there is no difference in the number of biopsies between the groups with and without liver dysfunction, with both 15 mg and 20 mg doses of estetrol monohydrate. In particular, when the separate groups are normalized for sample size, there is no difference in the number of biopsies in women with mild or moderate liver dysfunction compared with the number of biopsies in women with normal liver function. In conclusion, the metabolism of estetrol monohydrate in women with liver dysfunction is not affected to the extent that dose adjustment is necessary. Instead, women with liver dysfunction can simply receive the same dose as women with normal liver function.

Claims

1. 1. A composition formulated as an oral dosage unit for use in alleviating symptoms of estrogen deficiency in a subject with impaired hepatic function, said composition comprising an estetrol component, said composition being administered in a daily amount equivalent to about 15 mg to about 25 mg of estetrol.

2. 2. The composition for use of claim 1, wherein the subject with hepatic impairment is characterized by mild hepatic impairment (Child-Pugh score of 5 or 6), moderate hepatic impairment (Child-Pugh score of 7 to 9), or severe hepatic impairment (Child-Pugh score of 10 to 15), as classified by the Child-Pugh scoring system.

3. 3. The composition for use according to claim 1 or 2, wherein the estrogen deficiency symptoms are menopausal-related symptoms in a menopausal, peri-menopausal, or post-menopausal female subject.

4. 4. The composition for use according to any one of claims 1 to 3 for use in reducing the frequency of vasomotor symptoms (VMS), the severity of VMS, the weighted weekly hot flash score, vaginal dryness, dyspareunia, or any combination thereof, or for use in improving quality of life according to the Menopause Rating Scale (MRS) and / or the Menopause Specific Quality of Life (MENQOL) questionnaire.

5. 5. The composition for use according to any one of claims 1 to 4, wherein said VMS is selected from hot flashes, sweating attacks, night sweats, chills, increased sweating, palpitations and combinations thereof.

6. 6. A composition for use according to any one of claims 1 to 5 for use in alleviating the emotional aspects of the menopausal transition selected from depression, irritability, mood changes, insomnia, sleep disturbances, anxiety, nervous tension and combinations thereof.

7. 7. A composition for use according to any one of claims 1 to 6 for use in alleviating physiological aspects of the menopausal transition selected from joint pain, loss of bone density, urinary tract infections, urinary incontinence, vaginal dryness, uterine prolapse, changes in skin texture, weight gain, dyspareunia, cardiovascular disease, diabetes and combinations thereof.

8. 8. The composition for use according to any one of claims 1 to 7, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a geometric mean (GM) Cmax of estetrol (E4) that is less than 2-fold the corresponding GM Cmax in subjects with normal hepatic function, preferably wherein the geometric mean (GM) Cmax is 1.7-fold or less the corresponding GM Cmax in subjects with normal hepatic function.

9. 9. The composition for use according to any one of claims 1 to 8, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a GM AUCinf for E4 that is less than 2-fold the corresponding GM AUCinf in subjects with normal hepatic function, and preferably the GM AUCinf for E4 is 1.1-fold or less the corresponding GM AUCinf in subjects with normal hepatic function.

10. 10. The composition for use according to any one of claims 1 to 9, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a GM AUCinf for E4-3-glucuronide that is not significantly different from the corresponding GM AUCinf for E4-3-glucuronide in subjects with normal hepatic function.

11. 11. The composition for use according to any one of claims 1 to 10, wherein a single administration of the oral dosage unit provides a subject with impaired hepatic function with a pharmacokinetic profile characterized by a similar GM T1 / 2 for E4 when compared to the corresponding GM T1 / 2 in subjects with normal hepatic function.

12. 12. The composition for use according to any one of claims 1 to 11, wherein the number, frequency and / or severity of adverse effects do not differ between a population of subjects with impaired liver function and a population of patients with normal liver function.

13. 13. The use composition according to any one of claims 1 to 12, wherein the estetrol component is estetrol monohydrate, preferably the estetrol component is about 15 mg or about 20 mg of estetrol monohydrate.

14. 14. The composition for use according to any one of claims 1 to 13, wherein the composition further comprises a progestogen component, preferably the progestogen component is selected from the group consisting of progesterone, drospirenone, norethisterone, norethisterone acetate (NETA), dydrogesterone, levonorgestrel (LNG), etonogestrel, norgestrel, nomegestrol, nomegestrol acetate (NOMAC), trimegestone, nestorone, dydrogesterone, gestodene, desogestrel, norgestimate, cyproterone acetate, dienogest, and chlormadinone, or the composition further comprises bazedoxifene.

15. 15. The composition for use according to claim 14, wherein the progestogen component is drospirenone, preferably from about 1 mg to about 4 mg of drospirenone, more preferably about 3 mg of drospirenone, or the progestogen component is administered in an amount equivalent to from about 1 mg to about 4 mg of drospirenone, preferably in an amount equivalent to about 3 mg of drospirenone.

16. The composition for use according to any one of claims 1 to 15, which is formulated to correspond to a daily dosage unit.

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